Richters Transformation: When a Slow-Growing Cancer Turns Aggressive – SurvivorNet

Dr. Nicole Lamanna Columbia University Medical Center

Chronic lymphocytic leukemia (CLL) is a slow-growing type of cancer. It grows so slowly, in fact, that you can live for many years with your cancer, without having any symptoms or needing treatment. Sometimes, though, CLL can suddenly turn into a more serious condition, a change called Richters transformation.

Richters transformation is a condition in a small subset of CLL patients about 10 to 15% of patients where their disease can transform to a more aggressive lymphoma, Dr. Nicole Lamanna, associate professor of medicine at Columbia University Medical Center, tells SurvivorNet.

CLL often changes into a type of non-Hodgkin lymphoma called diffuse large B-cell lymphoma. Rarely, it turns into a form of Hodgkin lymphoma. If your cancer does change, your doctor will need to put you on a more aggressive treatment to control it.

Doctors dont know exactly why CLL suddenly takes a more serious turn. One theory is that certain people have a few aggressive cancer cells hidden behind their slow-growing ones. Eventually, those cells multiply to the point where they change into a new kind of lymphoma and take over.

How do you know that your cancer has transformed? Theres a big change in their disease, says Dr. Lamanna.

Look for signs like these:

Another important clue is the size of your lymph nodes. They may have a lymph node thats growing out of proportion to whats going on with the rest of their body, Dr. Lamanna says.

Lymph nodes are the little bean-shaped bumps in your neck, armpit, belly, and groin area. Youve likely felt them swollen in your neck at some point when you had an infection. If you notice any unusual swelling in these areas, tell the doctor who treats your cancer about it.

Richters transformation leads to a totally different disease than CLL, and it requires a different kind of treatment. Unlike CLL, which is chronic and we can treat intermittently or over the years, this is something they cant live with, Dr. Lamanna tells SurvivorNet. This is a much more difficult condition to treat.

Doctors usually use the same treatment as they do for large cell lymphoma, she adds. That can be a cocktail of chemotherapy drugs such as R-CHOP the monoclonal antibody rituximab (Rituxan), plus a combination of three chemotherapy drugs and the steroid, prednisone. Or, it can include a different monoclonal antibody called obinutuzumab (Gazyva) plus other combinations of chemo drugs such as EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin) or ICE (ifosfamide, carboplatin, etoposide).

Because of the aggressiveness of this disease, some people will ultimately need a stem cell transplant. This treatment starts with high doses of chemotherapy to destroy the cancer cells. Thats followed by an infusion of stem cells immature blood cells either from yourself or a donor. Those cells will grow into healthy new blood cells.

Researchers are studying new combinations of drugs, such as monoclonal antibodies paired with the targeted drug ibrutinib (Imbruvica) or other targeted therapies, to see if they work better against this cancer. This is an area under a lot of investigation. Were looking for new therapies all the time, Dr. Lamanna says.

In the meantime, your situation will determine which treatment your doctor recommends for you. Try to learn as much as you can about your new type of cancer. Dont be afraid to ask questions, including why your doctor is suggesting a specific treatment, how it might help you, and what side effects it could cause. Because this is an aggressive cancer, make sure you have the support you need, whether thats from your family, your medical team, or a lymphoma support group.

Learn more about SurvivorNet's rigorous medical review process.

Dr. Nicole Lamanna is a hematologist/oncologist at Columbia University Medical Center. Her research interests include lymphoid leukemias, specifically chronic lymphocytic leukemia (CLL). Read More

Dr. Nicole Lamanna Columbia University Medical Center

Richters transformation is a condition in a small subset of CLL patients about 10 to 15% of patients where their disease can transform to a more aggressive lymphoma, Dr. Nicole Lamanna, associate professor of medicine at Columbia University Medical Center, tells SurvivorNet.

Doctors dont know exactly why CLL suddenly takes a more serious turn. One theory is that certain people have a few aggressive cancer cells hidden behind their slow-growing ones. Eventually, those cells multiply to the point where they change into a new kind of lymphoma and take over.

How do you know that your cancer has transformed? Theres a big change in their disease, says Dr. Lamanna.

Look for signs like these:

Another important clue is the size of your lymph nodes. They may have a lymph node thats growing out of proportion to whats going on with the rest of their body, Dr. Lamanna says.

Lymph nodes are the little bean-shaped bumps in your neck, armpit, belly, and groin area. Youve likely felt them swollen in your neck at some point when you had an infection. If you notice any unusual swelling in these areas, tell the doctor who treats your cancer about it.

Richters transformation leads to a totally different disease than CLL, and it requires a different kind of treatment. Unlike CLL, which is chronic and we can treat intermittently or over the years, this is something they cant live with, Dr. Lamanna tells SurvivorNet. This is a much more difficult condition to treat.

Doctors usually use the same treatment as they do for large cell lymphoma, she adds. That can be a cocktail of chemotherapy drugs such as R-CHOP the monoclonal antibody rituximab (Rituxan), plus a combination of three chemotherapy drugs and the steroid, prednisone. Or, it can include a different monoclonal antibody called obinutuzumab (Gazyva) plus other combinations of chemo drugs such as EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin) or ICE (ifosfamide, carboplatin, etoposide).

Because of the aggressiveness of this disease, some people will ultimately need a stem cell transplant. This treatment starts with high doses of chemotherapy to destroy the cancer cells. Thats followed by an infusion of stem cells immature blood cells either from yourself or a donor. Those cells will grow into healthy new blood cells.

Researchers are studying new combinations of drugs, such as monoclonal antibodies paired with the targeted drug ibrutinib (Imbruvica) or other targeted therapies, to see if they work better against this cancer. This is an area under a lot of investigation. Were looking for new therapies all the time, Dr. Lamanna says.

In the meantime, your situation will determine which treatment your doctor recommends for you. Try to learn as much as you can about your new type of cancer. Dont be afraid to ask questions, including why your doctor is suggesting a specific treatment, how it might help you, and what side effects it could cause. Because this is an aggressive cancer, make sure you have the support you need, whether thats from your family, your medical team, or a lymphoma support group.

Learn more about SurvivorNet's rigorous medical review process.

Dr. Nicole Lamanna is a hematologist/oncologist at Columbia University Medical Center. Her research interests include lymphoid leukemias, specifically chronic lymphocytic leukemia (CLL). Read More

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Richters Transformation: When a Slow-Growing Cancer Turns Aggressive - SurvivorNet

Detroit Pistons, Make-A-Wish put a smile on the face of Commerce Township boy – The Oakland Press

In the spring Dylan Findling seemed to be a typical 9-year-old boy who loved sports.

