The Top Doctors in the Twin Cities, 2021 – Mpls.St.Paul Magazine

As medicine evolves with lightning speed, our medical community, built on a tradition of excellence, is taking a leading role in delivering transformative care. Local doctors are constantly shaping innovations that go on to become common practice and exploring new ideas about where care should be heading. The resultsimproved lives and outcomes, cutting-edge targeted treatments, and patient-centric care strategiesbenefit us all.

This year, as we celebrate the 25th edition of our Top Doctors list, we talked with professionals who have been on this list for decades and others newer to the ranks about the changes theyve seen and whats coming next in their fields. Read on to discover more than 800 local top doctors from 46 specialties who have been selected through a process involving extensive research and peer review.

See the complete list of doctors selected to this year's Top Doctors.

Theres much that is sobering about brain cancer: Glioblastoma (the most common type of brain tumor in adults) remains one of the deadliest cancers, and one of the most challenging to treat. Even with the most advanced care, it is a devastating disease. But patients today benefit from some major advancements of the past 15 years: Before 2005, there was no common standard for treating glioblastoma. Now, the protocol of surgery, radiation, and chemotherapy has extended life expectancyand much more is on the horizon. Im optimistic that before the end of my lifetime, we are going to see major changes for glioblastoma patients and achieve meaningful benefits, says Dr. Clark Chen. We asked him for his thoughts on the milestones in his field and whats giving him hope.

Surgically implanted radioactive seeds have the potential to improve life expectancy and quality of life for brain tumor patients.

Dr. Clark Chen

Why is brain cancer one of the most challenging/deadly cancers? The brain is a very different organ than the rest of the body. Our brain is so precious to us that our body has evolved barriers to protect it. For example, if you get food poisoning, your brain is protected from those toxins. And many chemotherapies are like toxins, so they cant get into the brain. Surgeons also have a very challenging task in figuring out how much of a tumor to remove, since one millimeter of difference could be the difference between the patient talking and understanding and not.

What improvements have been made in treatments over the past few decades? Surgically removing as much of a tumor as possible dictates how a patient will do. We have a number of tools to help with that, including MRI. But an MRI machine weighs tonsits not like you could easily bring it into the operating room. In the 1970s, the University of Minnesota started using one of the first intraoperative MRIs in the world, so we could do a surgery and bring in this state-of-the-art MRI and look in and know how much was removed during the surgery. It gives you real-time feedback. So surgeons could see when they could remove more and save a second surgery. That was a major, major milestone. We just installed the newest generation in 2019.

Another milestone allowing us to remove more of a tumor is a drug called 5-ALA. Its a drug that the patient drinks before surgery so that if you shine a blue light on the tumor, it will become fluorescent red. We were the first in the state, at the University of Minnesota, to have it during surgerywe started using it the moment the FDA approved it in 2017. Sometimes its very difficult to tell where the tumor ends, and this dye gives us that tool.

Im optimistic that before the end of my lifetime, we are going to see major changes for glioblastoma patients and achieve meaningful benefits.

Dr. Clark Chen

Also, surgically implanted radioactive seeds have the potential to improve life expectancy and quality of life for brain tumor patients. Picture cancer cells as unruly students, and the seeds as teachers. Having one teacher for 10,000 students is not going to work. But after a surgeon removes the majority of the cancer cells, the seed can be used to destroy the microscopic cells that are invisible to the naked eye. Because of its short range, which is five to eight millimeters, the radiation is concentrated in the region of the tumor and does not affect the rest of the brain. In the old days, the patient would have had to go back to the operating room if the tumor grew back after surgery.

When will immunotherapy be able to be used in brain cancer? Injection of a genetically engineered virus into glioblastomas will solicit immune responsesresponses that can be further enhanced with the immunotherapy that was awarded the 2018 Nobel Prize. Tumors that tend to benefit from immunotherapy are known as hot tumors. They are tumors with a lot of immune cells in there already; thats why theyre called hot. Cold tumors are ones that dont have a lot of immune cells. So a really exciting thing that we are doing is to surgically inject this virus into a cold glioblastoma that is devoid of immune cells and does not respond to immunotherapy and convert the tumor into a hot glioblastoma that responds to immunotherapy. In this way, we can engage the patients innate immune system to fight off the tumor cells. People have survived beyond expectation, but it doesnt work for everybody. Were trying to figure out why it works for some and not others. We are beginning to see extraordinary responses, and with each extraordinary response, we are one step closer to a cure for every patient. S.M.E.

Dr. Brian Swiglo, an endocrinologist with Allina Health, specializes in the treatment of conditions related to hormones and their effects on the bodys organs. Two-thirds of his practice is devoted to the treatment of people with diabetes.

Its been standard procedure for many people with type 1 diabetes to check their glucose levels with a finger stick about four times a day. However, modern technology is changing all of that. Dr. Brian Swiglo says that continuous glucose monitors are replacing finger sticksand theyre doing a much better job. Abbott, Dexcom, and Medtronic make small wearable devices (FreeStyle Libre, Dexcom G6, and Guardian Connect) that adhere to your arm or stomach and automatically read your blood sugar levels every 5 to 10 minutes. Then the information is sent to your phone or device. For people taking insulin, this is a huge boon. You really need that information in order to choose the right dose, Swiglo says. They can just look at their phone and know, Oh, Im 220. Well, now I need an extra three units on top of what I take for my food. It helps them dose their insulin a lot more accurately.

This knowledge is powerful, both for the patient, who gets a better understanding of how their glucose levels are affected by certain foods, activity, and insulin, and for the endocrinologist, who gets a better understanding of their patients meal and exercise habits. When were in clinic with them, we can download that information, look at it, and make more accurate adjustments in their insulin regimen, Swiglo says.

Insulin pumps have been around for about 30 years and are now being replaced with closed-loop insulin pumps, which talk to continuous glucose monitors. Its a huge step toward an artificial pancreas, Swiglo says. And its giving people greater freedomespecially at night. The biggest advantage is when someone goes to bed, they can fall asleep and sleep through the night while still having good control. Thats because the pump and the monitor are in constant communication and making any needed adjustments.

The newest medicines for type 2 diabetes can do more than lower a persons blood sugar. Theyre helping with weight loss and lowering the risk of cardiovascular disease. Most people with type 2 diabetes struggle with their weight, Swiglo says. So anything we can do to help them with weight loss is a benefit. J.J.

A cardiologist since the 1990s, Dr. Pamela Paulsen has worked at all three Level 1 trauma centers in the Twin Cities. After starting her career at Hennepin Healthcare, she moved to North Memorial Health Hospital for 17 years, and shes now with Regions Hospital. She also started the first womens heart clinic in Minnesota, which she ran for 10 years. Paulsen has cared for patients in acute emergency situations. Today, she practices all areas of general cardiology.

Dr. Pamela Paulsen completed her fellowship training in interventional cardiology at the University of Minnesota more than 25 years ago. We had reasonable treatment in 1994, but its unbelievably different now for patients, Paulsen says. Its our advancements in preventionbut also in heart attack carethat really revolutionized during the time I have been a cardiologist.

A combination of technological advancements and medications are helping to reduce heart disease and death from heart disease. Paulsen lists the three biggest game changers, the first of which is the use of stents. The ability to treat heart attack and chronic coronary artery disease with revascularizationor restoring blood flow predominantly through stentsreplaced a more invasive approach and had excellent outcomes, she says. Bonus: Todays stents come in all sizes and are drug-coated so that they are less likely to narrow as time goes on.

The second is the less invasive method now used to replace aortic heart valves. Transcatheter aortic valve replacement (TAVR) is performed by creating a small incision in the chest or using a blood vessel in the leg rather than through open-heart surgery. Advanced imaging guides a catheter to the aortic valve, where a new valve is positioned with the help of an inflated balloon. Its the preferred strategy for replacing aortic valves when theyre narrowed, Paulsen says.

Lastly, statins followed by injectable cholesterol drugs have significantly helped lower the risk of heart disease altogether. Since the 1970s, the risk of death from heart disease is down an average of 60 percent in the United States.

Paulsen is hopeful that the wave of the future will include incorporating personalized medicine in heart care that would pinpoint the best drugs and diet for an individual. She also is encouraged by the future potential of wearable technology for monitoring blood pressure, heart rhythms, and sleeping patterns and helping doctors care for patients. J.J.

In the 20 years that Dr. Gigi Chawla has been practicing as a pediatrician, advancements have fundamentally altered childrens health care experiences. If you still call a well-child visit a yearly checkup, heres a glimpse into the way todays parents and children experience the doctors office. First, new routine childhood immunizations for rotavirus, approved in 2006 and 2008, mean parents have one less thing to fret about. Hospitalizations from severe gastroenteritis, caused by rotavirus, have almost been eliminated. Kids would have serious morbidity, and some would die with the rotavirus, says Dr. Chawla, recalling the days when wards of kids would be hospitalized with the disease every winter.

With every scientific breakthrough, we have to think about how we apply those breakthroughs. This piece has got to be elevated.

Dr. Gigi Chawla

And COVID-19 vaccines may have a similar impact, she predicts. Even though most children dont experience serious illness from COVID-19, the technology used to create the Pfizer and Moderna vaccines could be applied to vaccine development for other illnesses, such as respiratory syncytial virus (RSV), a common respiratory virus that can hit infants hard, she says. That will also change the face of how pediatric illness is experienced, she says, explaining that RSV is the number one cause of childhood hospitalizations in winter.

But the COVID vaccines also revealed a negative side, highlighting disparities in health careand further accentuating them, Chawla says. Its not going to do us much good to have these breakthroughs if all it does is divide the haves and have-nots, she says.

Chawla has devoted the past three years to better understanding disparities in immunization rates between patients of color and white patients. With every scientific breakthrough, we have to think about how we apply those breakthroughs, she says. This piece has got to be elevated.

