Clinical Commentary: Tawbi Assesses Toxicities of Therapies in … – Targeted Oncology

We have randomized phase 3 data for pembrolizumab [Keytruda], nivolumab, andnivolumab plus ipilimumab [Yervoy], so I completely agree that all of these [agents are considered] category 1 treatments by the NCCN [National Comprehensive Cancer Network] because all have shown improvements over single-agent ipilimumab.1 That is kind of where the category 1 comes from when including overall survival [OS] benefit. I consider NCCN guidelines to bevery safe. They dont include options just because they exist.

However, [combination] pembrolizumab and low-dose ipilimumab has been tried in 1 large single-arm study called KEYNOTE-29 [NCT02089685] and [found to be]safer than the combination of ipilimumab and nivolumab or high-dose ipilumumab.2 Yet, most of[the] relevant data are from a second-line study that showed about a 25% response rate in the second line low dose of ipilimumab or pembrolizumab. So, personally, I dont necessarily agree with this recommendation as a first-line regimen for low-dose ipilimumab/ pembrolizumab, but obviously this is up for discussion.

Relatlimab is a novel antibody that blocks LAG3. Its one of those interesting receptors and is quite different than PD-1. Its expressed on activated T cells and exhausted T cells. Initially, people were thinking that it has an association with MHC class II, the primary ligand, but more and more data are arising to show that its directly associated with the TCR CD3, basically signaling cascade.3 It actually modulates TCR signaling, so it makes a bigger impact in a place where theres a lot more TCR signaling happening, and thats probably why it works better in the first line than in the second line.

We just published in Nature [results of a] neoadjuvant study where the response rate in our neoadjuvant patients was 57%, so the earlier you use it, the more signaling happens through TCR, and the more you can modulate anti-LAG3.4 Now, the RELATIVITY-047 study [NCT03470922] was a phase 3 trial followed by the FDA approval of nivolumab plus relatlimab [for patients 12 years and older with unresectable/metastatic melanoma].5,6

With ipilimumab/nivolumab in any setting, you get grade 3 to 4 toxicity of at least 50%, and the highest discontinuation rate because of an adverse event [AE] was 36% in the CheckMate 067 [NCT01844505] study.7 [The rate of any grade 3/4 AEs with] nivolumab and relatlimab was 21%, and this is why I do feel like its slightly more toxicbut the pattern oftoxicity is similar [Table7]. With [this combination] every toxicity Ive encountered feels the same as when you encounter a singleagent toxicity. It doesnt feel a lot more recalcitrant and its not a lot harder, and you get 1 toxicity per patient, just like you would get it with the single-agent PD-1 inhibitor. The other factor that I share with [patients] is that Ive run 2 trialswith it. Both are randomized, double-blind studies vs nivolumab as a single agent. I had a fellow in my clinic who was seeing a patient on the adjuvant trial,[and I challenged him to find out which treatment the patient was on based on toxicity presentation]. He told me he wasnt sure he could do that and thats the point. If we were treating the patient with ipilimumab/nivolumab, you would know which arm. If it was blinded and [using] ipilimumab/nivolumab, you would know which arm, but because its nivolumab/relatlimab, it was impossible to tell.

The phase 1 [portion of the] study had about 25 patients treated with [relatlimab as a] single agent in the second line, and it had no activity, but we only use it in combination because of the way it works; it has a lot more potential for working only in combination because it potentiates the TCR signaling. So once you use a PD-1 [inhibitor], you increase the TCR signaling, and then the LAG3 amplifies that signal and makes it better.

If you have an immune-suppressed individual who is already [being treated in the] second line and [is] resistant to immunotherapy, the TCR signaling is going to be so much more limited, and youll not [be] able to reverse the exhaustion with either single agent, whereas with a combination, you get about a 13% response in the second line [From the Data5]. Now, 13% [is a smaller response] and 1 out of 7 patients responded, so Im not surprised that some patients feel like it never works. Every time Ive used it in the metastatic [setting] in the second or third line, Im just candid with patients [and I discuss how much of a response] I expect. I dont do 3 months in that situation. I just repeat their scans in 2 months because if they are going to progress I may want to do something different.

The data that we have [show] that if the patient is requiring steroids at the time of initiation, when youre starting ipilimumab and nivolumab, their chances of a response are only 18%, so its limited. If you have already treated them with ipilimumab and nivolumab, and now youre treating the toxicity with steroidsI would focus on finishing the steroids completely tapering them off if you canand thenconsider rechallenging.

In CheckMate 067, the study that I ran in that population, if you had a grade 3 to 4 toxicity, they basically never rechallenged you with immunotherapy. They just took you off. We allowed [rechallenging] on the study after they taper off steroidsand we got away with it about half the time. The other halfwould get hepatitis back or other things back, but you can get away with a rechallenge about half the time.

KEYNOTE-006 [NCT01866319], which compared 2 doses of pembrolizumab with single agent ipilimumab,is interesting because we used to dose [patients] so high, [at about] 10 mg/kg every 2 weeks.8 The 200 mg that you currently use every 3 weeks is equivalent to 3 mg/kg every 3 weeks, so imagine how much more of a dose that was. And it didnt matter, so theres not a lot of dose-response relationship with pembrolizumab. By even decreasing the dose by almost twothirds, you still get the same outcome.