His parents thought he might have attention deficit hyperactivity disorder but they didnt suspect a serious disease.

When COVID hit and I was kind of staying at home to work with him at home we started to know he was having balance issues. He was having issues kind of tracking when he was reading, he would fall all the time. I thought hes getting taller so maybe hes going through an awkward stage, his mom, Elissa Findling said.

Then it got more progressive and he could no longer ride his bike which he had done since he was 5.

Due to COVID-19 lockdowns of non-essential medical appointments, he couldnt get into an eye doctor until May 29.

His dad, Michael, took him for the appointment. It was discovered he had pressure on both optic nerves and was sent to the emergency room at Detroit Medical Center. An MRI revealed the bad news.

Dylan was diagnosed that day with Adrenoleukodystrophy (ALD), a genetic brain disorder. He also has Addisons Disease. The two go hand in hand. He was in kidney failure and his parents didnt know it.

Theres a very easy test to determine whether your child might have ADHD versus this disease. Its a blood test but not a required test they ask pediatricians to do, Elissa Findling said. The sad thing is Dylans disease is so far progressed that hes not eligible for what would cure it which is a bone marrow transplant.

They didnt like the news they were told that night.

We were told to go home and enjoy our time. Were not that kind of people - that wasnt a good enough answer, Findling said.

The Commerce Township couple contacted a specialist in Minnesota and through him Dylan has been undergoing an experimental treatment to stop progression of the disease at Beaumont.

In July when Dylan started the treatments he was still able to walk, talk, run, play, like a normal 9 year old. He just had some balance issues. In a matter of weeks he went from being able to do all of that, hes wheelchair bound. He cant talk, he has a G tube. This decline that weve seen has happened very quickly for him and for us, its obviously been hard for our family, his mom said.

The hope is to stop progression of the disease and then he might be eligible for a stem cell transplant.

Theyre thinking this may stop his disease, but I dont know that well get back what we had. Hes going to always be disabled which is hard to swallow and so thats where were at, Findling said. We go to therapy four days a week. Were doing the best we can with it.

Along the way, the staff at Beaumont mentioned Dylan would be eligible for a wish from the Make-A-Wish Foundation. They came through big-time along with the Detroit Pistons.

Due to the coronavirus pandemic, Make-A-Wish cant offer trips and meeting a celebrity can only happen with a Zoom call.

The Findlings were familiar with Make-A-Wish because their older son, Evan, survived Burkitts Lymphoma. While he was going through it they were granted the wish of going on a family cruise. Hes in remission.

So now they had to come up with a wish for Dylan.

At some point hed gravitated to always wearing jerseys to school. Hed wear Pistons jersey, soccer jerseys, and hed have football jerseys. All the kids knew him for being the jersey kid. He always loved sports and jerseys for sure, his dad Michael Findling said.

So he decided he would like to design a Detroit Pistons jersey.

When all of this came crashing down in such a short period of time that was the thing that came up for the Make A Wish, he loved jerseys, he liked sports and he cant do it any longer so this was a way to marry the two together. I thought they did an amazing job of putting it together for him, Michael Findling said.

The jersey design process, with Dylans help, was done on Zoom.

Then this week the Pistons brought the show to the Findling home in Commerce Township. They had a rubber mat for a runway with dance team members modeling the jerseys Dylan designed. Even the mascot, Hooper, was present and wearing the special jersey which includes a blue ribbon honoring ALD. There were jerseys, hats, T-shirts, face masks and much more for Dylan.

Dylan had a big smile on his face all that morning.

With all the swag that hes gotten its going to keep giving to him, because we can show him new things all the time hes going to love having the socks on. It definitely got him excited, his dad said.

Elissa Findling said, I dont know if thank you covers it.

This experience will be shared by the family on social media, hoping to spread awareness about ALD.

Right before he lost the ability to talk, he was talking a lot to me - he knew his brother had been sick, it was a rare cancer. We were talking about how rare his disease is and trying to make him understand its not your fault that youre sick, you didnt do anything wrong, Elissa Findling said. He was like. You know mommy since its so rare we could try to find something to cure me. That stuck with me through this process - thinking if we could do some good from it.''

ALD generally affects boys ages 2-11 and can be diagnosed through a blood test.

The key is to catch it early, the child can get a bone marrow transplant and its basically cured. If you dont, then youre going to deal with what were dealing with and we dont want to see another family dealing with this, Elissa Findling said.

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Detroit Pistons, Make-A-Wish put a smile on the face of Commerce Township boy - The Oakland Press

NexImmune Establishes Research Initiative with City of Hope to Focus on Novel Immunotherapeutic Approaches to Acute Myeloid Leukemia – Yahoo Finance

City of Hope will combine its world-leading expertise with NexImmune technology to explore tumor escape mechanisms and to identify unique leukemia stem cell targets for next generation immunotherapeutics

GAITHERSBURG, Md., Oct. 27, 2020 (GLOBE NEWSWIRE) -- NexImmune, a clinical-stage biotechnology company developing unique non-genetically-engineered T cell immunotherapies, announced today that it has signed a research initiative related to its AIM nanoparticle technology with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases.

City of Hope is a participating clinical site in the ongoing Phase 1/2 study of NEXI-001. The cancer center will leverage both patient samples from the ongoing NexImmune Phase 1/2 clinical study of NEXI-001 in acute myeloid leukemia (AML) patients with relapsed disease after allogeneic stem cell transplantation and the centers tumor repository bank of primary leukemia samples, one of the largest collections in the world, to drive the research.

NEXI-001 is a cellular product candidate that contains populations of naturally occurring CD8+ T cells directed against multiple antigen targets for AML, and it is the first clinical product generated by the Companys AIM nanoparticle technology.

NexImmune has developed a unique and versatile technology platform that lends itself very effectively to important areas of ongoing research in the field of AML, said Guido Marcucci, M.D., Chair and Professor with City of Hopes Department of Hematologic Malignancies Translational Science. Our collective goal is to translate future research findings into new, more effective T cell immunotherapies to the benefit of these very difficult to treat patients.

A key objective of the research will focus on the identification of new antigen targets that are expressed on both leukemic blasts as well as leukemic stem cells, and those which represent survival proteins to both. Once identified, these antigen targets will be loaded on NexImmune AIM-nanoparticles to expand antigen-specific CD8+ T cells, and evaluated in pre-clinical models for anti-tumor potency, tumor-specific killing, and response durability.