Its something Chawla thinks about constantly, she says, working to help health care overcome generations of institutional racism. Looking at vaccine disparity, for example, reveals a gap of 40 percent between Black and white patients in completion rates of the entire routine vaccination series before age 2, she found. For me, the first step is really understanding that vaccine disparity, which has likely been present during my entire career and weve just never been brave enough to look at it or willing as clinicians to understand what our role is in mitigating it, she says. To close the gap, Childrens Minnesota has implemented drive-up vaccination and mobile vaccination clinics and recognized other access hurdles, including the ability to make an appointment during clinic hours and to speak a language understood by front desk staff and providers, as well as the ability of clinicians to earn a patients trust.

Another important shift thats happened over Chawlas career, she says, is a recognition of just how important early childhood development is, as well as understanding the science behind it. Understanding how critical that bonding is with a trusted adult/caregiver/parent, and really engaging infants, toddlers, and young children in experiencing and exploring the worldincluding facilitating early language development, she says. There are 700 neural connections being made every second. Its immense. The time and energy we can all put into things like early language development pay off in multiple ways, including decreasing educational or opportunity gaps, which has inspired her to serve as Reach Out and Read Minnesotas Medical Director.

Childrens Minnesota and others have also integrated behavioral health into routine pediatric exams. Therapists, psychologists, and social workers are available during well-child and primary care visits should families need them. And given the high impact social determinants beyond the clinic have on kids healthwhere they live, learn, and playprimary care appointments at Childrens Minnesota now include screening for food insecurity, educational needs, housing concerns, and legal issues. After witnessing the value of this more comprehensive approach to caring for children, Chawla notes, Hopefully, every health care organization is working toward families experiences. S.M.E.

Dr. Mohamed Hassan has spent his nearly 32-year career specializing in gastroenterology and hepatology (diseases of the liver). In the last 17 years, he has also been practicing transplant hepatology. Today, he practices at M Health Fairview Clinics and Surgery Center in Minneapolis and M Health Fairview Clinics and Specialty Center in Edina.

More than 30 years ago, Drs. Harvey Alter, Michael Houghton, and Charles Rice identified the hepatitis C virus. In 2020, they received the Nobel Prize for their discovery. That was a big deal because hepatitis C went from not being known before 1989 to a disease that can easily be treated more than 93 percent of the time with direct-acting antiviral agents (DAAs), says Dr. Mohamed Hassan.

The field of liver transplantation has also made great strides since the first successful procedure in 1967. These days, a liver donor doesnt need to have a perfect bill of health. Patients in need of a liver transplant can even receive a good-functioning liver from a donor who has the hepatitis C virus. There are people who are very sick and cannot wait for a negative hep C liver or donor, Hassan says. After the transplantation is complete, the latest DAAssuch as sofosbuvirtreat the hep Cpositive liver. That is really remarkable and probably one of the best things thats happened. Hassan hopes in the near future there will be medications that can eliminate hepatitis B, a disease more likely to affect people born in Southeast Asian and African countries. It is now being tested, he says.

Hassan enjoys helping others, and his influence reaches beyond the clinic with the work he does in the local Somali community. Recently, to help build trust around the COVID-19 vaccine, Hassan was in a video with an imam at a mosque getting the vaccine. A lot of people gave me feedback and told me it did work, he says. Even family and friends back in Somalia saw the video in their community. J.J.

Back in 1990, Dr. John Wagner conducted the first-ever cord blood transplant for a leukemia patient. Now, he looks back on those early days of transplant medicine and exploration of the potential of cell therapies as a preamble to a future with endless possibilities for treating all types of diseases: manipulating cells to do what doctors and scientists want them to do. Whether you call it immunotherapy or precision or personalized medicine, Wagners work is on the fast track to curing some types of cancer.

What has been the biggest game changer in your specialty in the last few decades? Engineered cells, living drugs that can last in the body for days or a whole lifetime. One example is the use of genetically modified immune cells that specifically target a cancer. I became involved in the mid-80s during my training at Johns Hopkins School of Medicine, when we first started working with bone marrow for transplantation, but weve learned how to engineer cells more precisely since then.

Today, we can take cells from a sample of blood or skin biopsy and generate cells called induced pluripotent stem cellsreplacing the need for embryonic stem cells.

Dr. John Wagner

Has your work ever yielded any unintended results with a positive impact? A decade and a half ago, we thought that the embryonic stem cell was the only way you could make the various tissues of the body. Today, we can take cells from a sample of blood or skin biopsy and generate cells called induced pluripotent stem cells (IPSC)replacing the need for embryonic stem cellscells which can be used to test drugs and other treatments as well as repair damaged tissues. For example, our lab is working on using IPSC to make a nearly endless supply of blood-forming stem cells from a small sample of blood. You wont need any other donors, potentially.

What advancements are on deck? Even though the current approach is very effective, I cant tell when a patient with leukemia is going to come in the door and then everything stops to make it happen. Say you had leukemia. First, wed have to give chemotherapy to beat down the number of leukemia cells so that sufficient numbers of normal T cells can be collected for genetic engineering. It takes a month for manufacturing and testing the cell therapy before it is shipped back to the hospital where they give it to you. There are a couple of problems with that. One, you have to have chemo. Two, its an individual product for every single patient. That makes it logistically challenging and much more expensiveand you might not have a month. Many people are lost while waiting for the manufacturer. My guess is we may, for the first time, be able to cure cancer without using chemotherapy, radiation, or surgery. Thats the path were pursuing. So when youre diagnosed with leukemia, we will be able to forget about the traditional way of treating it and use cell therapy as the only treatment. Thats what we hope to move forward in the next one to two years. And we could move it into other fields . . . cardiology or multiple sclerosis or brain injury. All are in development with the same concept of taking a cell and modifying it to do what we want. This is going to be the game changer, and its sitting on the shoulders of the work of the prior 30 years.

How do these advancements impact previously overlooked or underserved communities? In the past, getting patients to take advantage of new advancements was more of a passive process. If you had a specific disease and you figured out how to get to the University of Minnesota and to me, I would check to see if you met the eligibility requirements and treat you. Today, we go to much greater lengths to find patients and make sure they know what is available, potentially, to them. We want to make sure the patients being enrolled into clinical trials appropriately reflect the makeup of our larger communitythat is, we want to ensure that we have people of all races and ethnicities.

One example: We want to develop off-the-shelf, cryopreserved products. Youd make them all in advance, and theyd be immediately available. Otherwise, some treatments, like immunotherapy, when manufactured as individual products, may never be available for the majority because of logistics and expense. But if I could take one sample of starting material and make 1,000 or more products and verify their potency in advance, we could send them anywhere in the world and people could get it the day theyre diagnosed.S.M.E.

Dr. Siobhan Flanagan is an interventional radiologist at University of Minnesota Health (M Physicians) who does minimally invasive procedures under imaging guidance. She treats liver cancer, vascular malformations, aortic aneurysms, peripheral arterial disease, and more.

University of Minnesota physician Kurt Amplatz helped invent interventional radiology more than three decades ago when he created a small plug-shaped medical device that could be passed through a catheter from the leg to the heart, thus repairing an atrial septal defect (hole in the heart) and avoiding open-heart surgery. Today, Dr. Siobhan Flanagan continues to move the field forward by providing targeted treatments to patients with serious medical problems, including liver cancer. If we can treat patients liver cancers effectively, we can then bridge them to transplant, Flanagan says.

With the help of a catheter and x-ray guidance, the treatment is injected directly into the artery that leads to the liver. As opposed to chemotherapy that circulates all throughout the body, were targeting the treatment just where it needs to go: the local blood supply to the tumor, Flanagan says. And thats especially great news for people with a liver tumor thats less than three centimeters. We can cure tumors less than three centimeters with some specific treatments and control tumors larger than three centimeters with a local therapy.

Compared to cancer, an abscess that develops in the abdomen after surgery might seem like an easy fix. But its not for a surgeon who has to navigate an area that was recently operated on and has a lot of inflammation. Thankfully, an interventional radiologist can come to the rescue. We can place an abscess drain under CT or ultrasound guidance to help drain the infected fluid so the patient doesnt have to have another operation, Flanagan says.

Vascular malformations, abnormal groupings and developments of blood vessels throughout the body, can also be treated with this technology. A lesion can be biopsied to test its genetics and determine which medication will help shrink it.

Flanagan is excited to see whats on the horizon in terms of personalized medicine, especially with tumor-specific therapy, determined by tissue receptors and genetics. Theres this continued opportunity for us to be involved with these treatments by delivering them directly to a tumor, she says. J.J.

Dr. Charles E. Crutchfield III practices dermatology at his clinic in Eagan, where he sees patients for the treatment of a variety of medical and cosmetic conditions. He also teaches dermatology to medical students, residents, and other clinical physicians at the University of Minnesota, Carleton College, and around the world.

Crutchfield has made it his mission to share the knowledge he has with others, including those in the medical field. Skin conditions in skin of color can look a lot different than what were trained on. So I coauthored a textbook of dermatology and made sure to include over 3,000 photographs, half of them in skin of color. He also covers the topic in lectures at the University of Minnesota and around the country. And he writes a weekly health column for the Minnesota Spokesman Recorder, the oldest Black newspaper in the state of Minnesota. Were doing our part to educate and further the knowledge in treating skin of color, he says.

Crutchfield is excited about the advances he sees in the treatment of various skin conditions. Were seeing treatments now for psoriasis, atopic eczema, and vitiligo that are extraordinarily effective for treating skin and inflammatory conditions in the human body, he says. They are changing the lives of our patients, he says.

And the advancements in aesthetic dermatology are also big game changers. Hyaluronic acid fillers and Botox injections rejuvenate the skin with natural-looking results. Crutchfield estimates he does 5 to 10 aesthetic treatments a day. And many of his patients will express to him that they wish they would have done the treatment years ago. I tell them, Well, we couldnt have done it years ago because we didnt have it, but we have it now. And well use it moving forward.

As everyone learned in 2020, COVID-19 created a paradigm shift in the delivery of care. And physicians had to pivot their practices to meet the needs of patients in a safe manner. These days, telehealth visits make up 30 to 40 percent of Crutchfields appointments. A year and a half ago, I had not done one telehealth visit, he says. And now Ive done 10,000-plus. Its surprising how much can be covered in a visit with a dermatologist via a webcam. Platforms such as Zoom, FaceTime, and Google Duo have great clarity of picture for medical evaluations and discussions. Crutchfield uses them for triage purposes, follow-up visits, and prescription refills. This will be part of our practice moving forward, he says. Patients love it, and I like it too.