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Clinical Commentary: Tawbi Assesses Toxicities of Therapies in ... - Targeted Oncology

American Association for Cancer Research Recognizes 2022-2023 … – American Association for Cancer Research (AACR)

PHILADELPHIA TheAmerican Association for Cancer Research(AACR) is proud to announce its newest class of grant recipients.

Since 1993, the AACR has allocated $133 million and awarded 880 research grants to support hundreds of scientists devoted to advancing the understanding, prevention, diagnosis, and treatment of cancer. Our grants support researchers domestically and abroad at every stage of their careers, representing a global commitment to cancer prevention, early detection, interception, and cure.

Fellowships

2021 AACR-Bristol Myers Squibb Immuno-oncology Research Fellowship

2022 AACR-Amgen Fellowship in Clinical/Translational Cancer Research

2022 AACR-Day One Biopharmaceuticals Pediatric Cancer Research Fellowship

2022 AACR-Exelixis Renal Cell Carcinoma Research Fellowship

2022 AACR-Genmab Non-Hodgkin B-Cell Lymphoma Research Fellowship

2022 AACR-Merck Cancer Disparities Research Fellowship

2022 AACR-Merck Immuno-oncology Research Fellowship

2022 AACR-Mirati Cancer Chemical Biology Research Fellowship

2022 AACR-QuadW Foundation Sarcoma Research Fellowship, in Memory of Willie Tichenor

2023 AACR Fellowship to Further Diversity, Equity, and Inclusion in Cancer Research

2023 AACR-Bristol Myers Squibb Immuno-Oncology Research Fellowship

2023 AACR-D-Team Sarcoma Research Fellowship

2023 AACR-D-Team Sarcoma Research Fellowship

2023 AACR-Incyte Immuno-oncology Research Fellowship

2023 AACR-John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship

2023 AACR-QuadW Foundation Sarcoma Research Fellowship, in Memory of Willie Tichenor

Career Development Awards

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Clinical Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Clinical Cancer Research

2022 AACR Career Development Award to Further Diversity, Equity, and Inclusion in Clinical Cancer Research

2022 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant

2022 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant

2022 AACR-Novocure Career Development Award for Tumor Treating Fields Research

2022 Victorias Secret Global Fund for Womens Cancers Career Development Award, in Partnership with Pelotonia & AACR

2022 Victorias Secret Global Fund for Womens Cancers Career Development Award, in Partnership with Pelotonia & AACR

2022 Victorias Secret Global Fund for Womens Cancers Career Development Award, in Partnership with Pelotonia & AACR

2022 Victorias Secret Global Fund for Womens Cancers Career Development Award, in Partnership with Pelotonia & AACR

2022 Victorias Secret Global Fund for Womens Cancers Career Development Award, in Partnership with Pelotonia & AACR

2023 Lustgarten Foundation-AACR Pancreatic Cancer Career Development Award, in Honor of John Robert Lewis

2023 Lustgarten Foundation-AACR Pancreatic Cancer Career Development Award, in Honor of Ruth Bader Ginsburg

Independent Investigator Awards

2021 AACR-Bayer Innovation and Discovery Grant

2021 AACR-Bristol Myers Squibb Midcareer Female Investigator Grant

2021 AACR-Novocure Tumor Treating Fields Research Grant

2022 Friends of the AACR Foundation Early Career Investigator Award

2023 Lustgarten Foundation-Swim Across America-AACR Pancreatic Cancer Early Detection Research Grant

2023 Victorias Secret Global Fund for Womens Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & AACR

2023 Victorias Secret Global Fund for Womens Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & AACR

2023 Victorias Secret Global Fund for Womens Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & AACR

2023 Victorias Secret Global Fund for Womens Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & AACR

2023 Victorias Secret Global Fund for Womens Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & AACR

Grants Supporting Researchers in Africa

2022 Beginning Investigator Grant for Catalytic Research (BIG Cat)

2022 Beginning Investigator Grant for Catalytic Research (BIG Cat)

2022 Beginning Investigator Grant for Catalytic Research (BIG Cat)

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American Association for Cancer Research Recognizes 2022-2023 ... - American Association for Cancer Research (AACR)

2023 drug discovery forecast: emerging trends and disruptors … – Drug Target Review

With advancements in artificial intelligence, precision medicine and gene editing, the field of drug discovery is undergoing a rapid transformation. In this article, Drug Target Reviews Izzy Wood gets the insider knowledge from industry leaders at SLAS 2023, who are experiencing these changes first hand.

AI has seen quite a boom in the last couple of years, overcoming challenges such as limited and low-quality data. Researchers can avoid numerous delays by employing AI for drug discovery, often using computational approaches in combination with their own techniques, for a faster and smoother path to the clinic.1

Getting to grips with what AI can do and how best to acquire and utilise its skills.

According to Cyrill Brunner, Application Specialist at Bruker Daltonics, effective AI calls for good data because you can predict a lot of things, but if your data is not good, your results will lack quality. Its therefore vital to invest in high quality instruments that have the ability to deliver quality data in a short time.

Yet, even with the positive advances in AI, it does not come without its challenges. Brunner continued to explain that one of the biggest changes in the pharmaceutical industry is that AI has moved over from just making data predictions to also analysing data.