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In addition, the research initiative will aim to further understand different mechanisms of tumor escape, such as tumor antigen and human leukocyte antigen (HLA) downregulation due to immune pressure.

Research between NexImmune and City of Hope will inform a scientific understanding of how the immune system can address certain tumor escape mechanisms to more effectively fight aggressive cancers like AML, and how this might be accomplished with NexImmunes AIM technology and T cell products, said Monzr Al Malki, M.D., Director of City of Hopes Unrelated Donor BMT Program and Haploidentical Transplant Program and an Associate Clinical Professor with Department of Hematology and Hematopoietic Cell Transplantation. Based on our current clinical experience with this technology, were excited to learn what more this research will tell us.

City of Hope is a world-class clinical research institution that has built one of the largest banks of leukemia samples in the world, said Han Myint, M.D., NexImmune Chief Medical Officer. The depth of expertise that Drs. Marcucci, Al Malki and their team bring to this research initiative will help NexImmune continue to develop innovative products that can help patients with AML and other hard-to-treat cancers.

City of Hope is a leader in bone marrow transplantation. More than 16,000 stem cell and bone marrow transplants have been performed at City of Hope, and more than 700 are performed annually. City of Hopes BMT program is the only one in the nation that has had one-year survival above the expected rate for 15 consecutive years, based on analysis by the Center for International Blood and Marrow Transplant Research.

About NexImmune NexImmune is a clinical-stage biotechnology company developing unique approaches to T cell immunotherapies based on its proprietary Artificial Immune Modulation (AIM) technology. The AIM technology is designed to generate a targeted T cell-mediated immune response and is initially being developed as a cell therapy for the treatment of hematologic cancers. AIM nanoparticles (AIM-np) act as synthetic dendritic cells to deliver immune-specific signals to targeted T cells and can direct the activation or suppression of cell-mediated immunity. In cancer, AIM-expanded T cells have demonstrated best-in-class anti-tumor properties as characterized by in vitro analysis, including a unique combination of anti-tumor potency, antigen target-specific killing, and long-term T cell persistence. The modular design of the AIM platform enables rapid expansion across multiple therapeutic areas, with both cell therapy and injectable products.

NexImmunes two lead T cell therapy programs, NEXI-001 and NEXI-002, are in Phase 1/2 clinical trials for the treatment of relapsed AML after allogeneic stem cell transplantation and multiple myeloma refractory to >3 prior lines of therapy, respectively. The Companys pipeline also has additional preclinical programs, including cell therapy and injectable product candidates, for the treatment of oncology, autoimmune disorders, and infectious diseases.

For more information, visit http://www.neximmune.com.

Media Contact: Mike Beyer Sam Brown Inc. Healthcare Communications 312-961-2502 mikebeyer@sambrown.com

Investor Contact: Chad Rubin Solebury Trout +1-646-378-2947 crubin@soleburytrout.com

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NexImmune Establishes Research Initiative with City of Hope to Focus on Novel Immunotherapeutic Approaches to Acute Myeloid Leukemia - Yahoo Finance

HBS and Harvard’s Department of Stem Cell and Regenerative Biology Receive $25 Million Gift from The Chris and Carrie Shumway Foundation to Support…

Harvard Business School (HBS) and Harvards Department of Stem Cell and Regenerative Biology (HSCRB) have received a $25 million gift from The Chris (MBA 1993) and Carrie Shumway Foundation to fund programs promoting leadership in life sciences, including the MS/MBA Biotechnology: Life Sciences, a joint degree offered by HBS and the Graduate School of Arts and Sciences and Harvard Medical School through HSCRB. The gift will help bridge the worlds of business and science by fostering an environment of collaboration and innovation at HBS and across Harvard, supporting work on pathbreaking research and educating a new generation of leaders in the life sciences. The gift will provide support for curriculum development and programming, faculty research, and student financial aid.

Every day we are contending with the challenges posed by a worldwide pandemic and seeing firsthand the importance of strong connections between the lab bench and the private sector, said Harvard President Larry Bacow. The Shumways have given us the opportunity to think deeply about how we train leaders at this intersection that will only grow in complexity and importance. We are grateful for their foresight and their exceptional generosity.

This gift will provide the University with the resources to support future leaders in life sciences, dramatically increase innovation and the commercialization of new discoveries, and efficiently and quickly take transformative discoveries from the laboratory to patients and the marketplace, said HBS Dean Nitin Nohria. The world needs more business leaders working at the intersection of science and society, with deep understanding of not only biotechnology and life sciences, but the management skills needed to help these important companies thrive.

To meet this need, the MS/MBA Biotechnology: Life Sciences Program, welcomed its first cohort of students this past August. In supporting financial aid that will cover the incremental costs of the MS/MBA program for these students, this gift will enable Harvard to attract and support outstanding students who already have experience and knowledge in life sciences. To recognize this support, the students in this program will be known as Shumway Fellows and this program will prepare them to take on leadership roles in biotechnology and life sciences organizations.

The program builds upon students existing biotech and life sciences knowledge and equips them with the latest business and scientific insights. This empowers them to launch, grow, and lead transformative organizations that will advance new drug discoveries or therapeutics. Students in the program study general management at HBS and life-sciences at HSCRB, which is a joint department of Harvards Faculty of Arts and Sciences (FAS) and Harvard Medical School (HMS). They benefit from the leadership of program co-chairs Amitabh Chandra (Henry and Allison McCance Professor of Business Administration at HBS and the Ethel Zimmerman Winer Professor of Public Policy and Director of Health Policy Research at the Harvard Kennedy School of Government) Mark Fishman (Professor of Stem Cell and Regenerative Biology at Harvard University and Chief of Pathways Consult Service at Massachusetts General Hospital), and Douglas Melton (Xander University Professor at Harvard University and Co-Director of the Harvard Stem Cell Institute).

The MS/MBA program is a collaborative effort from several schools across Harvard to fill a unique need we see in the industry, said Emma Dench, dean of GSAS. The program provides students with the opportunity to become conversant in both biomedical science and business, and this generous gift will help to ensure that we can prepare them to lead in the rapidly growing life sciences fields.

The future of life sciences innovation will increasingly require deep scientific knowledge coupled with targeted business acumen, said George Q. Daley, dean of HMS. With this joint degree, Harvard will be uniquely positioned to educate students to lead at this nexus.