After more than two decades of being the doctor, Crutchfield is now the patient. In early 2021, he was diagnosed with non-Hodgkins lymphoma, for which he is currently receiving treatments at the Mayo Clinic in Rochester. And the cancer treatment he has received has a medical legacy that ties back to early efforts by friends in the medical community. I have colleagues that were on the development team at Genentech 30 years ago that helped develop the [monoclonal antibody treatment] thats being used to treat me right now, Crutchfield says. My friends are so delighted that the medicine they helped develop is actually helping their friend. J.J.

Back when Dr. Elizabeth Arendt was playing sports in her first few years of college, the training room was only for male athletes. When Arendt or a female teammate got injured, they went to student health services, where ankle sprains were sometimes mistakenly treated with a hot-water bath.

Arendt, who played everything growing up, from Ping-Pong to horseshoes, competed in varsity volleyball and basketball in college in the early days of Title IX, the federal civil rights law aimed at preventing discrimination based on sex in education. As a premed student studying biology and anatomy, she was encouraged by administrators to fill a gap in the training room by treating female athletes. By her senior year, she was a student athletic trainer, challenging inequities in the newly coed training room. This experience not only motivated her to work to change the culture of athletics at the University of Rochester in New York; it also inspired her to pursue orthopedics and sports medicine instead of pathology, she says.

Research suggests that simple warm-up exercises can drastically lower the risk of ACL injuries.

Dr. Elizabeth Arendt

The world of orthopedic surgery is heavily male-dominated. In a 2015 survey, according to the Association for American Medical Colleges, 95 percent of orthopedic surgeons were male. The field is also lagging in diversity as a subspecialty field, but that is improving, Arendt says. But since graduating from medical school in 1979, shes seen some shift in the way athletic injuries are viewed in the field, placing less emphasis on gender.

When it was first discovered that females tear their anterior cruciate ligaments (ACL) more than males, some doctors theorized this was related to the hormonal environment due to menstrual cycles. While that hasnt been ruled out conclusively, theres much more evidence linking the risk to anatomic risk factors present in both sexes and body movement patterns, Arendt says. I think the focus has been less on the sex of the patient and more on what it is that characterizes knee injuries, says Arendt, who conducts research in the area.

This has led to a better understanding of acute injuries to the ACL and the patellofemoral joint, including an increased recognition of risk factors such as body movement patterns and anatomy in other musculoskeletal injuries. And thats helpful because smart training and coaching can reduce the risk of injury. Research suggests that simple warm-up exercises can drastically lower the risk of ACL injuries, for example.

The biggest change across knee surgeries, however, is probably the push toward outpatient surgeries. Ultimately, Arendt says, the shift comes with pros and cons, but to optimize the experience, patients should understand their insurance plans more than most do. For example, even patients who stay in the hospital overnight may be counted as outpatient surgeries, she says, meaning they dont qualify for a skilled nursing facility and would be expected to complete physical therapy with in-home physical therapy or on an outpatient basis.

And, love it or hate it, the biggest change in medicine in the past 30 years is the advancement of electronic medical records (EMR), she says, recalling the days of taking charts home to work on at night. From the patients perspective, there are clear benefits.

As much as it burdens us, theres no doubt the ability to document a patients pertinent information electronically and share it across medical systems is a huge improvement, she says. And its greatly improved our ability to deliver service at all hours. S.M.E.

Dr. BJ Harris specializes in gynecology and urogynecology at Womens Health Consultants and the Pelvic Floor Center.

In her 21-year career, Dr. BJ Harris has witnessed many gynecological and medical game changers. One of the big ones is the reduction in the number of hysterectomies, which used to be much more common and not always a medical necessity. Today, she says, minimally invasive hysteroscopies allow doctors to manage many issues in the uterus, such as abnormal bleeding and the removal of polyps and some fibroids. Also, some types of IUDstypically used for contraceptionhave been FDA-approved to help mitigate heavy bleeding. And tranexamic acid, originally prescribed to women to help make their periods less heavy, is now being used to help reduce blood loss from C-sections or other big surgeries, she says.

Other discoveries, such as the fact that some of the more aggressive types of ovarian cancers can begin in the fimbriae (fingers) of the fallopian tubes, help women make decisions about how to manage their long-term health. So, if one of Harriss patients is having a procedure, like removing an ovarian cyst, and this person is not planning on having (more) children, Harris also recommends removing the patients fallopian tubes at the same time. The fallopian tubes have never provided any hormone in the past, and they never will in the future, she says. All they provide is a cancer risk once women are done childbearing.

The majority of her practice focuses on patients with pelvic floor issues, such as vaginal prolapse or urinary incontinence. She helps them assess treatment options. For those with incontinence, she says, I do quality-of-life surgeries. One womans quality of life versus another womans is very different. I have some people that leak urine like a sieve, and they dont want surgery. And I have other people that say, I leaked twice at my aerobics class last week and I want surgery yesterday. She helps these individuals weigh risks and find healthy solutions and alternatives if they dont want surgery. J.J.

Dr. Mumtaz Kazim grew up watching her parents take care of patients in their 17-bed hospital on the island of Trinidad. She went to college in Canada and med school in India. Shes seen plenty of changes in health care in her career as a physician in the field of family medicine and as president of Edina Family Physicians.

What has been the biggest game changer in your specialty in the last 20 to 25 years? You said game changer, but maybe youll allow me three! The first everyone will agree with: EMR. Its increased access and ability to share information with specialists, allowing for better communication for multidisciplinary care. Also, the concept of what has happened with outpatient clinics. Edina Family Physicians used to be an independent family practice; most of these are now being purchased by larger systemsEdina Family Physicians is now affiliated with Allina. Its a big change. Then theres the concept of virtual visits. With COVID, our clinic was closed for a while, except for emergency care and phone calls, and you cant imagine the expressions of patients who were so lonely. When you see each other face-to-face, there is such delight to talk to somebody. And you can call back to check up on them. It was very helpful. It shouldnt be used for all medical care, but when they cannot come in, seeing them face-to-face in their own home gives you a whole different perspective.

I believe the increased number of women and minorities in all medical fields has had a positive impact on patient care.

Dr. Mumtaz Kazim

Whats the most exciting advancement just around the corner in family medicine? Personalized medicine, including genomic sequencing to target drugs for certain diseases, immunologic approaches to treat cancer, and CRISPR, which is a technology that adds or deletes genes to improve and cure medical conditions. It will help to improve the medical health of the community from sickle cell disease to diabetes and various cancers. Think about it, how great it would be if we could cure diabetes.

How has the diversity of our medical community changed things, and how have advances impacted previously overlooked or underserved communities? I believe the increased number of women and minorities in all medical fields has had a positive impact on patient care. Providers are so much more sensitive to disparities in the medical services available nowso much more than 30 years ago. I think that will eventually have a positive effect on delivery of care to underserved communities. And with the continuity of care now with EMR, we can provide better tracking of patients. Even though EMR is far, far from perfect (this is not an ad for it!), it provides us a tool to have continuity of care. And access to previous medical records is a tremendous help. For example, take the case of a patient who has mental health issues, in addition to some dementia, and no family in the Twin Cities. Hes gone to different emergency rooms and been seen by different providers across all of the systems. We have the EMR, and we can then get access to some of those records, which will then educate me on what has been happening.

Patients dont always offer a detailed medical history, and many patients, especially with cardiac disease, get shipped from one hospital to the next. So we may have patients with records from Abbott and then Southdale, and by the time they come back to me, I can check all of it. Thats very important because doctors shuffle around medications and dosages all the time, and cardiac patients are often on 6 to 10 medications.S.M.E.

Dr. Marjorie Hogan is a pediatrician at Hennepin Healthcare whos been caring for the needs of infants, children, adolescents, and young adults for 41 years.

When Dr. Marjorie Hogan started her practice in 1980, office visits typically involved the usual litany of questions regarding nutrition, sleep, and vaccines. Since then, pediatric careand the worldhas become much more complicated. We used to think brain development stopped sort of abruptly in childhood, but thats not the case, she notes. The brain continues evolving and maturing and arborizing and getting more complex and wonderful in many kids up to their 20s.

One of the dramatic shifts she has seen recently is in the number of school-aged children and teens expressing feelings about anxiety, fear, and stress, Hogan says. Thankfully, during these unprecedented times, providers like Hogan can put patients and their families in touch with a team of resourcesincluding nurses, social workers, educators, community health workers, and morethat will support the whole health of the child. However, she says, We need more mental health providers for children and teens. Its a crisis. It impacts every part of their lives. I am seeing more teensboth male and femalegrapple with eating disorders, with the risk of self-harm, [and] with substance abuse.

One of the complicating factors in the struggle: media. Back in the 80s, Hogan authored some of the first American Academy of Pediatrics (AAP) media statements that recommended parents limit childrens TV watching to less than 2 hours a day. Today, young people have access to more media than ever. In this past year, theres not one family Ive seen that has not had concerns about their childrens screen time and media use. Hogan recommends that parents be good media role models and develop a family plan. That means no electronic devices at the dinner table and certain shows and games should be off-limits. Be aware of what your children are watching or using as much as you can.

In recent years, the medical community has become more aware of the role that social determinants and inequities play in a childs overall health. Hogan is pleased that todays medical students and residents take courses on the topic so they can be better prepared to help children in a changing world. J.J.

See the complete list of doctors selected to this year's Top Doctors.

The 25thedition of our Top Doctors list includes 816doctors in 46specialties. Heres how we put it together. When compiling a list thats as relied upon as our annual Top Doctors list, research is essential. We asked physicians to nominate one or more doctors (excluding themselves) to whom they would go if they or a loved one were seeking medical care. From there, candidates were grouped into 46specialties and evaluated on myriad factors, including (but not limited to) peer recognition, professional achievement, extensive research, and disciplinary history. Doctors who had the highest scores from each grouping were invited to serve on a blue-ribbon panel that evaluated the other candidates. It should be noted that doctors cannot pay to be included on this list, nor are they paid to provide input. Only doctors who acquired the highest total points from the surveys, the research, and the expert physician review panel were selected to this list. Of course, no list is perfect. Many qualified doctors providing excellent care are not included on this years list. However, if youre looking for exceptional physicians who have earned the confidence and high regard of their peers, you can start your search here.In addition, this years crop of Top Doctors will join a prestigious group of doctors from more than 20 cities around the country who have been selected to Super Doctors, the full list of which you can find at superdoctors.com.