For instance, if we look at mass spectrometry, the data is increasingly being analysed by computational methods, so it can be faster to keep up with all of the other screening technologies. Given the increasing amounts of generated data, manual analysis becomes unfeasible from a timescale perspective.

Michael A Norman, Lab Automation GM & VP of Sales at Flow Robotics, concurred that advancements in AI and machine learning were disrupting the drug discovery landscape.

Norman reflected that AI and machine learning will usher in an era of quicker, cheaper and more effective drug discovery. But whether this remains a good or bad thing remains sceptical.2

Most experts do expect these tools to become increasingly important. This shift presents both challenges and opportunities for scientists, especially when the techniques are combined with automation.2 Yet it is this combination of tying in automation and equipment that will create the lab of the future.

As emphasised by the experts, it is a case of getting to grips with what AI can do and how best to acquire and utilise its skills.

According to the National Health Service (NHS), the basis for personalised medicine is understanding the role DNA plays in ones health, transforming healthcare by delivering the four Ps:

Analysing the genome allows patterns to be identified that can help determine individual risk of developing diseases.

Jovi Jenkins, VP of Business Development at SPT Lab Tech, explained: Scientifically, what we are seeing is a lot more interest in genomic applications within the drug discovery process. Using genomics is becoming routine, such as CRISPR screening.

Norman echoed these predictions, suggesting that there will be advancements in individualised personal medicine, like gene therapy and CRISPR, on a much larger level.

The use of automation in drug discoveryprovides more consistent data that allows labs to make better decisions, faster. It also facilitates the testing of hundreds of thousands of compounds and samples.

Automation involves a verybroad range of technologiesincluding robotics and expert systems.4

Nick Ritzo, Genie Life Sciences, suggested that a big trend in drug discovery is going to be how modular lab spaces can gain the ability to quickly pivot from the discovery of one molecule to another. In this space, that is going to be really important to bring more drugs into the market.

Following on, Steven Watters, North America Sales Manager at HighRes Biosolutions, explained how automation is all about how we get more connected data into scientists hands. He emphasised the importance of the enablement of scientists to review their work, make predictions, and then drive forwards.

References:

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2023 drug discovery forecast: emerging trends and disruptors ... - Drug Target Review

Roundtable Discussion: Kishtagari Reviews Treatment and … – Targeted Oncology

KISHTAGARI: The challenge as treating clinicians these days in the clinic is that almost 34% of the patients present with severe thrombocytopenia of less than 50 109/L platelets at the time of initial diagnosis of myelofibrosis. Most patients, 66%, presented with thrombocytopenia of over 50 109/L.1,2 This is a significant challenge when treating patients, especially with ruxolitinib [Jakafi], the medication that has had FDA approval for the longest time. The medication itself can cause [decreased] blood counts as well. A lot of patients do have anemia at baseline, and that gets worse with the disease evolution as well. So both thrombocytopenia and anemia are huge challenges for us. I think this is important in the sense that we need to monitor these patients frequently while they are on treatment. I think one [issue] is how frequently to monitor them. We should monitor them frequently initially, but once theyve stabilized, we can probably monitor them every 6 weeks to 2 months. Its been my practice to do 6 weeks to 2 months once they have

stability in their platelet counts, based on their treatment. Of course, if any drop in the platelet counts or hemoglobin happens, I tend to monitor them more frequently and include dose reduction of the treatment they are on.

ZAMAN: Recently I had a couple of patients who had hemolytic anemia, so they didnt take the prednisone. I gave rituximab [Rituxan] to a patient and she did not respond. I stopped it after 4 cycles with no response. Suddenly, 3 or 4 months later, she was not requiring as many transfusions. How often do you see hemolytic anemia?

KISHTAGARI: In my practice, I have seen 1 patient with hemolytic anemia with myelofibrosis. Its not that common, if you look at the literature as well. I keep thinking about management for this patient. Fortunately, my patient responded very well to high-dose steroids. But, like you said, its a challenge. That is something [that reminds us] when we see a drop in hemoglobin, we should always think broadly, not [only] of the disease but of the adverse effects [AEs] of the medication. We need to think broadly and keep our differentials broad. Look for hemolysis as a cause as well. But its rare, and it is reported in less than 5% [of patients], based on the literature.

BHANDARI: In my opinion, [the goals are] improvement of the symptoms and improved quality of life. The platelet count of 43 109/L is less concerning. I think the symptoms are more important.

KISHTAGARI: I think thats a good [approach]. A lot of these patients come with such a huge symptom burden, and I think thats the most important thing to address while we are thinking about the long term for this patient.

MAHAJAN: This is a 68-year-old patient. [Although] his ECOG performance status is 2, will a stem cell transplant [SCT] be a possibility for him? He is relatively young.

KISHTAGARI: Absolutely. I think a lot of times I give these patients the benefit of the doubt. I always refer for SCT, just for an evaluation. It doesnt mean that they will go for SCT. I think they need to at least be evaluated by a transplant physician to see if they can be considered for SCT. The oldest I have sent for transplant [was a 79-year-old patient], and this was a patient who was very active with an ECOG performance status of 0 to 1. This patients ECOG performance status of 2 is likely from the severe symptom burden he has been experiencing secondary to myelofibrosis. Given that, it is always good to initiate treatment and send them for transplant evaluation because we all know that the ultimate treatment or cure, especially for high-risk myelofibrosis, is SCT.