Sometimes it is at the intersection of disciplines where we find opportunities to ask new questions that have the potential to completely change the way we think about a problem, said Edgerley Family Dean of the Faculty of Arts and Sciences Claudine Gay. This gift will enable Harvard to attract and support talented scholars in the life sciences and equip them with the tools they need to work at the interface of business and life sciences, asking the new questions that promote discovery and innovation in this important area.

Harvard has created an exceptional ecosystem that can develop and cultivate talented professionals across medicine, business and life sciences who are best positioned to tackle the worlds biggest global health challenges today and in the future, said Chris Shumway, managing partner and founder of Shumway Capital. As Harvard is geographically situated at the epicenter of the life sciences community with access to some of the worlds leading hospitals, pharma and biotechnology companies, we believe a tremendous opportunity exists to foster cross-pollination of ideas by marshalling the resources of Harvard and connecting with industry leaders to quickly understand and solve problems.

The gift will also support HBS as it engages and works closely with entrepreneurs and practitioners in the field on the creation of new research and the development of executive education training to serve their unique needs.

The acceleration of global health issues, including the current pandemic, demonstrates the need for entrepreneurial thinking, Chris Shumway added. Leaders born out of these programs will be equipped to drive organizations at the forefront of groundbreaking discoveries with the mindset needed to solve complex problems worldwide.

As an entrepreneur and Managing Partner of Shumway Capital, Chris Shumway has invested in, advised, and built growth businesses for over 25 years, including in biotechnology and life sciences. The Shumways are long-time supporters and advocates for philanthropic initiatives. As strong proponents of education reform, they established the Shumway Foundation with the primary goal of helping to break the cycle of poverty through better opportunities in education. The Shumway Foundation also actively supports other results-based non-profit organizations.

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HBS and Harvard's Department of Stem Cell and Regenerative Biology Receive $25 Million Gift from The Chris and Carrie Shumway Foundation to Support...

Harnessing regeneration of retinal tissues: An option almost within reach – Ophthalmology Times

This article was reviewed by Russell N. Van Gelder, MD, PhD

Neuronal cell replacement therapies remain a challenge in retinal diseases. Some fish and salamanders have the innate ability to regenerate retinal tissue after injuries and, as Russell N. Van Gelder, MD, PhD, pointed out, if researchers could harness this ability in humans, the possibilities would be great for repairing or replacing damaged tissue in a wide variety of retinal diseases. Stem cells are the key to cell replacement therapies.

Stem cells are cells that have not terminally differentiated and still have the potential to become many types of terminal cells, said Van Gelder, from the Department of Ophthalmology at the University of Washington in Seattle. We all started as embryonic stem cells in the earliest phases of development.

Related: Retinal pathologies challenging to image with current technologies

Van Gelder went on to explain that there are now methods to create equivalently totipotent stem cells from individual induced progenitor stem cells derived from an individuals blood or epithelial cells.

The overarching goal is to create a cell type that needs replacement from a stem cell precursor, he said.

A major achievement in this quest for regenerative ability occurred in 2014 when an entire eye cup was grown from progenitor stem cells.

Van Gelder also described a study1 in which green fluorescent proteinlabeled retinal precursors derived from embryonic stem cells were transplanted into the subretinal space of macaques. Three months after the procedure, the researchers demonstrated that the bolus of cells persisted and had outgrowth of axons that were seen going to the optic nerve and on to the brain.

This result establishes the validity of a stem cell-based approach for doing regenerative medicine in primates, he said.

Related: Persistent retinal detachment associated with retinoblastoma

Replacement therapy hurdles As of now, however, no stem cell-based replacement treatment has received FDA approval. The problems preventing establishment of a treatment have been technical in nature and include correct cellular differentiation as well as generating adequate numbers of cells for large transplantation experiments, establishing correct cell polarity and connectivity, and ensuring the safety of these approaches regarding tumor or hamartoma formation, Van Gelder explained.

Managing inflammatory responses is a problem after cell transplantation. He cited a Japanese study2 of individual progenitor cell-derived retinal progenitor cells transplanted subretinally in monkey models.

Even with an immune HLA-matched donor, there was still a marked inflammatory response at the site of the transplantation, Van Gelder said. This and other inflammatory responses will have to be managed for cell transplantation to be successful. Related: Intravitreally injected hRPCs improve vision in retinitis pigmentosa cases

There are regulatory hurdles to clear. The FDA Center for Biologics Evaluation and Research regulates cellular therapy products, human gene therapy products, and certain devices related to cell and gene therapy.

Van Gelder recalled the well-publicized case of transplantation of fat-derived mesenchymal cells into patients eyes, resulting in loss of vision bilaterally. He pointed out that it is important to temper patient expectations regarding these therapies and to ensure that the work is being done with the highest degree of ethical integrity.

While great progress has been made in this field, significant barriers remain to the successful adoption in the clinical setting in the coming years, Van Gelder concluded. The barriers to cell replacement should be overcome.

Read more by Lynda Charters

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Russell N. Van Gelder, MD, PhD e: russvg@uw.edu Van Gelder has no financial interests in this subject matter. He serves on the advisory committee for the National Eye Institute Audacious Goals Initiative.

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References

1. Chao JR, Lamba DA, Kiesert TR, et al. Transl Vis Sci Technol. 2017;6:4; doi:10.1167/tvst/6/3/4

2. Fujii S, Sugita S, Futatsugi Y, et al. A strategy for personalized treatment of iPS-retinal immune rejections assessed in cynomolgus monkey models. Int J Mol Sci. 2020;21(9):3077. doi:10.3390/ijms21093077

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Harnessing regeneration of retinal tissues: An option almost within reach - Ophthalmology Times

Fate Therapeutics’ and Celyad’s CAR therapies in oncology offer potential – pharmaceutical-technology.com

by Manasi Vaidya in New York.

Fate TherapeuticsandCelyadsnatural killer (NK) cell biology-focused cell therapies could overcome cell persistence challenges and consequent efficacy concerns with redosing strategies, experts said.

One of Fate Therapeutics lead products, FT596, is an allogeneic, multitargeted, chimeric antigen receptor (CAR) NK cell product. Celyads autologous CYAD-01 and CYAD-02 and allogeneic CYAD-101 are CAR T cell products using NK cell specificity to target T-cells. One analyst considered the potential to redose allogeneic products as a key item to consider while assessing clinical potential. While clinical data establishing the additive efficacy advantages of giving multiple doses is still preliminary, redosing allogeneic products could increase their expansion and persistence, experts said. Autologous therapies carry source constraints, so the ability to manufacture and administer allogeneic therapies is an advantage, they said.