Editors Note: Many of our Top Doctors have specialty certification recognized by the American Board of Medical Specialties. This board certification requires substantial additional training in a doctors area of practice. We encourage you to discuss this board certification with your doctor to determine its relevance to your medical needs. More information about board certification is available at abms.org.

2021MSP Communications. All rights reserved. Super Doctors is a registered trademark of MSP Communications. Disclaimer: The information presented is not medical advice, nor is Super Doctors a physician referral service. We strive to maintain a high degree of accuracy in the information provided. We make no claim, promise, or guarantee about the accuracy, completeness, or adequacy of the information contained in the directory. Selecting a physician is an important decision that should not be based solely on advertising. Super Doctors is the name of a publication, not a title or moniker conferred upon individual physicians. No representation is made that the quality of services provided by the physicians listed will be greater than that of other licensed physicians, and past results do not guarantee future success. Super Doctors is an independent publisher that has developed its own selection methodology; it is not affiliated with any federal, state, or regulatory body. Self-designated practice specialties listed in Super Doctors do not imply recognition or endorsement of any field of medical practice, nor do they imply certification by a Member Medical Specialty Board of the American Board of Medical Specialties (ABMS) or that the physician has competence to practice the specialty. List research concluded April 19, 2021.

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The Top Doctors in the Twin Cities, 2021 - Mpls.St.Paul Magazine

Case study: Use of platelet-rich plasma and bone marrow …

April 21, 2018

The patient is a fit 83-year-old who, as a former flight attendant, is used to being on her feet. In 2014, she presented with osteoarthritis pain that started to affect her left knee and threatened her mobility, and she was searching for treatments that wouldn't interfere with her active lifestyle.

In January 2015, the patient had received two separate injections of platelet-rich plasma (PRP). The PRP injections alone did not provide adequate symptom relief. In July, she received an injection of bone marrow aspirate concentrate (BMAC) and PRP.

Jay Smith, M.D., a physiatrist and the director of Regenerative Medicine within the Rehabilitation Medicine Research Center at Mayo Clinic's campus in Rochester, Minnesota, evaluated the patient and administered the BMAC and PRP injections. To date, Dr. Smith and colleagues at Mayo have administered PRP or BMAC injections in more than 400 patients. Current scientific literature indicates that between 40 and 70 percent of individuals who receive this treatment find some level of pain relief, according to Dr. Smith. "It doesn't work 100 percent of the time," he says. "But we have a pretty good success rate when the primary goal is to improve symptoms and allow patients to do the things they want to do."

Dr. Smith says that a portion of the conversation he has with patients is that regenerative medicine strives to restore health by harnessing the body's natural ability to heal itself. "We tell our patients that it's an acceptably safe orthopedic procedure, and it may or may not modify their level of pain," Dr. Smith says.

What is known about the treatments is that they most likely lessen the inflammatory process caused by degrading joint cartilage. "Treatment with PRP is built upon the knowledge that platelets carry a multitude of growth factors," Dr. Smith says. "They are the first responder cells when we get injured, and they control the damage and start the healing process."

For PRP therapy, platelets are extracted from a vein in the patient's arm and concentrated using a centrifuge. The concentrate is then injected back into the patient's joint, where the growth factors mitigate inflammation.

BMAC contains not only platelets but also a variety of other powerful cells, including stem cells. Stem cells also have significant anti-inflammatory properties and can powerfully influence other cells involved in inflammation and healing. They also have the ability to become other types of cells. The bone marrow is drawn from a patient's pelvic bone, concentrated in a centrifuge and then injected into the problematic area. "The bone marrow concentrate and platelet rich plasma very naturally modify the inflammatory and immune response," Dr. Smith says.

A few hours after receiving treatment, the patient walked out of the procedure room with the aid of crutches and a knee brace, which she used for one week. The patient indicated that the injections eased the pain enough for her to return to her previous level of activity.

Dr. Smith notes that the patient's overall health contributed to the treatment's chance of success.

"One of the things I feel is relevant to her success is that she's very healthy," Dr. Smith says. "We are working with biologic products. They are only as healthy as the people they come from. I strongly believe that the healthier you are, the more likely these treatments are to succeed."

PRP and BMAC are not yet approved by the Food and Drug Administration (FDA) for use in treating osteoarthritis pain and therefore are typically not covered by insurance. In addition to treating patients with PRP and BMAC, Dr. Smith and colleagues are conducting FDA-approved clinical trials on the use of purified stem cells to treat knee arthritis. And researchers at Mayo Clinic's campus in Jacksonville, Florida, are conducting clinical trials comparing conventional PRP treatment with concentrated bone marrow stem cell injections for osteoarthritis of the knee.

A Study of the Safety and Usability of Culture Expanded STEM Cells Derived from the Patient's Own Fat Tissue for Treatment of Knee Osteoarthritis. Mayo Clinic.

Conventional Platelet-Rich Plasma Versus Concentrated Bone Marrow Stem Cell Injections for Osteoarthritis of the Knee. Mayo Clinic.

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Case study: Use of platelet-rich plasma and bone marrow ...

Global Induced Pluripotent Stem Cell (iPSC) Market to Reach $2.3 Billion by 2026 – PRNewswire

FACTS AT A GLANCE Edition:9;Released:April 2021 Executive Engagements:1737 Companies:51 - Players covered include Axol Bioscience Ltd.; Cynata Therapeutics Limited; Evotec SE; Fate Therapeutics, Inc.; FUJIFILM Cellular Dynamics, Inc.; Ncardia; Pluricell Biotech; REPROCELL USA, Inc.; Sumitomo Dainippon Pharma Co., Ltd.; Takara Bio, Inc.; Thermo Fisher Scientific, Inc.; ViaCyte, Inc. and Others. Coverage:All major geographies and key segments Segments:Cell Type (Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells, Other Cell Types); Research Method (Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering, Other Research Methods); Application (Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine, Other Applications) Geographies:World; USA; Canada; Japan; China; Europe; France; Germany; Italy; UK; Rest of Europe; Asia-Pacific; Rest of World.

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ABSTRACT-

Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2.3 Billion by 2026Induced pluripotent stem cells (iPSCs) hold tremendous clinical potential to transform the entire therapeutic landscape by offering treatments for various medical conditions and disorders. These cells are derived from somatic cells like blood or skin cells that are genetically reprogrammed into embryonic stem cell-like state for developing an unlimited source of a diverse range of human cells for therapeutic applications. The global market is propelled by increasing demand for these cells, rising focus on researchers in the field, and their potential application in treatment of various diseases. The market growth is supplemented by rising prevalence of several chronic disorders such as diabetes, heart disease, stroke and cancer. Moreover, increasing awareness about stem cells and associated research, potential clinical applications and rising financial assistance by governments and private players are expected to contribute significantly to the market expansion. The iPSC technique is anticipated to find extensive adoption in the pharmaceutical industry for developing efficient cell sources like iPSC-derived functional cells to support drug screening and toxicity testing.

Amid the COVID-19 crisis, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.6 Billion in the year 2020, is projected to reach a revised size of US$2.3 Billion by 2026, growing at a CAGR of 6.6% over the analysis period. Vascular Cells, one of the segments analyzed in the report, is projected to record a 7.2% CAGR and reach US$835.8 Million by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Cardiac Cells segment is readjusted to a revised 7.9% CAGR for the next 7-year period. The demand for iPSC-derived cardiac cells is attributed to diverse applications including cardiotoxicity testing, drug screening and drug validation along with metabolism studies and electrophysiology applications.

The U.S. Market is Estimated at $767.1 Million in 2021, While China is Forecast to Reach $82.4 Million by 2026The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$767.1 Million in the year 2021. China, the world`s second largest economy, is forecast to reach a projected market size of US$82.4 Million by the year 2026 trailing a CAGR of 8.5% over the analysis period. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 5.5 % and 6.8% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 6.5% CAGR. North America leads the global market, supported by continuing advances related to iPSC technology and access to functional cells used in pre-clinical drug screening. The market growth is supplemented by increasing insights into the iPSC platform along with high throughput analysis for drug toxicity. The iPSC market in Asia-Pacific is estimated to post a fast growth due to increasing R&D projects across countries like Australia, Japan and Singapore.

Neuronal Cells Segment to Reach $336.9 Million by 2026In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the 6.4% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$202.9 Million in the year 2020 will reach a projected size of US$308 Million by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets. Led by countries such as Australia, India, and South Korea, the market in Asia-Pacific is forecast to reach US$19.8 Million by the year 2026. More

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Global Induced Pluripotent Stem Cell (iPSC) Market to Reach $2.3 Billion by 2026 - PRNewswire

Impact of NK cell-based therapeutics for Lung Cancer Therapy | BTT – Dove Medical Press

Background

Lymphoid non-T cells that can kill virally infected and tumor cells were described more than four decades ago and termed natural killer (NK) cells.1 NK cells can attack tumor cells without priming and their activity depends on a range of stimulatory and inhibitory receptors.2,3 NK cells comprise about 515% of the human peripheral blood mononuclear cells (PBMCs) and are part of the native immune system that screen cell membranes of autologous cells for a reduced expression of MHC class I molecules and increased expression of cell stress markers.4,5 NK cells mediate the direct and rapid killing of freshly isolated human cancer cells from hematopoietic and solid tumors.6,7 (Figure 1) NK cells in human peripheral blood, bone marrow and various tissues are characterized by the absence of T cell receptors (TCR) and the corresponding CD3 molecules as well as by the expression of neural cell adhesion molecule (NCAM/CD56).8 Human NK cells are generated from multilineage CD34+ hematopoietic progenitors in the bone marrow and their maturation occurs at this site of origin as well as in the lymphoid organs but not in thymus.9 In blood, NK cells show a turnover time of approximately 2 weeks with a doubling within 13.5 days in vivo and in vitro cytokine stimulation of peripheral blood NK cells can result in expansion with a median of 16 (range 1130) population doublings.10

Figure 1 NK cells and other immune cells in the tumor microenvironment. NK cells of the CD56dim CD16+ phenotype secrete interferon- (IFN-), which increases the expression of MHC class I of tumor cells, enhancing the presentation of tumor antigens to T cells. Inhibitory checkpoint molecules expressed by NK cells can be blocked using specific monoclonal antibodies (ICIs). NK cells of the CD56bright CD16- phenotype recruit dendritic cells (DCs) to the tumor microenvironment (TME) and drive their maturation via chemokine ligands CCL5, XCL1 and FMS-related tyrosine kinase 3 ligand (FLT3L). DCs in turn stimulate NK and T cells via membrane-bound IL-15 (mbIL-15) and 41BBL secretion. Eventually, NK cells lyse tumor cells resulting in release of cancer antigens, which are then presented by DCs, to provoke specific T cell activation in relation with MHC class I molecules. The immunotherapeutic effect of NK cells includes the removal of immunosuppressive MDSCs.