ZAMAN: If they are symptomatic, we start them on ruxolitinib. We look for the risk assessment, and Johns Hopkins [Sidney Kimmel Comprehensive Cancer Center] is approximately 100 miles from here, so I call them for an evaluation to see what they think. I try to cover both things, unless they are frail and cannot travel, which also is sometimes an issue.

MENDOZA: I have a similar approach. I sit down with them, and tell them that they need pharmacologic intervention, and we look at the performance status. We say that if they have some comorbid conditions, and they are highly symptomatic andhigh-risk, typically by guidelines, they would be candidates for transplant. But if the performance status is 2 and we start treatment and that improves their symptoms, then thats when I say we are 50 miles away from [a transplant center in] Baltimore, Maryland. So we also do something different, and typically the response is quick. Now in this case, discussing the specific pharmacologic agent is a little bit tough because of the platelet count. I would be careful with the choice. I would probably phone the transplant [specialist], go over the case, and say this is what I want to do. I want to see if they improve on pacritinib [Vonjo] or some other type of agent, and if it is indicated, Ill start that, and 2 to 4 weeks later I will see them and they have improved. The patients can tell when the spleen gets smaller. That by itself improves their symptom burden, and if thats the case, then the next thing we do is send them to Baltimore [for transplant evaluation].

KISHTAGARI: Thats fantastic. I like that approach a lot.

KALRA: Most of us who are in the community dont have open trials for patients with myelofibrosis, but at least I am in Baltimore and have access to 2 large academic centers, and if this is a patient who would qualify for a trial, and its open at one of those centers, then [I would refer for clinical trials].

LANG: If a patient has high-risk myelofibrosis but does not have clinical symptoms and is a candidate for transplant, do they still benefit from bridging therapy with a JAK [Janus kinase] inhibitor?

KISHTAGARI: If they have splenomegaly, I would consider JAK inhibitor therapy prior to proceeding to allogeneic SCT because if you can control the spleen size as much as possible before going for transplant, [data from] multiple studies have shown that it has a good outcome post transplant.3,4 So at least for the spleen reduction, I recommend initiating a JAK inhibitor.

ISLAS-OHLMAYER: Would you continue the JAK inhibitor during SCT?

KISHTAGARI: That is something a lot of centers have been doing. We have also been doing it after SCT, not during SCT. After SCT we have been initiating JAK inhibitor therapy because the symptom burden sometimes comes back, and we continue them on ruxolitinib. [N]ot all of them, [however,] only a few patients. This is being done as a part of a clinical trial, not as a standard of care.

KISHTAGARI: Getting a donor is something we all face whenever we refer the patient for allogeneic SCT evaluation. I have a lot of patients in my clinic right now who do not have a donor, and thats a significant challenge. Access is also something we all face for transplant evaluation, and even the cost is something we dont talk about often, which we should. They need to be very close to the transplant center, at least for the 90 to 100 days when they are undergoing allogeneic SCT evaluation. Do you always refer for transplant if they have high-risk myelofibrosis?

MAITI: Yes, the high-risk patients. I am at a regional oncology center close to the Cleveland Clinic main campus [in Ohio], so if I see a patient with high-risk myelofibrosis, I would refer them to a [transplant physician] on the main campus and work on the bridging therapy.

KISHTAGARI: OK, good.

MISBAH: Usually [the transplant physician] will tell us the bridging therapy they want us to use.

KISHTAGARI: Do they have any preference for the bridging therapy that they recommend?

MISBAH: I havent referred anyone recently, so I wouldnt be able to speak to that. But usually they will guide us very well on what we should use or what their preference is.

KISHTAGARI: Do you have any experience? [For] how long do you use bridging therapy? I know that very few patients subsequently undergo transplant.

LANG: In the past couple of years, I referred 3 patients for transplant. I was thinking they continue the bridging therapy until you find a transplant donor.

KISHTAGARI: So until the transplant donor is identified, and then until they go to transplant, the bridging therapy is continued.

LANG: Right.

KALRA: I think its the patient population. Myelofibrosis is not a disease of young people. Its the comorbidities. Its obviously the availability of donors. Its a lot of those factors, and then, eventually, whether they can even tolerate a transplant.

KISHTAGARI: Good. I think those are the challenges we face as clinicians on getting these patients [to transplant] with their advanced age, as well as donor availability and their performance status. Other factors such as cost and access are at play. Lately we have been seeing debulking of the disease before going for transplant. I think thats less of a challenge compared with other diseases such as AML [acute myeloid leukemia] or MDS [myelodysplastic syndrome] where they prefer the [myeloablative conditioning] before going for SCT. I dont think we have that challenge here. We have other challenges with myelofibrosis.

BHANDARI: I think its promising. I have used it in 1 of my patients.

MAITI: I have not used pacritinib yet. I have only used ruxolitinib as first-line therapy. But with the data,5 I think especially in patients with a platelet count of less than 50 109/L, I would consider pacritinib.

KISHTAGARI: In patients with a platelet count greater than 50 109/L, also, one can consider pacritinib, especially in the second-line setting.