While past NK cell therapy data has been mixed, experts saw potential in CAR NKs like FT596 or CAR T-cell products engineered to express NKG2D like CYAD-101, given the advancements in cell production.

Phase I FT596 results in B-cell lymphomas/ CLL are expected at either the American Society of Hematology (ASH) meeting in December or an investor meeting in early 2021, as per a second analyst report. Phase I data for CYAD-01 and CYAD-02 in relapsed/refractory (r/r) acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are expected by YE20, as per the companys August corporate presentation. Celyads allogeneic CYAD-101 is being tested in a Phase I alloSHRINK trial (NCT03692429) in metastatic colorectal cancer (CRC), which has a primary completion date of November 2020.

FT596s sales are expected to reach $136m in 2026, according to a GlobalData Consensus forecast. Celyad did not respond to a request for comment.

Increasing the persistence of cell therapies once they are infused into a patient has been a challenge, especially with NK cell-based therapies, experts said. The issue of persistence and consequent efficacy is significant because the potential efficacy with Celyad and Fate Therapeutics platforms remains largely unknown, they added.

Because the immune system can recognise foreign cells, cell products would not last for more than a few weeks, said Dr Marco Davila, medical oncologist, in the Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida. With CAR T-cell therapies, the expansion and persistence of CAR cells are said to correlate with the durability of response, said Dr David Sallman, assistant member, Department of Malignant Hematology, Moffitt Cancer Center.

Strategies involving multiple doses of cell therapies could maximise the total dose, improve duration, and increase efficacy magnitude with both autologous and allogeneic cell therapies, said Dr Tara Lin, associate professor of medicine, University of Kansas Medical Center, Kansas City. Multiple infusions of therapy could also potentially lead to complete remission, said Sallman. In Fate Therapeutics Phase I FT500 (NCT03841110) study, patients had been given up to six doses of the therapy, which was not found to be toxic, according to Fate Therapeutics CEO Scott Wolchko. Redosing has the potential to offer multiple infusions as maintenance therapy, said Dr Jeffrey Miller, professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis.

The persistence of allogeneic therapies is not well understood, and it is unknown how long cells need to persist to be effective or whether persisting cells confer durability of response, said Wolchko. Giving multiple doses is one way to overcome the lack of persistence if it is an important factor for efficacy, he said. In a 4Q19 call, the FDA said it was allowing the dose to be repeated on a patient-by-patient basis, Wolchko said. In the alloSHRINK study, CYAD-101 is administered three times with a two-week interval between each administration in metastatic CRC, as per ClinicalTrials.gov.

However, even if the engineered cells do not persist in the body, the response rate and ability to eradicate the disease should not be limited, said Davila. With a limited lifespan, allogeneic cell therapies would dissipate as the patients immune system recovers, said Dan Kaufman. With the incorporation of interleukin (IL)-12 or IL-15 into the cell product, the cell therapy could persist without exogenous cytokines, said Kaufman. The FT596 construct contains an IL-15 fusion protein.

Experts cited the data from a Phase I / II (NCT03056339) investigator-led effort at MD Anderson Cancer Center using cord blood-derived anti-CD19 CAR NK cells as an example of an effective CAR NK therapy. The study by Rezvani and colleagues showed a persistence challenge did not seem to hamper the response, because once a critical threshold for cell expansion is crossed, the activity can be mediated, Davila said. Eleven r/r patients with CD19-positive cancers, such as non-Hodgkins lymphoma or CLL, were treated with a single infusion; eight had a response, including seven with a complete remission (Rezvani et al. [2020] N Engl J Med, 382, pp. 545553). Even if the cells do not persist, they expand to sufficient levels to eradicate the disease before they are lost, Davila added.

In the Phase I THINK(NCT03018405) CYAD-01 data, decreased bone marrow blasts were observed in eight patients, including five objective responses and one stable disease for three or more months, as per the company presentation. Responding patients did have blast clearances, but some of the remissions were short-lived and the cells did not persist in the system, said Sallman. However, the short hairpin (sh) ribonucleic acid (RNA) technology employed CYAD-02, which could increase persistence and expansion, said Sallman (Fontaine et al., [2019]Blood, 134[Suppl 1], p. 3931). ShRNA technology allows T cell engineering without the need for gene editing to inhibit alloreactivity and increase persistence, according to Celyad.

Ongoing research on improving preconditioning regimens by combining additional drugs could also help with the persistence of allogeneic products, said Davila. It is not known whether every dose needs a conditioning regimen, but since conditioning regimens can suppress a patients immune system for several months, it may not be necessary before every therapy infusion, he added.

Patients will not have to receive a preconditioning regimen before every cell infusion, said Wolchko, adding redosing FT500 was found to be safe. Celyads protocol does not specify the preconditioning strategy for redosing. No predictive biomarkers are available to explain why some patients respond well and others do not, said Sallman, adding it is critical to identify potential responders. Nonetheless, there is no way to predict clinical efficacy based only on preclinical data, so data is still needed, said Miller.

The economic advantage to developing off-the-shelf therapies has driven interest in NK-cell based platforms, said Miller and Davila. If quick treatment is needed, then an allogeneic NK cell therapy would be better than an autologous therapy, which may take up to six weeks to manufacture, said Sallman. While the results with autologous CAR T-cell therapies have been significant, their scale-up and costs are challenging, said Kaufman.

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The ability to use induced pluripotent stem cell (iPSCs) or cord blood cells as a source would help scale up the cell manufacture and allow effective results, said Kaufman. iPSCs provide advancement in expansion protocols, which can provide multiple doses, Miller added. Fate Therapeutics has an iPSC-derived NK cell franchise. Also, since T cell therapies require donor apheresis to collect cells in a process lasting four to five hours, it is not feasible to keep going back to the same donor, said Miller.