NK cells are not only present in peripheral blood, lymph nodes, spleen, and bone marrow but they can also migrate to sites of inflammation in response to distinct chemoattractants. The majority of CD56dim subpopulation of the whole NK cells in peripheral blood (approximately 90%) exhibits high expression of the Fc receptor FcRIII (CD16), killer cell immunoglobulin-like receptors (KIRs) and perforin-mediated cytotoxicity whereas a minor population of CD56bright CD16- KIR- CD94/NKG2A+ (approximately 515%) of NK cells is primarily producing cytokines, including IFN- and TNF-1113 These two NK cell populations have been termed conventional NK cells in contrast to distinct tissue-resident NK cell populations localizing to liver, lymphoid tissue, bone, lung, kidney, gut and uterine tissue as well as distinct adaptive NK cell populations.14 However, CD56 and CD16 are not specific for NK cells and, furthermore, the heterogeneous tissue-resident populations show expression of adhesion molecules and CD69 and may represent an immature NK cell type. Adaptive NK cells are observed in connection with viral infections and exhibit memory cell-like properties. Overall, a wide diversity of receptor expressions of NK cells has been observed and, so far, the function of many of these subpopulations has not been fully characterized.

NK cells can eliminate target cells controlled by signals derived from activating (eg, NCRs or NKG2D) and inhibitory receptors (eg, KIRS or NKG2A).1517 Normal host cells are protected from NK cells attacks through inhibitory KIRs, that identify the self-MHC class I molecules.15 In particular, the germline-encoded NK receptors include the activating receptors NKG2D, DNAM-1, the natural killing receptors NKp30, NKp44, NKp46, and NKp80, the SLAM-family (Signaling Lymphocyte Activating Molecule) receptors for the elimination of hematopoietic tumor cells and the inhibitory KIRs.18 The activating signaling molecules promote tumor cell killing, cytokine production, immune cell activation, and proliferation and the NKpXX receptors, when engaged, all trigger alterations of the cellular calcium flux and NK cell-mediated killing and secretion of IFN- (Figure 1).

The interaction between KIRs and self-MHC molecules governs the maturation of NK cell, a process termed licensing.11,19,20 As alternative of MHC downregulation, cancer cells may be recognized by the overexpression of binding molecules for activating NK cell receptors. Ligands for the activating NKG2D receptor, such as MHC class I polypeptide-related sequence A (MICA), MICB and others are presented by cancer cells preferentially in response to cellular stress.21 A separate mechanism known as antibody-dependent cell cytotoxicity (ADCC) results in elimination of antibody-coated cell via the CD16 FcRIII receptor.22

NK cell-mediated lysis of target cells is mainly achieved through the release of the cytotoxic effector perforin and granzymes A and B but NK cells also produce a range of cytokines, both proinflammatory and immunosuppressive, such as IFN-, TNF- and IL10, respectively, as well as growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-3 (Figure 1). CD56dim NK cells can produce very rapidly IFN- within 2 to 4 hours after triggering through NKp46 and NKp30 activating receptors (ARs).12,13 NK cellderived cytokine production impacts dendritic cells, macrophages and neutrophils and empower NK cells to regulate subsequent antigen-specific T and B cell responses. Activated NK cells lose CD16 (FcRIII) and CD62 ligand through the disintegrin and metalloprotease 17 (ADAM17), and inhibition of this protease enhances CD16-mediated NK cell function. Cytokine stimulation also downregulates CD16 and upregulates CD56 expression. Moreover, certain cytokines can greatly enhance the cytotoxicity and cytokine production of the CD162 CD56bright and CD161 CD56dim NK cell subsets, respectively.23,24

In cancer patients, NK cells target cells low/deficient of MHC-class I or bearing altered-self stress-inducible proteins.17,25 Besides tumor cell killing through release of perforin and granzyme and secretion of immunoregulatory mediators such as nitric oxide (NO) effects cell death mediated by TNF-family members such as Fas-L or TRAIL. The degree of tumor infiltration of NK cells seems to have prognostic value in gastric carcinoma, colorectal carcinoma and lung carcinomas, thus indicating a protective role of the NK cell infiltrate.26,27 NK cell infiltration of tumors depends on their expression of heparinase.28 NK cells may further attract T cells to the tumor region and elevate inflammatory responses through secretion of cytokines and chemokines.29 Furthermore, NK cells have been suggested to suppress metastasis through elimination of circulating tumor cells (CTCs).30

NK cells seem well suited for anticancer immunotherapy and cells for clinical administration can be isolated from peripheral or umbilical cord blood. Peripheral blood NK cells are prepared by leukapheresis and further enriched by density gradient centrifugation (Figure 2). Subsequently, the combination of T cell depletion with CD56 cell enrichment yields highly purified NK cell populations.31 NK cells gained from peripheral blood of healthy persons are typically in a resting state and can be activated by exposure to IL-2. However, supplementation with IL-2 and infusion to cancer patients has resulted in severe side effects, such as vascular leak syndrome and liver toxicity.32 Studies with native autologous NK cells have yielded disappointing results. The most efficient NK cell expansion was observed with K562 NK target cells co-expressing membrane-bound IL-15 (mbIL-15) and 41BBL.31 This technique yields enough NK to provide cells for at least four infusions at 50 million cells/per kg from one leukapheresis product observing GMP conditions.31 However, many mechanisms mediate NK cell suppression in the tumor microenvironment (TME), several of which also impair T cell responses.33,34 In case of NK cells, NKG2D ligand release can occur by shedding and these soluble ligands prevent NK cell-tumor cell interaction and the cytotoxic response.35,36

Figure 2 Isolation, activation and propagation of allogeneic NK cells. Peripheral blood mononuclear cells (PBMCs) are prepared from healthy donors by leukapheresis. PBMC depletion of CD3+ T cells, prevents GvHD after infusion and further purification is achieved by positive CD56+ cell selection. These cell preparations are infused or activated with IL-2 or a mixture of IL-12, IL-15 and IL-18. Another method for NK cell stimulation involves ex vivo coculture with the K562 cell line expressing membrane-bound IL-15 (mbIL-15) and 41BBL that is irradiated to abolish expansion. Umbilical cord blood NK cells can be used similar to peripheral blood NK cells or enriched for CD34+ hematopoietic progenitors, followed by differentiation to NK cells. NK cells can be gained from induced pluripotent stem cells (iPSCs) via successive hematopoietic and NK cell differentiation, followed by stimulation with cells expressing mbIL-21. Before infusion of allogeneic NK cells, patients receive lymphodepleting chemotherapy to facilitate temporary engraftment of the infused NK cells.

In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future.

The lungs are frequently challenged by pathogens, environmental damages and tumors and contain a large population of innate immune cells.37,38 Involvement of NK cells in lung diseases, such as cancer, chronic obstructive pulmonary disease (COPD), asthma and infections, has been amply reported.39 Chronic inflammation drives the irreversible obstruction of the lung function in COPD and local NK cells show hyperresponsiveness in COPD and kill autologous lung CD326+ epithelial cells.40 Therefore, targeting NK cells may represent a novel strategy for treating COPD. Furthermore, NK cells from cigarette smoke-exposed mice produce higher levels of IFN- upon stimulation with cytokines or toll-like receptor (TLR) ligands.41

Lung NK cells account for approximately 1020% of local lymphocytes and have migrated to the lungs from bone marrow.42 These cells exhibit the phenotype of the CD56dim CD16+ subset and are located in the parenchyma.43 Lung NK cells show major differences in phenotype and function to those from other tissues and, for example, KIR-positive NK cells and differentiated CD57+ NKG2A cells are found in higher numbers in the lungs compared to matched peripheral blood.37,38 In vivo, human lung NK cells respond poorly to activation by target cells in comparison to peripheral blood NK cells, most likely due to suppressive effects of alveolar macrophages and soluble factors in the fluid of the lower respiratory tract.44 The presence of hypofunctional NK cells seems to regulate the pulmonary homeostasis in the presence of constantly irritation by environmental and autologous antigens.

Unlike other tissues, the lung NK cell diversity and its acquisition have been very little studied, especially regarding the resident lung populations. Although the majority of lung NK cells are of a non-tissue-resident phenotype, a small CD56bright CD49a+ lung NK cell subset has been found.45 NK cell diversity occurs for the main resident population within the lung, namely CD49a+CD56bright CD16 NK cells that can be split into four different resident subpopulations according to the residency markers CD69 and CD103.47 The CD69+CD103+ subset is the most important as compared to single positive or double negative subsets. The respective significance of these subsets in terms of ontogeny, differentiation, or functionality remains to be characterized.