KNAPP: Patients had platelet counts of less than 100 109/L on the trial, but they only approved it for those with less than 50 109/L. Is there a reason for that?

KISHTAGARI: In the [PERSIST-2] clinical trial [NCT02055781], they looked at both groups, but patients with platelet counts below 50 109/L derived maximal benefit [From the Data5], and so the FDA only approved it for that.6

MENDOZA: If I have a patient who is on dose-adjusted ruxolitinib, hes borderline, he had initial counts greater than 50 109/L, but he developed a platelet count of less than 50 109/L, do you recommend switching to pacritinib at that point? Or would you rather hold the dose, wait, and then adjust ruxolitinib again?

KISHTAGARI: It all depends. If the patient is getting benefit from ruxolitinib and you only noticed significant thrombocytopenia, dose reduce first before switching to pacritinib. If with the dose reductions you do not see any improvement in blood counts, then definitely switch to pacritinib.

MAHAJAN: What about pacritinibs effect on anemia? Is it like ruxolitinib, or other than that do you have to wait for momelotinib [GS-0387] to be approved?

KISHTAGARI: What we have seen is pacritinib also inhibits a protein called ACVR1 more than momelotinib.7 We also see this in the clinic as well, where there is a significant improvement in hemoglobin. But you need to treat the patient longer, and there are some retrospective data where they are noticing an improvement in hemoglobin along with a stabilizing platelet count.8 So there might be a role for pacritinib in the future for patients with myelofibrosis and anemia.

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Roundtable Discussion: Kishtagari Reviews Treatment and ... - Targeted Oncology

Getting Creative To Combat Foodborne Norovirus – Technology Networks

Every year, norovirus causes hundreds of millions of cases of food poisoning and the deaths of at least 50,000 children yet there exists no real way to control it. The virus has proven exceptionally difficult to study in the lab, and scientists have struggled to develop effective vaccines and drugs.

A new study at Washington University School of Medicine in St. Louis describes a creative way to make a vaccine against norovirus by piggybacking on the highly effective vaccines for rotavirus, an unrelated virus that also causes diarrhea.

The researchers created an experimental rotavirus-norovirus combo vaccine by adding a key protein from norovirus to a harmless strain of rotavirus. Mice that received the experimental vaccine produced neutralizing antibodies against both rotavirus and norovirus. The study, available online in Proceedings of the National Academy of Sciences, outlines an innovative approach to preventing one of the most common and intractable viral infections.

Pretty much everyone has had norovirus at some point, said senior author Siyuan Ding, PhD, an assistant professor of molecular microbiology. You go out to eat, and the next thing you know youre vomiting and having diarrhea. You will recover, but its going to be a rough three days or so. For kids in the developing world who dont have access to clean water, though, it can be deadly. The rotavirus vaccines work really well, and there are already global distribution systems set up for them, so based on that, we saw an opportunity to finally make some headway against norovirus.

Before the first rotavirus vaccines were rolled out in 2006, half a million children around the world died every year of diarrhea caused by rotavirus infection. Now, the number is estimated to be about 200,000 still high but a huge improvement. Four rotavirus vaccines are in use around the world. All are live-virus vaccines, meaning they are based on weakened forms of rotavirus capable of triggering an immune response but not of making people sick.

Human norovirus, on the other hand, has stymied scientific investigation for decades. It doesnt infect mice or rats or any other ordinary lab animals, so the kinds of experiments that led to the development of rotavirus vaccines have been impossible to replicate with norovirus.

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Ding and colleagues including first author Takahiro Kawagishi, PhD, a staff scientist in Dings lab, and co-corresponding author Harry B. Greenberg, MD, a professor emeritus of medicine at Stanford University came up with the idea of using rotavirus to bypass the technical difficulties of working with norovirus. They worked with a laboratory strain of rotavirus as a stand-in for one of the approved rotavirus vaccines, which are proprietary.

The researchers inserted the gene for the protein that forms the outer surface of human norovirus into the genome of the rotavirus lab strain. Then, they administered the modified rotavirus to immunocompromised infant mice by mouth, the same way rotavirus vaccines are given to children. They took blood and fecal samples four, six and eight weeks later. Nine weeks after the initial immunization, the researchers gave the mice a booster by injection and took samples again a week later.

A strong antibody response was evident in the blood of nine of 11 mice tested, and in the intestines of all 11 mice. Even better, some of the antibodies from the blood and the intestines were able to neutralize both viruses in human mini-gut cultures in a dish. Such cultures, also known as organoids, are grown from human stem cells and replicate the surface of the human gut.

Traditionally, vaccine studies have focused on the antibody response in the blood, because we understand that part of the immune response the best, Ding said. But norovirus and rotavirus are gut viruses, so antibodies in the blood are less important than the ones in the intestines in terms of fighting off these viruses. The fact that we saw a strong antibody response in the intestines is a good sign.

The next step is to show that animals immunized with the experimental vaccine are less likely to get sick or die from norovirus. Ding has such experiments underway.

The power of this study is that it outlines a novel approach that could accelerate vaccine development for a variety of troublesome organisms that cause diarrhea, especially in resource-limited countries where many of these infections occur.

There are a lot of intestinal pathogens out there for which we dont have good treatments or vaccines, Ding said. In principle, we could put a gene from any organism that infects the intestinal tract into the rotavirus vaccine to create a bivalent vaccine. Wed have to find the right targets to produce a good immune response, of course, but the principle is simple.