Moreover, newer platforms are expected to improve on past NK cell therapy trials, specifically those showing mixed efficacy. Past studies had feasibility limitations in getting the required number of cells, said Miller. Those small studies were conducted at a time when cell isolation and production systems were not as advanced as they are now, said Davila.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalDatas investigative journalism team. A version of this article originally appeared on the Insights module of GlobalDatas Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

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Fate Therapeutics' and Celyad's CAR therapies in oncology offer potential - pharmaceutical-technology.com

World Wide Stem Cell Treatment Centers Provides Exceptional Regenerative Treatment Options To Those in Need – GlobeNewswire

October 16, 2020 12:00 ET | Source: World Wide Stem Cell Treatment Centers

PITTSBURGH, Oct. 16, 2020 (GLOBE NEWSWIRE) -- Those who are looking for an alternative treatment option when compared to traditional medicine are now in luck. Recently, World Wide Stem Cell Treatment Centers announced that it was opening the first of its more than 300 planned locations all over the world. With access to a wide range of treatment options, it is possible for patients to visit World Wide Stem Cell Treatment Centers and enjoy a more comprehensive recovery process than they ever have in the past. Therefore, it is important to highlight some of the major benefits that come with visiting World Wide Stem Cell Treatment Centers or health treatment options.

An Introduction to World Wide Stem Cell Treatment Centers: The First Location is Open

Right now, the first location has opened for World Wide Stem Cell. This treatment center location is in Pittsburgh, Pennsylvania. Currently, more than 300 locations are scheduled to open worldwide.

In many situations, treatment options from World Wide Stem Cell can actually work very well when working in combination with traditional medical therapy. The goal of World Wide Stem Cell Treatment Centers is to provide patients with more options, allowing them to tailor their treatment options to meet their individual needs and avoid invasive surgery whenever possible. In this manner, patients can work with the professionals at World Wide Stem Cell to develop a custom treatment plan to meet their unique needs.

Who Might Need Stem Cell Therapy from World Wide Stem Cell Treatment Centers?

The reality is that anyone is able to benefit from stem cell therapy from World Wide Stem Cell. At the same time, it is also important for people to know what goes into stem cell therapy.

First, one of the most common patient populations that might benefit from a visit to World Wide Stem Cell is athletes who have suffered an injury. While participating in their sport. While sports are great for conditioning and staying in shape. Injuries are always a very real risk. When an athlete suffers an injury, World Wide Stem Cell is able to treat that athlete and in most cases have that athlete participating back in his sport again in up to 1/10th of the time without invasive surgery. So with that being said the entire population at one time or another are candidates for stem cells. Whether it be a knee, hip, shoulder or any other orthopedic joint. Stem cells in most cases are able to replace invasive surgery; with a stem cell injection. World Wide Stem Cell always treats every condition with the proper cells for that particular situation. We only use orthopedic surgeons and neurosurgeons that do all our injections and they are all done with ultrasound guided needle injections. Whether you are interested in orthopedic treatments, facial rejuvenation, anti-aging cells, hair replacement, erectile dysfunction. We have them all at World Wide Stem Cell. Call, email, inquire!

Contact:

300 Chapel Harbor Drive Suite 204 Pittsburgh, Pa 15238 Contact: JS Genslinger (founder) 412-408-3183

World Wide Stem Cell Treatment Centers

Pittsburgh, Pennsylvania, UNITED STATES

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World Wide Stem Cell Treatment Centers Provides Exceptional Regenerative Treatment Options To Those in Need - GlobeNewswire

BrainStorm Announces Financial Results for the Third Quarter of 2020 and Provides a Corporate Update – PRNewswire

NEW YORK, Oct. 15, 2020 /PRNewswire/ -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, announced today financial results for the third quarter ended September 30, 2020, and provided a corporate update.

"The most important near-term event for BrainStorm will be the upcoming top-line data readout for the NurOwn Phase 3 trial in ALS, expected by the end of November. A successful outcome will set us on the path to filing a Biologic License Application (BLA) for what we believe will be a valuable new treatment for ALS," said Chaim Lebovits, Chief Executive Officer of BrainStorm Cell Therapeutics. "In parallel to our preparations for upcoming data read out, we are very busy planning and executing on other pre-BLA activities. On the management front, we appointed William K. White and Dr. Anthony Waclawski, adding valuable commercial and regulatory expertise to our leadership team. This expertise will be crucial as we work towards obtaining regulatory approval for NurOwn and ensuring that, if approved, it will be readily accessible to ALS patients in need of new treatment options for this devastating disease."

NurOwn has an innovative mechanism of action that is broadly applicable across neurodegenerative diseases and BrainStorm continues to invest in clinical trials evaluating the product in conditions beyond ALS to maximize value creation for its various stakeholders. The company remains on track to complete dosing in its Phase 2 clinical trial in progressive multiple sclerosis (PMS) by the end of 2020. In addition, the Company recently unveiled a clinical development program in Alzheimer's' disease (AD) and is planning a Phase 2 proof-of-concept clinical trial at several leading AD centers in the Netherlands and France.

Third Quarter 2020 and Recent Corporate Highlights:

Presented at the following Investor Conferences:

Cash and Liquidity as of October 14, 2020

Total available funding as of October 14, 2020, which includes cash, cash equivalents and short-term bank deposits of approximately $33.1 million as well as remaining non-dilutive funding from CIRM, IIA and other grants, amounts to approximately $36 million.

Financial Results for the Three Months Ended September 30, 2020

Conference Call & WebcastThursday, October 15, 2020 at 8 a.m. Eastern TimeFrom the US:877-407-9205 International: 201-689-8054 Webcast:https://www.webcaster4.com/Webcast/Page/2354/37811

Replays, available through October 29, 2020 From the US:877-481-4010 International: 919-882-2331 Replay Passcode: 37811

About NurOwn

NurOwn (autologous MSC-NTF) cells represent a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. BrainStorm has fully enrolled a Phase 3 pivotal trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm also recently received acceptance from theU.S. Food and Drug Administration(FDA) to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS) and completed enrollment inAugust 2020.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc.is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from theU.S. Food and Drug Administration(FDA) and theEuropean Medicines Agency(EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at sixU.S.sites supported by a grant from theCalifornia Institute for Regenerative Medicine(CIRM CLIN2-0989). The pivotal study is intended to support a filing forU.S.FDA approval of autologous MSC-NTF cells in ALS. BrainStorm also recently receivedU.S.FDA clearance to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The Phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed enrollment inAugust 2020. For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

ContactsInvestor Relations: Corey Davis, Ph.D. LifeSci Advisors, LLC Phone: +1 646-465-1138 [emailprotected]

Media:Paul Tyahla SmithSolve Phone: + 1.973.713.3768 [emailprotected]