The CD16 NK cells in the human lung comprises a heterogeneous cell population and the CD69+CD49a+CD103 and CD69+CD49a+CD103+ tissue-resident NK cells are clearly distinct from other NK cell subsets in the lung and other tissues, whereas CD69spCD16 NK cells (lacking expression of CD49a and/or CD103) largely represent conventional CD69CD16 NK cells.47 Furthermore, lung tissue-resident NK cells are functionally competent and constitute a first line of defense in the human lung. Protein and gene expression signatures of CD16 NK cell subsets correlated with distinct patterns of expression of CD69, CD49a, and CD103 and corroborated the CD69+CD49a+CD103 and CD69+CD49a+CD103+ NK cells as tissue-resident NK cells.48 In contrast, CD69spCD16 NK cells are more similar to CD69CD16 NK cells and showed lower expression of genes associated with tissue-residency.

On the course of NK cell differentiation less differentiated NK cells are hypofunctional but respond stronger to cytokine stimulation and more differentiated NK cells exert more potent ADCC-dependent cell killing.46,49 The early activation antigen CD69 is expressed on a wide range of tissue-resident lymphocytes, including T cells and NK cells, and promotes retention of the cells in the tissue.38,50 Highly differentiated and hypofunctional CD69+ CD56dim CD161+ NK cells constitute the dominant NK cell population in the human lung. In summary, these results indicate that the human lung is mainly populated by NK cells migrating between lung and blood, rather than by CD69-positive tissue-resident cells. The mechanisms controlling this distribution of the lymphocyte populations is not known but may comprise changes in the homing of NK cells, increased apoptosis of NK cells and increased expansion or recruitment of tissue-resident T cells.

Although the incidence of lung cancer is declining, the survival rates remain poor due to a lack of early detection and only recent progress in targeted cancer therapies that are still only feasible for a limited subpopulation of patients.51,52 The host of immune cells involved in lung cancer include CD4+ and CD8+ T lymphocytes, neutrophils, monocytes, macrophages, innate lymphoid cells (ILCs), dendritic cells and NK cells. In lung cancer patients, peripheral NK cell cytotoxicity and INF- production was reported to be reduced.5356 Especially, a lower cytotoxic activity in NK cells was observed in smokers due to the suppression of the induction of IL-15 and IL-15-mediated NK cell functions in human PBMCs.57 Furthermore, the granzyme B release by NK cells from lung cancer tissue is lower compared to adjacent normal tissue.58 Additionally, peripheral NK cells of NSCLC patients are present in lower cell numbers and display a distinctive receptor expression with downregulation of NKp30, NKp80, CD16, DNAM1, KIR2DL1, and KIR2DL2, but upregulation of NKp44, NKG2A, CD69, and HLA-DR. Furthermore, low levels of IFN- and CD107a result in impaired cytotoxicity and promotion of tumor growth.54,59,60 The CD56bright CD16-NK cell subset is highly enriched in the tumor infiltrate and show activation markers, including NKp44, CD69, and HLA-DR.5961 However, the release of soluble factors by NSCLC tumor cells inhibit the activity of granzyme B and perforin and the induction of IFN- in intratumoral NK cells and suggest a local inhibition of NK cells by the NSCLC TME.62 T cell immune checkpoint molecules programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA4), lymphocyte activation gene 3 protein (LAG3) and TIM3 are expressed by subpopulations of NK cells and might reduce NK antitumor responses. In solid tumors, vascular supply may be ineffective causing hypoxia and low nutrient levels in the TME that may impair NK cell metabolism and antitumor cytotoxicity as demonstrated in lung experimental animal models.63,64 Additionally, the CD56bright CD16- NK cells enhance protumor neoangiogenesis through secretion of VEGF, placental growth factor and IL-8/CXCL8.65

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer linked to smoking that has a dismal prognosis and invariably develops resistance to chemotherapy within a short time.66 Despite a high tumor mutational burden, immune checkpoint inhibitors show minor prolongation of survival in SCLC patients.66,67 In particular, Nivolumab (anti-PD1 antibody) was approved for third-line treatment and the combination of atezolizumab (anti-PDL1 antibody) with carboplatin and etoposide was approved for first-line treatment of disseminated SCLC, resulting in minor survival gains.68,69 NK cells are critical in suppressing lung tumor growth and while low MHC expression would make SCLC resistant to adaptive immunity, this should make SCLCs susceptible to NK cell killing.64,70 In comparison to the peripheral blood NK cells of healthy individuals, the NK cells of SCLC patients are present in equal cell counts but exhibit lower cytotoxic activity, downregulation of NKp46 and perforin expression.55 Lack of effective NK surveillance seems to contribute to SCLC progress, primarily through the reduction of NK-activating ligands (NKG2DL). SCLC primary tumors possess very low levels of NKG2DL mRNA and SCLC lines largely fail to express NKG2DL at the protein level.66,71 Accordingly, restoring NKG2DL in experimental models suppressed tumor growth and metastasis in a NK cell-dependent manner. Furthermore, histone deacetylase (HDAC) inhibitors induced NKG2DL re-expression and resulted in tumor suppression by NK and T cells. Actually, SCLC and neuroblastoma are the two tumor types with lowest NKG2DL-expression. In conclusion, epigenetic silencing of NKG2DL results in a defect of NK cell activation and immune escape of SCLC and neuroblastoma. Poor immune infiltrates in SCLC tumors combined with reduced NK and T cell recognition of the tumor cells seem to contribute to immune resistance of SCLCs.72

A majority of NSCLC patients do not benefit from the current IC-directed immunotherapy. CD56dim CD16+ NK cells comprise the majority of NK cells in human lungs and express KIRs and a more differentiated phenotype compared with NK cells in the peripheral blood.38,73 However, human lung NK cells were hyporesponsive toward target cell stimulation, irrespective of priming with IFN-. NK cells are activated by MICA and MICB expressed by stressed tumor cells and are recognized by NK cell receptors NKG2D.74 Preclinical studies show that NKG2A or TIGIT blockade enhances antitumor immunity mediated by NK cells.2 However, the poor infiltration of NK cells into solid tumors, alterations in activating/inhibitory signals and adverse TME conditions decrease the NK-mediated killing. NK cells can be inactivated by different cells such as Tregs and MDSCs but also by soluble mediators such as adenosine.75,76 Adenosine represents one of the most potent immunosuppressive factors in solid tumors that is produced in the tumor stroma by degradation of extracellular ATP.7779 ATP and ADP are degraded by membrane-expressed ectonucleotidases such as CD39 and enhance the influx and the suppressive capacity of Tregs and MDSCs in solid tumors. NK cells are strongly involved in eliminating circulating tumor cells (CTCs), but their activity can be inhibited by soluble factors, such as TGF- derived from M2 macrophages.80,81 One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of peripheral NK cells.82 The gene signature of NK cell dysfunction in human NSCLC revealed an altered migratory behavior with downregulation of the sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1).83 Additionally, the expression of the immune inhibitory molecules CTLA-4 and killer cell lectin like receptor (KLRC1) were elevated in intratumoral NK cells and CTLA-4 blockade could partially restore the impaired MHC class II expression on dendritic cell (DC). In summary, the intratumoral NK dysfunction can be attributed to direct crosstalk between tumor and NK cells, activated platelets and soluble factors, such as TGF-, prostaglandin E2, indoleamine-2,3-dioxygenase, adenosine and IL-10.19,26,54,83 In addition, a specific migratory signature could explain the exclusion of NK cells from the tumor interior. NK cells in NSCLC distribute to the intratumoral fibrous septa and to the borders between tumor cells and surrounding stroma.54,59 It has been suggested that a barrier of extracellular matrix proteins may be responsible for the restriction of NK cells primarily to the tumor stroma, such preventing direct NK celltumor cell interactions.84,85 In contradiction, ultrastructural investigations demonstrated NK cells are rather flexible and capable of extravasation and intratumoral migration.59 CD56bright CD162+ NK cells express CCR5 that is known to mediate the chemoattraction of specific leukocyte subtypes and explain their accumulation in tumor tissues.13 Infiltration of the tumors by NK cells was reported to be linked with a favorable prognosis in lung cancer.26,86 However, Platonova et al reported that NK cell infiltration lacks any correlation with clinical outcomes in NSCLC.47,54 The poor prognostic significance of NK cells in NSCLC seems to be associated with the intratumoral NK cell dysfunction in patients with intermediate or advanced-stage tumors.

It would be of great importance to target chemokine receptors on NK cells to enable them to enter tumor tissues. NK cells acquire inhibitory functions within the TME, the reversion of which will enable NK cells to activate other immune cells and exert antitumor cytotoxic functions.87 In addition, several clinical trials based on NK cell checkpoints are ongoing, targeting KIR, TIGIT, lymphocyte-activation gene 3, TIM3 and KLRC1.88 NK cell dysfunction favors tumor progress and restoring NK cell functions would represent an important potential strategy to inhibit lung cancer. These approaches include the activation of NK cells by exposing to interleukins such as IL-2, IL-12, IL-15, IL-18, the blockade of inhibitory receptors of NK cells by targeting NKG2A, KIR2DL1 and KIR2DL2 as well as the enhancement of NK cell glycolysis by inhibition of fructose-1,6-bisphosphatase 1 and altering the immunosuppressive TME by neutralization of TGF-.37,53 Pilot clinical trials of NK cell-based therapies such as administration of cytokines, NK-92 cell lines and allogenic NK cell immunotherapy showed promising outcomes on the lung cancer survival with less adverse effects. However, due to the lack of larger clinical trials, the NK cell targeting strategy has not been approved for lung cancer treatment so far.