As basic scientists, we rarely get the chance to actually move something forward into the clinic, Ding continued. We study what the virus does and how the host responds at a basic level. This is a rare opportunity for our work to affect human health directly and make peoples lives better.

Reference:Kawagishi T, Snchez-Tacuba L, Feng N, et al. Mucosal and systemic neutralizing antibodies to norovirus induced in infant mice orally inoculated with recombinant rotaviruses. PNAS. 2023;120(9):e2214421120. doi:10.1073/pnas.2214421120

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Getting Creative To Combat Foodborne Norovirus - Technology Networks

The bared external anal sphincter (BEAS), a new technique for high … – Nature.com

Study design and population

The study was a retrospective analysis of prospectively collected data from a cohort from the tertiary referral center (Shuguang Hospital). Consecutive adult patients diagnosed with HHAF undergoing BEAS technique between June 2020 and January 2021 were included. Ethical approval was obtained from the ethics committee of Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine (Approval No. 2020-823-30-01). Written informed consent was obtained from each participant. All methods were carried out in accordance with relevant guidelines and regulations.

Magnetic resonance imaging (MRI) was performed on every patient, which helped to determine the extent of the HHAF lesion and its relationship with surrounding tissues. The diagnosis of HHAF was made and confirmed by at least two senior imaging specialists.

The inclusion criteria were the following: (1) male or female patients aged 18 to 65years; and (2) patients diagnosed with high cryptoglandular fistula-in-ano (involving more than one-third of the sphincter complex as assessed on MRI and intraoperative examination under anesthesia). Both primary and recurrent horseshoe fistulas were included. Patients with Crohn's disease, cancer, tuberculosis, diabetes, autoimmune diseases or patients receiving long-term steroids or corticosteroid therapy were excluded.

Patient demographics, clinical information, and short-term clinical outcome data were collected through outpatient follow-up, a WeChat questionnaire and telephone follow-up. Forty-one patients were followed-up by WeChat questionnaire and seven patients were followed-up by phone. There is no difference between these methods. The main outcomes included the 6-month cure rate, Visual Analog Scale pain score (VAS-PS) and Cleveland Clinic Florida incontinence score (CCF-IS). The secondary outcomes included the Quality of Life in Patients with Anal Fistula Questionnaire score (QoLAF-QS), Bristol stool chart and postoperative complications. Postoperative pain was measured using an 11-point Visual Analog Scale pain score (VAS-PS)14. The severity of fecal incontinence symptoms was evaluated using the Cleveland Clinic Florida incontinence score (CCF-IS)15. The Quality of Life in Patients with Anal Fistula Questionnaire score (QoLAF-QS) was used to assess the quality of life of patients with anal fistula16. Stool consistency was assessed using the 7-point Bristol stool scale17. Disease recurrence, as was reported by Mei et al., was defined as persistence or recurrence of symptoms or the relapse of the perianal sepsis within or more than 6months following surgical intervention18,19.

SPSS Statistics 25.0 (IBM Inc., IL, USA) software was used for ststistical analysis. Continuous variables are presented as the meanstandard deviation (SD) or median with interquartile range (IQR) based on distribution. The independent t test was used to compare normally distributed continuous variables, and the MannWhitney U test was used to compare nonnormally distributed continuous variables. Categorical data are expressed as the number of cases and percentages. P<0.05 was considered to indicate a ststistically significant difference.

Preparation for surgery begins with a careful evaluation of preoperative MRI to assess the location of the internal opening and the extent of inflammation as well as the relationship between the fistula and the muscles. The imaging also informs about the anatomical structure of anal canal, aiding in operative planning (Fig.1).

The diagrams of preoperative MRI. (a) The cross section of the perianal structure showing the relationship between IAS, EAS and HHAF. (b) The coronal section of the pelvis showing layers of anal sphincter, especially the levator ani muscle, and HHAF. IAS=internal anal sphincter; EAS=external anal sphincter; HHAF=high horseshoe anal fistula.

The patient is given spinal anesthesia and then placed in prone jackknife position. After preparing and draping, the operating table is placed in a 10 to 15 head-side-down position. This allows the muscles and spaces exposed more clearly in posterior aspect of anal canal during the operation. The internal opening, the external opening and the fistula of HHAF is then identified again to begin dissection (Fig.2).

Anatomic Structure of HHAF. (a) View of the outside appearance. The dotted line represents the scope HHAF. (b) Sagittal section of the pelvis. (c) Schematic diagram of posture for surgical exposure. (d) Preoperative visual field. The green shaded part represents HHAF. HHAF=high horseshoe anal fistula.

The dissection is initiated with a curvilinear incision (IS approach) along the intersphincteric groove to identify the internal anal sphincter (IAS) and external anal sphincter (EAS). This incision is directly behind the anal canal, which is approximately 1/41/3 of a quadrant of the anus. Then, the dissection is performed along the plane of the intersphincteric groove to separate the IAS from EAS with an electrical scalpel. The internal opening should be concerned during the dissections. Through both the anal canal and intersphincteric plane, the internal opening can be identified easily. There is barely no blood supply in the intersphincteric plane, therefore it is a safe dissection plane. However, care should be taken to observe the muscle contraction of EAS during this dissection. Because dissection is close to the IAS and EAS, the surgeon should take care during the dissection to avoid inadvertent injury. To avoid complications of incontinence or bleeding, the surgeon should dissect the IAS and EAS strictly along the plane (Fig.3).