BRAINSTORM CELL THERAPEUTICS INC. AND SUBSIDIARIES INTERIM CONDENSED CONSOLIDATED BALANCE SHEETS U.S. dollars in thousands (Except share data)

September30,

December31,

2020

2019

U.S.$ inthousands

Unaudited

Audited

ASSETS

Current Assets:

Cash and cash equivalents

$

24,770

$

536

Short-term deposit (Note 4)

4,038

33

Other accounts receivable

1,473

2,359

Prepaid expenses and other current assets (Note 5)

56

432

Total current assets

30,337

3,360

Long-Term Assets:

Prepaid expenses and other long-term assets

27

32

Operating lease right of use asset (Note 6)

1,377

2,182

Property and Equipment, Net

950

960

Total Long-Term Assets

2,354

3,174

Total assets

$

32,691

$

6,534

LIABILITIES AND STOCKHOLDERS' EQUITY (DEFICIT)

Current Liabilities:

Accounts payable

$

3,283

$

14,677

Accrued expenses

917

1,000

Operating lease liability (Note 6)

1,216

1,263

Other accounts payable

1,013

714

Total current liabilities

6,429

17,654

Long-Term Liabilities:

Operating lease liability (Note 6)

284

1,103

Total long-term liabilities

284

1,103

Total liabilities

$

6,713

$

18,757

Stockholders' Equity (deficit):

Stock capital: (Note 7)

12

11

Common Stock of $0.00005 par value - Authorized: 100,000,000 shares at September 30, 2020 and December 31, 2019 respectively; Issued and outstanding: 31,567,592 and 23,174,228 shares at September 30,2020 and December31,2019 respectively.

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BrainStorm Announces Financial Results for the Third Quarter of 2020 and Provides a Corporate Update - PRNewswire

Proposition 14: Stem cell research bonds City Times – City Times

New bonds would continue to fund an existing institute

Brandon Manus

California is voting on selling $5.5 billion in new bonds for research and development of stem cell research. Graphic by Brandon Manus

Brandon Manus, Staff Writer October 15, 2020

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California is voting on selling $5.5 billion in new bonds to continue funding grants for research and development of stem cell treatments.

A yes vote on this measure means Proposition 14 would issue $5.5 billion in funding to an existing state stem cell research institute. The California Institute for Regenerative Medicine, based in Oakland, was created in a 2004 voter-approved measure to support scientific research toward finding treatments and a deeper understanding of diseases such as Alzheimers, heart disease, cancer and strokes. Voters originally approved $3 billion, but that money is now on its last legs. As of June 2020, only $30 million remained.

A no vote on this measure means the state could not sell $5.5 billion in bonds primarily for stem cell research and the development of new medical treatments in California. Some opponents say the institute hasnt produced the kind of life-saving treatments that were promised when it was created. There is also no longer a ban on federal funding for stem cell research, which led to the institutes creation in 2004. The institute is funded with public money, but does not have any legislative oversight or address potential conflicts of interest. Some opponents have also criticized the requirement that $1.5 billion be cordoned off for brain and central nervous system diseases, saying it hampers the institutes flexibility to respond to changing needs.

Vote No on Prop. 14, a costly, unnecessary bond measure, The Sun (article) Stem-cell agency doesnt merit additional funding, The Mercury News (article)Why Prop. 14 is unaffordable, unnecessary, fatally flawed and unsupportable, The San Diego Union-Tribune (article) What Proposition 14 Tells Us About California, The New York Times (article) More borrowing for stem cell research, Los Angeles Times (article)

Californians for Stem Cell Research California Democratic Party Juvenile Diabetes Research Foundation University of California Board of Regents Californians For Stem Cell Research

Marcy Darnovsky, executive director of the Center for Genetics and Society

For more information about Prop 14, go to Ballotpedia.org.

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Proposition 14: Stem cell research bonds City Times - City Times

How a UCSF team is giving Cronutt the sea lion a second chance with neuroscience – University of California

A cellular therapy for epilepsy developed at UC San Francisco has been employed for the first time in a sea lion with intractable seizures caused by ingesting toxins from algal blooms. The procedure is the first-ever attempt to treat naturally occurring epilepsy in any animal using transplanted cells.

The 7-year-old male sea lion, named Cronutt, first beached in San Luis Obispo County in 2017 and was rescued byThe Marine Mammal Center(TMMC), based in Sausalito, Calif. His epilepsy is due to brain damage caused by exposure to domoic acid released bytoxic algal blooms. Each year, domoic acid poisoning affects hundreds of marine mammals, including both sea lions and sea otters, up and down the West Coast, a problem that is on the rise as climate change warms the worlds oceans, making algal blooms more common.

Like many of these animals, Cronutt cannot survive in the wild due to his epilepsy, and he was transferred by TMMC in 2018 to Six Flags Discovery Kingdom in Vallejo, Calif., which has facilities to care for wildlife with special veterinary needs.

In recent months, Cronutts health has declined due to increasingly frequent and severe seizures. With all other options exhausted, his veterinary team sought help from epilepsy researcherScott C. Baraban, Ph.D., in a last-ditch effort to save the sea lions life. For over a decade, Baraban, who holds the William K. Bowes Endowed Chair in Neuroscience Research in UCSFsDepartment of Neurological Surgery, has been developing the cell-based therapy, which has been shown by his research team to be highly effective in experimental lab animals.

This method is incredibly reliable in mice, but this is the first time it has been tried in a large mammal as a therapy, so well just have to wait and see, said Baraban, a member of the UCSF Weill Institute for Neurosciences. Over the years Ive come to learn how many marine mammals cant be released into the wild due to domoic acid poisoning, and its our hope is that if this procedure is successful it will open the door to helping many more animals.

On Tuesday, Oct. 6, a team of 18 specialists, including veterinarians from Six Flags and neurosurgeons and researchers from UCSF, successfully completed a precisely targeted injection of brain cell precursors taken from pig embryos called neural progenitor cells into Cronutts hippocampus, the brain region responsible for seizures. Based on extensive observations in rodents, Baraban said, the injected embryonic cells should migrate through his damaged hippocampus over the course of days and weeks, integrating and repairing the brain circuitry causing his seizures.

It was a remarkable convergence. Every year there are many animals suffering from epilepsy for which there isnt any treatment available, while, just across the bridge from The Marine Mammal Center, we at UCSF are trying to develop this new form of therapy and looking for ways to one day translate it to the clinic, saidMariana Casalia, Ph.D., a postdoctoral researcher who joined Barabans lab in 2015 to work ontranslating the groups successes in rodentsinto therapies, and who has taken the helm of the sea lion epilepsy project. It seemed very natural for us that these animals could be first patients to hopefully benefit from this therapy.