Most of studies regarding NK cell-based immunotherapy have been performed in hematologic malignancies. However, there are increasingly data available that show that NK cells can selectively recognize and kill cancer stem cells in solid tumors.89 Furthermore, Kim et al showed the essential role of NK cells in prevention of lung metastasis.90 Additionally, Zhang et al studied the efficacy of adaptive transfer of NK and cytotoxic T-lymphocytes mixed effector cells in NSCLC patients.91 A prolonged overall survival was detectable in patients after administration of NK cell-based immunotherapy. In a trial of Lin et al, the clinical outcomes of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced NSCLC were improved with elevated immune functions and quality of life.92

The efficacy of NK cell-based adoptive immunotherapy was also investigated in SCLC patients. Ding et al studied the efficacy and safety of cellular immunotherapy with autologous NK, T cells and cytokine-induced killer cells as maintenance therapy for 29 SCLC patients and demonstrated an increased survival of the patients.93 Importantly, lung cancer-infiltrating NK cells can mainly function as producers of relevant cytokines, either beneficial or detrimental for the antitumor immune response, and activation can transform CD56bright CD162+ KIR2+ NK cells into CD56dim CD161+ KIR1+ NK cells with higher cytotoxic activity.94 The switch from a CD56bright phenotype to a CD56dim NK cell signature can take place in lymph nodes during inflammation and these cells circulate into peripheral blood as KIR+CD16+ NK cells with low cytotoxic ability. However, the secondary lymphoid organ (SLO) NK cells acquire cytotoxic activity upon stimulation with IL-2. Malignant NSCLC tumor areas show high presence of Tregs and minor NK cell infiltration, whereas non-malignant regions were oppositely populated, containing NK cells with marked cytotoxicity ex vivo.95 IL-2 activation of PMBCs exhibit increased cytotoxic activity against primary lung cancer cells, that is further elevated by IL-12 treatment.96 The adoptive transfer of NK cells is a therapeutic strategy currently being investigated in various cancer types. For example, Krause et al treated a NSCLC patient and 11 colorectal cancer patients with autologous transfer of NK cells activated ex vivo by a peptide derived from heat shock protein 70 (Hsp70) plus low-dose IL-2.97 The NK cell reinfusion revealed minor adverse effects and yielded promising immunological alterations.

Adaptive-like CD56dim CD16+ NK cells that were found in studies in mice and humans in peripheral blood have a distinctive phenotypic and functional profile compared to conventional NK cells.31,98 These cells have a high target cell responsiveness, as well as a longer life time and a recall potential comparable to that of memory T cells.99 Whereas adoptive NK cell transfer showed promising activities in the treatment of hematological malignancies, elimination of solid tumor cells failed due to insufficient migration and tumor infiltration.100 Furthermore, a CD49a+ KIR+ NKG2C+ CD56bright CD16 adaptive NK cell population with features of residency exists in human lung, that is distinct from adaptive-like CD56dim CD16+ peripheral blood NK cells.43 NK cells with an adaptive-like CD49a+ NK cell expansion in the lung proved to be hyperresponsive toward cancer cells. Despite their in vivo priming, the presence of adaptive-like CD49a+ NK cells in the lung did not correlate with any clinical parameters.

At the time of diagnosis, the majority (80%) of lung cancer patients present with locally advanced or metastatic disease that continues to progress despite chemotherapy.101 Lung cancer remains the leading cause of cancer death worldwide despite the responses found for immune checkpoint inhibitors (ICIs), including programmed death receptor-1 (PD1) or PD ligand 1 (PDL1)-blockade therapy.102 These ICIs has achieved marked tumor regression in some patients with advanced PD1/PDL1-positive lung cancer; however, lasting responses were limited to a 15% subpopulation of patients.103 IFN-, released by cytotoxic NK and T cells, is a critical enhancer of PDL1 expression on tumors and a predictor of response to immunotherapies.104 The high failure rate of immunotherapy seems to be a consequence of low tumor PDL1 expression and the action of further immunosuppressive mechanisms in the TME.105

NK cells expanded from induced-pluripotent stem cells (iPSCs) increased PDL1 expression of tumor cell lines, sensitized non-responding tumors from patients with lung cancer to PD1-targeted immunotherapy and killed PDL1- patient tumors (Figure 2).102 In contrast, native NK cells, that are susceptible to immunosuppression in the TME, had no effect on tumor PDL1 expression. Accordingly, only combined treatment of expanded NK cells and PD1-directed inhibitors resulted in synergistic tumor cell kill of initially non-responding patient tumors. A randomized control trial in patients with PDL1+ NSCLC found that the combination treatment of NK cells with the PD1 inhibitor pembrolizumab was well-tolerated and improved overall and progression-free survival in patients compared single agent pembrolizumab treatment.106 Importantly, during this clinical study no adverse events associated with the administration of NK cells were detected.

Early trials of autologous NK cell therapy from leukapheresis have demonstrated potency against several metastatic cancers but patients developed vascular leak syndrome due to a high level of IL-2.32,107 In contrast, other studies reported that these autologous NK cells failed to demonstrate clinical responses or efficacy at large.108,109 Adoptive transfer of ex vivo IL-2 activated NK cells showing better outcomes than the systemic administration of IL-2.107,110 The development of novel NK cell-mediated immunotherapies presumes a rich source of suitable NK cells for adoptive transfer and an enhancement of the NK cell cytotoxicity and durability in vivo. Potential sources comprise haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, permanent NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor (CAR) NK cells (Figure 2). Augmentation of the cytotoxicity and persistence of NK cells under clinical investigation is promoted by cytokine-based agents, NK cell engager molecules and ICIs.111,112 Despite some successes, most patients failed to respond to unmodified NK cell-based immunotherapy.113

Clonal NK cell lines, such as NK-92, KHYG-1 and YT cells, are an alternative source of allogeneic NK cells, and the NK-92 cell line has been extensively tested in clinical trials.114116 NK-92 cells are easily expanded with doubling times between 24 and 36 hours.115 NK-92 has received FDA approval for trials in patients with solid tumors.116 These cells are genetically unstable, which requires them to be irradiated prior to infusion. Irradiated NK-92 cells have been observed to kill tumor cells in patients with cancer, although irradiation limits the in vivo persistence of these cells to a maximum of 48 hours.117 The results are still short of a significant clinical benefit.118 An NK-92- derived product (haNK) has been engineered to express a high-affinity variant of CD16 as well as endogenous IL-2 in order to enhance effector function (Figure 2).119121 For example, Dinutuximab is a product of human-mouse chimeric mAb (ch14.18 mAb), which has demonstrated high efficacy against GD2-positive neuroblastoma cells in vitro and melanoma cells in vivo.122 In MHC-I expressing tumor cells, the effector functions of autologous NK cells are often inhibited by KIR that can be blocked with the help of anti-KIR (IPH2101).123 Stem cell-derived NK cell products from multiple sources are currently being tested clinically, including those originating from umbilical cord blood stem cells or iPSCs.124,125 NK cells account for ~515% of all lymphocytes in peripheral blood, whereas they constitute up to 30% of the lymphocytes in umbilical cord blood.126 iPSC-derived NK cells were triple gene- modified to express cleavage-resistant CD16, a chimeric antigen receptor (CAR) targeting CD19 and a membrane-bound IL-15 receptor signaling complex in order to promote their persistence.127 Thus, investigations to provide highly active modified NK cells in numbers sufficient for clinical application are actively pursued.

CAR T cells are derived from autologous T cells and genetically engineered to express an antibody single-chain variable fragment (scFv) targeting a tumor-associated antigen.128 CAR T cell therapies achieved objective response rates of >80% in patients with acute lymphocytic leukemia (ALL) and B cell non-Hodgkin lymphoma.129131 However, the drawbacks of CAR T therapy include severe adverse events such as GvHD,cytokine-release syndrome and neurological toxicities, besides inefficiencies of T cell isolation, modification and expansion as well as exorbitant costs.132 CAR NK therapy is expected to circumvent some of these problems, including the high toxicities. Primary NK cells are not ideal sources for the generation of CAR cell products, due to difficulties in cell isolation, transduction and expansion. However, NK cell expansion could be greatly improved by involvement of a K562 leukemia cell line feeder modified to express membrane-bound IL-15 (mbIL-15; Figure 2).133 Denman et al improved this method adding membrane-bound 41BBL to the K562 cell line resulting in a high expansion of NK cells within a short time.134,135 Nevertheless, current clinical trials of CAR NK cells rely mainly on processing of stem cell-derived or progenitor NK cells.136 Genetic engineering of NK cells has been performed by viral transduction or electroporation of mRNA.3 Many clinical trials of CAR NK-92 cells are ongoing, but the requirement for irradiation and resulting short persistence are limitations to the clinical efficacy of these products. NK92-CD16 cells preferentially killed tyrosine kinase inhibitor (TKI)-resistant NSCLC cells when compared with their parental NSCLC cells.137 Moreover, NK92-CD16 cell-induced cytotoxicity against TKI-resistant NSCLC cells was increased in the presence of cetuximab, an EGFR-targeting monoclonal antibody. A number of Phase I trials of CAR NK cells from various sources, including autologous peripheral blood NK cells, umbilical cord blood NK cells, NK-92 cells and iPSCs were designed to target diverse cancers, such as ALL, B cell malignancies, NSCLC, ovarian cancer or glioblastoma, and are currently active.

CAR NK cells derived from iPSCs, such as the triple-gene-modified constructions are described as a promising alternative. For example, a tri-specific killer engager (TriKE) consists of two scFvs, one targeting CD16 on NK cells and the other targeting CD33 on AML cells, linked by an IL-15 domain that promotes NK cell survival and proliferation.138 Controlled clinical trials with larger patient cohorts are required to validate these early results. Immunosuppressive factors of the TME, such as low glucose, hypoxia and MDSCs, Treg cells and tumor associated macrophages (TAMs) still suppress the antitumor functions of CAR-NK cells. Low efficiency of CAR-transduction, limited cell expansion and the scarcity of suitable targets impede the use of CAR-NK therapy despite of reports of therapeutic efficacy and safety.139

The cytokine gene transfer approaches, including interleukins and stem cell factor (SCF), have been shown to induce NK cell proliferation and increases survival capacity in vivo.140 The use of primary CAR-NK and CAR-NK lines in hematological tumors showed high specificity and cytotoxicity toward the target cells.141,142 So far, only a few clinical trial studies of CAR-NK have been registered on ClinicalTrials.gov.143 The combination of blocking ICIs on CAR-NK cells can lead to a highly efficient cancer-redirected cytotoxic activity.144,145 However, hematological cancers are responsible for only 6% of all cancer deaths and solid tumor are much more difficult to target by NK/CAR NK-based immunotherapy.146

Both the unmodified and the engineered forms of NK cell treatment are showing promise in pilot clinical trials in patients with cancer.147 This kind of immunotherapy seems to combine efficacy, safety, and relative ease of effector cell supply. The lung is populated by NK cells at a specific differentiation stage releasing cytokines but exhibiting low cytotoxicity. Poor tumor infiltration, immunosuppressive factors and cell types as well as hypoxic conditions in the TME limit the activity of NK cells. Therefore, larger numbers of activated, cytotoxic competent and armed NK cells will be required for successful therapy.