The operation diagram of IS approach and LES approach. (a) View of the outside appearance. (b) Sagittal section of the pelvis. The dissection of IS approach is along the intersphincteric plane to separate the IAS from EAS. (c) IS approach. (d) LES approach. The dissection of LES approach is along the outer edge of the EAS to bare the EAS. IS=Intersphincteric; IAS=internal anal sphincter; EAS=external anal sphincter; LES=Lateral-external-sphincteric.

The next step involves the dissection of the EAS, which is initiated with a curvilinear incision (LES approach) along the outer edge of the EAS on one side behind the anal canal. The dissection is performed along the outer edge of the EAS until above the level of the deep EAS so as to bare the EAS. The lateral part of the EAS in the corresponding quadrant is exposed with the traction of a self-retaining retractor (Lone Star, Cooper Surgical, Trumbull, CT). The highest risk for incontinence, which is the most common postoperative complication, may be due to the injury of EAS. The bareness of EAS can completely expose the infection focus of HHAF. In this process, the surgeon should also be mindful of avoiding the anterior displacement of anal canal caused by the injury of anococcygeal ligament (Fig.3).

Once the IAS and EAS are separated, medial to lateral dissection of the muscles are continued along the intersphincteric plane to both sides. Then, the IAS is separated from EAS by a combination of sharp and blunt dissection. Through the IS approach, the suprasphincter anal fistula can be detected above the level of the deep EAS easily. Cephalad dissection is continued above or beneath the levator ani muscle so that the DPIS and the inner part of the EAS could be completely exposed (Fig.4).

The operation diagram of exposure of DPIS and DPAS. (a) View of the outside appearance. (b) Sagittal section of the pelvis. (c) Exposure of DPIS. (d) Exposure of DPAS. Expose DPIS and DPAS to reach the fistula through IS approach and LES approach, respectively. DPIS=deep intersphincteric space; DPAS=deep postanal space.

Continuing the dissection cephalad with the assist of self-retaining retractor along the LES approach reveals the DPAS, which can then be handled at the top of the infection. Both two approaches communicate at the top of the EAS (or at the top point of the pus cavity of the HHAF). Typically, the visualization of these approaches reveals the pus cavity under direct vision. The aim of these dissections is to utilize both the IS approach and the LES approach as a landmark to ensure a complete preservation of the EAS (Fig.4).

After the DPIS, the DPAS, and the pus cavity are irrigated repeatedly with povidone and hydrogen peroxide, the bare EAS is pushed proximally to confirm that the internal opening on the musculomucosal flap could reach the inferior edge of the EAS without tension. After the musculomucosal flap and the EAS advancement are performed, they are sutured and fixed with 20 Polyglactin suture (Coated VICRYL, 20, ETHICON Inc, China) to close the intersphincteric incision in an interrupted manner. At last, the LES approach is kept open and indwelled with povidone gauze to facilitate postoperative drainage (Fig.5).

The operation diagram of musculomucosal flap and EAS advancement. (a) View of the outside appearance. (b) Sagittal section of the pelvis. (c) Musculomucosal Flap and EAS Advancement. (d) Visual field after suture. Perform advancement of the musculomucosal flap and the EAS to confirm the internal opening could reach the inferior edge of the EAS without tension. Then close the intersphincteric incision (IS approach) in an interrupted manner and keep LES approach. EAS=external anal sphincter; IS=Intersphincteric; LES=Lateral-external-sphincteric.

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The bared external anal sphincter (BEAS), a new technique for high ... - Nature.com

Laser Pigmentation Treatment and Skin Rejuvenation Review – Expat Living Singapore

Heres our tried-and-tested lowdown on the fabulous new MOXI laser treatment we discover how it works with BBL Hero for effective pigmentation removal, skin rejuvenation and even pre-juvenation!

MOXI is a 30-45 minute clinical laser treatment thats perfect for working professionals. You could even do it in your lunchtime.

Like other light and laser-based technologies, it works by creating numerous microscopic areas of controlled injury.

This triggers a rejuvenating, wound-healing process that causes the skin to generate new collagen and shed unwanted pigment. The result? A smoother, brighter and firmer complexion.

By delivering energy to water in the skin layer, this remarkably versatile laser treats a wide range of skin concerns:

Unlike other light-based skin rejuvenation, says Bay Aesthetic Clinics Dr Bernard Tan, MOXI laser treatment is safe for all skin types in Singapore. Whats more, it can be used year-round, and you can have it done even after recent sun exposure. Now, thats unusual!

Its three settings make it unusually versatile, adds Dr Tan. For younger people, aged say 30 to 40, Level 1 works as an effective prejuvenation treatment that can delay early signs of ageing and reverse signs of sun damage. Level 2 is moderately intense, aiming at revitalisation and maintenance: youll probably want numbing cream and should expect downtime of three to five days. Level 3 promises to transform and renew your skin, requiring numbing cream and a longer downtime of up to a week.