Domoic acid poisoning in marine mammals causes hippocampal damage very similar to that seen in temporal lobe epilepsy, the most common form of epilepsy in humans. In this disease, damage to hippocampal inhibitory interneurons removes the brakes on electrical activity, leading to seizures. In a vicious cycle, seizures can further damage brain circuitry, which is why epilepsy often worsens over time.

Since 2009, theBaraban labhas been developing a way to replace these damaged interneuronsby transplanting embryonic MGE (medial ganglionic eminence) progenitor cells into the hippocampus. As discovered two decades ago by Barabans UCSF colleaguesArturo lvarez-Buylla, Ph.D., andJohn Rubenstein, Ph.D., MGE cells normallymigrate into hippocampus during brain developmentandintegrate themselves into the local circuitry as inhibitory neurons.

Barabans group has shown that its possible to transplant embryonic MGE cells into the brains of adult rodents with temporal lobe epilepsy, wherethey quickly spread through the hippocampus and repair its damaged circuitry. The procedure reliably reduces seizures in these animals by 90 percent, along with other side effects of epilepsy, such as anxiety and memory problems.

Our laboratorys work has been inspired by the desire to find new solutions for the 30 percent of temporal lobe epilepsy patients who dont respond to available drug treatments, and for whom no new medicines have emerged over the past 50 years. Baraban said. For a number of reasons, including regulatory hurdles, cellular therapies for people with epilepsy are probably still a long way off. However, marine mammals with brain damage from domoic acid poisoning are in a very similar boat with no effective treatments that would let them ever be returned to the wild.

Baraban learned about the hundreds of annual domoic acidrelated strandings of marine mammals from long-time colleague Paul Buckmaster, D.V.M., Ph.D., of Stanford University. Buckmasters seminal studies in collaboration with TMMC in Sausalito had found that these animalssuffer from hippocampal damage almost identical to human temporal lobe epilepsy.

As soon as Mariana and I learned about this issue it was clear that our approach could be a perfect solution to help rehabilitate these animals, Baraban said.

Casalia had spent four years developing and testing a pig source of MGE cells pig tissue is often used for transplants into humans in collaboration with colleagues at UC Davis, work the lab intends to publish soon. On learning about the plight of domoic acidpoisoned sea lions, she partnered with TMMC and the California Academy of Sciences to study sea lion skulls to begin planning an eventual transplant surgery. She ultimately worked with UCSF neurosurgery chairEdward Chang, M.D., and collaborators at the medical software firmBrainLabto create a custom targeting system for the sea lion brain.She had even spent months working closely with the Hamilton Company to create a custom needle for delivering the stem cells to the right spot in a sea lions hippocampus.

All that remained was to find the right patient. And then, in September, 2020, they got a call from a veterinarian at Six Flags asking if they could help save the life of a sea lion named Cronutt.

After rescuing Cronutt in 2017, TMMC had attempted three times to rehabilitate him and release him back into the wild. Each time he would beach himself again, emaciated, disoriented, and approaching humans. Then he began to have seizures. Most marine centers dont have facilities for the long-term care of marine mammals with special needs, but Six Flags volunteered to give Cronutt a new home.

We have cared for a lot of special needs animals over the years, said Dianne Cameron, director of animal care at Six Flags. We adore Cronutt and are committed to providing him a forever home. He has his own apartment in our Sea Lion Stadium with a pool and dry resting area. When hes doing well, he comes out and participates in training sessions. Unfortunately, recently it has been hard to get him to come out of his apartment.

Over this spring and summer, Cronutt had begun a serious decline his seizures were increasing, he was losing weight, and he often seemed disoriented. To oversee Cronutts care, Six Flags hiredClaire Simeone, DVM, a founder and CEO of Sea Change Health, who hadstudied the neurological effects of domoic acid poisoningduring her six years working with TMMC. But it soon became clear that no treatment was working for Cronutt.

Despite our best efforts and all the tools that we have, his seizures were becoming more prolonged and more frequent over time, Simeone said. His brain damage and the effects on his body were getting worse. His decline has been gradual, but we reached a point several months ago where we were questioning what quality of life he had. We had run out of options for how we could successfully manage Cronutts disease and knew that we were going to have to make some hard decisions soon.

Then Simeone recalled a talk Baraban had given at TMMC several years ago about the potential of MGE transplants for marine mammals with domoic acid poisoning. In September, she reached out to ask if the lab might be willing to attempt the procedure as a last-ditch effort to save Cronutts life.

Cronutts health was slipping fast, but Casalias years of preparation for this moment allowed her and her colleagues to quickly assemble everything that would be needed in just one month.

In a bit of serendipity that would prove crucial, Cronutts brain had already been imaged in 2018 by Ben Inglis, Ph.D., of UC BerkeleysHenry H. Wheeler Jr. Brain Imaging Centeras part of an ongoing study ofhow domoic acid poisoning affects the sea lion brain. These MRI images provided critical guideposts that made it possible for UCSF neurosurgeons to plan how they would inject stem cells at just the right spot in Cronutts hippocampus.

Cronutts surgery, conducted in accordance with COVID-19 protocols at the SAGE Veterinary Centers in Redwood City, Calif., went smoothly, and he was returned to Six Flags. In the days after the surgery his veterinary team reported that he had been sleeping and eating well.

Based on prior experiments transplanting pig MGE cells into rats, the researchers expect it to take about a month or so for the cells to fully integrate into Cronutts hippocampus. They will be following up to see if his seizures decrease and his health and behavior improves, and whether his antiseizure medications can be reduced.

This first-ever attempt has been made possible by funding from a Javits Award from the National Institutes of Health and from the UCSFProgram in Breakthrough Biomedical Research. Without these funds, this kind of high-risk, high-reward science would never have gotten off the ground, Baraban added. It also depended on Marianas fearlessness and perseverance in pursuing this very uncertain project.

Casalia, who has degrees in applied science and neurobiology from Universidad National de Quilmes and the University of Buenos Aires in Argentina, says the surgery felt like a culmination of everything shed been working on in her career so far. Ive always wanted to apply what we are doing in the lab to the clinical setting, she said. For me the ability to do this in reality to help these animals who are suffering is a dream come true.

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How a UCSF team is giving Cronutt the sea lion a second chance with neuroscience - University of California