We wish to thank B. Rath for help in the preparation of the manuscript and T. Hohenheim for enduring endorsement.

The authors report no conflicts of interest in this work.

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Impact of NK cell-based therapeutics for Lung Cancer Therapy | BTT - Dove Medical Press

Caribou eyes $100M IPO as it aims off-the-shelf CAR-Ts at the clinic – FierceBiotech

Another day, another $100 million. In a move thats starting to look like a rite of passage in biotech, Caribou Biosciences filed on Thursday to raise $100 millionin its Wall Street debut. The proceeds will propel three off-the-shelf CAR-T therapies into and through the clinic and boost Caribous work in natural killer (NK) cell therapies.

Caribou is developing all three programs for patients with blood cancers whose disease has come back despite undergoing other treatments or did not respond to those treatments in the first place.

The company's most advanced program, CB-010, is an anti-CD19 CAR-T thats in a phase 1 trial in B-cell non-Hodgkin lymphoma. Some of the IPO proceeds will support this trial through initial data, which are expected in 2022, according to a securities filing.

RELATED:Caribou nets $115M to boost CRISPR tech, advance off-the-shelf cell therapies

The funds will also bankroll IND-enabling activities for two other programs: CB-011, a BCMA-targeting CAR-T in development for the treatment of multiple myeloma and CB-012, a CAR-T targeting CD371 for the treatment of acute myeloid leukemia. The company hopes to start human trials for these programs in 2022 and 2023, respectively.

All three programs are allogeneic CAR-T treatments, meaning they are made from donor cells, rather than a patients own cells like the four approved CAR-T therapies from Novartis, Gileads Kite unit and Bristol Myers Squibb.

Those types of treatments, called autologous, can be complex and time-consuming to make: cells must be taken out of the patient, modified to fight cancer and then put back into the patient. Some patients dont have enough T cells, or T cells of good enough quality, to make those treatments. Others simply dont have much time.

RELATED: Blackstone, Cellex and Intellia form $250M CAR-T startup

Though Caribous CAR-T programs all target blood cancer, the company is working on allogeneic NK cell therapies based on induced pluripotent stem cells for solid tumors. Some of the IPO haul will support R&D in this area, as well as the development of the CRISPR technology it uses to make its cell therapies.

In recent years, the cell therapy space has been teeming with new entrants looking to break the barriers seen in the first generation of cell therapies. In 2018, a pair of former Kite Pharma executives unveiled Allogene, a biotech that started out with $300 million and 17 off-the-shelf CAR-T assets licensed from Pfizer.

France-based Mnemo Therapeutics is trying to make CAR-T work for solid tumors by identifying better targets. Other companies, like Catamaran Bio, are going after that same piece of the pie, but via NK cell treatments instead.

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Caribou eyes $100M IPO as it aims off-the-shelf CAR-Ts at the clinic - FierceBiotech

Genexine, Toolgen to co-develop CAR-NK cell gene therapy – Korea Biomedical Review

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Genexine said Monday that it signed an agreement with Toolgen to co-develop and commercialize CAR-NK cell gene therapy using the latters CRISPR/Cas9 technology.

The two companies will co-own patent rights, utility model rights, trademark rights, and R&D data resulting from their co-development at a 5:5 equity ratio. They will also equally shoulder the cost incurred for the patent application, revision, registrations, and maintenance.

Genexine will make the most of Toolgens genetic scissors technology to develop new cell gene therapy to cure incurable diseases and expand its strategic pipelines.

CAR-NK cell gene therapy is an anticancer drug -- homogeneous natural killer (NK) cells whose immunity efficacy is strengthened through genetic manipulation administered to patients.

Unlike the CAR-T cell treatment that has to utilize the patients own T cell, the production of CAR-NK therapy is much cheaper, and mass production is also possible because NK cells could be abstracted from ready-made cell strain or induced pluripotent stem cells (IPSC). NK cells also can attack a wide variety of cancer cells, aside from targets introduced by CAR technology, as they have perception ability and offensive power.

Toolgen has confirmed that it could improve anticancer and immunity capacity through gene-editing of not only CAR-T, TCR-T but CAR-NK and various other anticancer immunocytes.

Genexine will make the best use of Toolgens CRISPR/Cas9 technology to develop new drugs of gene therapy to cure incurable diseases. This co-development MOU will be its start, Genexine CEO Sung Young-chul said. NK cell gene therapy, which is rapidly emerging as the next-generation anticancer immunotherapy, has cost advantages. By developing new drugs through cooperation with Toolgen, we will bring about a paradigm change on the anticancer treatment market.

Toolgen Kim Young-ho also said, Toolgen had put in a lot of effort to apply gene-editing technology to cell therapies, such as CAR-T and CAR-NK, and has recently produced successful results.

Kim added that if the two companies develop global blockbuster cell and gene therapies using Genexines know-how and Toolglens genetic scissors technology, it will maximize their corporate values.

Link:
Genexine, Toolgen to co-develop CAR-NK cell gene therapy - Korea Biomedical Review

Reversal of biological age detected in mouse and human embryos – BioNews

5 July 2021

Germline cells seem to reset their biological clocks around the time of embryoimplantation, not when generating gametes, as previously thought.

Scientists measured an increase in genetic damage in embryonic cells during the early stages of embryogenesis in micebefore undergoing a total reset within a 'rejuvenation period', reversing any cell damage.

'This study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal ageing,' wrote the researchers from Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts.

Previously, it was thought that, unlike thesomatic cells which form our bodies, germline cells which differentiateinto either sperm or eggs were ageless and did not inherit genetic damage from their parent organisms. However, recent research has shown that germline cells do age and display hallmarks of genetic damage. Yet, babies do not inherit their parents' age, and start again from zero.

The team employed machine-learning algorithms as 'ageing clocks' to calculate the ages of human and mouse embryonic tissue by measuring the prevalence ofmethylation an epigenetic marker. These markers accumulate with age on certain sections of DNA and are influenced by environmental factors. Although these markers do not affect the DNA sequence, they can alter the way a gene is expressed and modify proteins produced.

Genetic data sets collected from mouse embryosduring different stages of embryonic development were analysed by these epigenetic ageing clocks. Data sets recorded from mouse embryos following fertilisation showed increased epigenetic ageing with time during the first six days of cell division. But, during its implantation within the uterus wall, the embryonic cells displayed a decrease in epigenetic damage, characteristic of a reversal in ageing.

The team were unable to perform the same experiment inhuman embryos but were able to compare methylation in human induced pluripotent stem cells and embryonic stem cell lines anddatasets detailing methylation in human fetal tissue samples and see that a similar reset appeared to have occurred.

The findings, published in the journal ScienceAdvances, have wide-reaching implications for aiding the treatment of age-related illnesses such as Alzheimer's and Parkinson's disease. These diseases feature cells with accelerated epigenetic ageing and through a greater understanding of these biological reset mechanisms, it is thought that epigenetic damage to these cells could be reversed. However, achieving this in practice may be challenging since knowledge of other causes of cellular ageing is needed.

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Reversal of biological age detected in mouse and human embryos - BioNews

Rheumatoid Arthritis Stem Cell Therapy Market Size, Status and Precise Outlook During 2020 to 2026 The Manomet Current – The Manomet Current

The Global Rheumatoid Arthritis Stem Cell Therapy Market Research Report 2020-2026, offers an in-depth evaluation of each crucial aspect of the Global Rheumatoid Arthritis Stem Cell Therapy industry that relates to market size, share, revenue, demand, sales volume, and development in the market. The report analyzes the Rheumatoid Arthritis Stem Cell Therapy market related to the time period, historical pricing structure, and volume trends that make it easy to predict growth momentum and precisely estimate forthcoming opportunities in the Rheumatoid Arthritis Stem Cell Therapy Market. The report explores the current outlook in global and key regions (North America, Europe, Asia-Pacific, and Latin America) from the perspective of players, countries (U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, Taiwan, Southeast Asia, Mexico, and Brazil, etc.), product types, and end use segments. This report provides the COVID-19 (Corona Virus) impact analysis (historic and present) in major regions and countries, also provides a futuristic analysis considering COVID-19.

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Rheumatoid Arthritis Stem Cell Therapy Market Size, Status and Precise Outlook During 2020 to 2026 The Manomet Current - The Manomet Current

Canine Stem Cell Therapy Market Sustains Competitiveness by Adoption of Technological Innovations by 2021-2027 The ERX News – The ERX News

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Market Analysis By Type:Allogeneic Stem Cells, Autologous Stem cells

Market Analysis By Applications:Veterinary Hospitals, Veterinary Clinics, Veterinary Research Institutes

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Key players in the Global Canine Stem Cell Therapy Market are:VETSTEM BIOPHARMA, VetMatrix, Vetbiologics, Stemcellvet, Regeneus, Okyanos, Medivet Biologics, Magellan Stem Cells, Cell Therapy Sciences, Aratana Therapeutics, ANIMAL CELL THERAPIES

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Canine Stem Cell Therapy Market Sustains Competitiveness by Adoption of Technological Innovations by 2021-2027 The ERX News - The ERX News

Global Rheumatoid Arthritis Market is Booming in Near Future with Speedy Growth, Key Players International Stem Cell Corporation, Takeda. The…

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Key Companies Operating in this Market

Mesoblast, Roslin Cells, Regeneus, ReNeuron Group, International Stem Cell Corporation, Takeda, and Others.

Market by Type Allogeneic Mesenchymal Stem Cells Bone Marrow Transplant Adipose Tissue Stem Cells Others

Market by Application Hospitals Ambulatory Surgical Centers Specialty Clinics Othe

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Global Rheumatoid Arthritis Market is Booming in Near Future with Speedy Growth, Key Players International Stem Cell Corporation, Takeda. The...