Dr Bernard typically uses MOXI on the face, neck and dcolletage but it can also be used on the body and arms.

I had always avoided beauty treatments with downtime, my colleague Danielle told me. I wrongly associated them with pain and the potential for skin damage.

Then she tried BBL Hero, another popular laser treatment in Singapore, and loved what it did for pore size, fine lines and pigmentation removal. Dr Bernard assured her that MOXI was the next logical step. He explained that the two treatments in fact paired very well together and could be done one after the other.

I was glad that my treatment would include the neck and dcolletage areas, said Danielle. Though Ive been careful to use sunscreen on my face, I havent always protected my neck and chest properly and the neglect neck-lect? was starting to show. From now on, I promise to do better!

Before we started, Dr Bernard assured me I would be red for only a couple of days. Then the top layer of skin would flake off over the course of five to seven days. One of his clinic nurses showed me her skin, which just looked a little scaly three days after her treatment. This was reassuring, because I had multiple events and activities lined up.

The whole treatment took around two hours. First up was BBL Hero, which takes half-an-hour and is totally painless. Then they applied numbing cream and left it to take effect.

During the 30-minute MOXI treatment that followed, I felt a little tingling around the forehead. I assumed this was where the skin was thinner, holding less water. Generally, though, it was pretty painless. I think the worst part of laser treatments is the sound effects, ranging from a distant jackhammer to the immediate crackle of burning hairs!

After the laser, I enjoyed 30 relaxing minutes of LED light treatment aimed at accelerating healing. Finally, they applied a healing stem cell serum, gave me some to take home and told me to continue using it twice a day for the next week.

I was also reminded to stay strictly out of the sun and avoid outdoor activities for at least a week, avoid skin products containing AHA or Vitamin C, and use lots of moisturiser.

The next day, it just looked just like a sunburn. I had a couple of client meetings, where I explained the colour of my face: not raging red, but not normal, either. On Day 3, I wore light makeup to a lunch and dinner event, and the redness was hardly noticeable at all.

By Day 4, I was starting to get a little scaly and dry. From Days 5 to 7, the pigmentation started to flake off. The neck and dcolletage areas lagged a couple of days behind the face, so I ended up using a gentle exfoliating cleanser around Day 7 to remove the dry skin.

The pigmentation marks on my neck have almost totally gone, and my skin is smoother, firmer and more even in tone. People are commenting that I am glowing! And strangely, though my skin tone is normally a little red, it looks less so now.

MOXI is a 1927nm thulium fractional non-ablative laser that targets the water in the skin layer.

For best skin rejuvenation results, Dr Bernard recommends monthly treatment for three to five months. How much will this cost?

Considering that the combined treatment is a two-hour procedure for both laser pigmentation removal and rejuvenation that includes face, neck and dcolletage, plus the LED healing treatment, we feel its a worthwhile investment depending on budget, of course. What do you think?

Bay Aesthetics ClinicB2-12 Marina Bay Link Mall, Marina Bay Financial Centre8A Marina Boulevard8428 7811 | FB: @bayclinicsg | IG: @bay.clinic

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Laser Pigmentation Treatment and Skin Rejuvenation Review - Expat Living Singapore

QurAlis Announces First Patient Dosed With QRL-201, a First-in … – PR Newswire

First patient dosed in Canada in Phase 1 ANQUR study the first-ever clinical trial to evaluate a therapy that rescues STATHMIN-2 expression in ALS patients

STATHMIN-2 is a well-validated protein important for neural repair and axonal stability, the expression of which is significantly decreased in nearly all ALS patients

CAMBRIDGE, Mass., April 6, 2023 /PRNewswire/ -- QurAlis Corporation, a clinical-stage biotechnology company developing breakthrough precision medicines for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases with genetically validated targets, today announced that the first patient has been dosed in its Phase 1 clinical trial of QRL-201 for the treatment of ALS (ANQUR).QRL-201 is a first-in-class therapeutic product candidate aiming to restore STATHMIN-2 (STMN2) expression in ALS patients. ANQUR is the first-ever study to evaluate a therapy that rescues STMN2 expression in ALS patients.

"STATHMIN-2 is a well-validated protein important for neural repair and axonal stability and is the most significantly regulated gene by TDP-43 exclusively in humans. Its expression is significantly decreased in nearly all ALS patients and it is the most consistently decreased gene over all sporadic ALS patient data sets. QRL-201 rescues STMN2 loss of function in QurAlis ALS patient-derived motor neuron disease models in the presence of TDP-43 pathology," said Angela Genge, M.D., FRCP(C), chief medical officer of QurAlis. "QRL-201 recently entered the clinic in Canada and we are pleased to dose our first patient. We look forward to advancing the ANQUR clinical trial of QRL-201 for the treatment of ALS so that we can make a meaningful difference in patients' lives."

The first participant in the ANQUR study was dosed at University of Montral Hospital Centre (CHUM) by Genevive Matte, M.D.C.M., FRCP(C), assistant clinical professor, Department of Neurosciences, University of Montral; ALS clinic director, CHUM; principal investigator, University of Montral Hospital Research Centre (CRCHUM); and an ANQUR study investigator.

"ALS is a serious neurodegenerative disease with limited treatment options. There is great need for therapies that could slow disease progression and improve outcomes. This study has the potential to show QRL-201 could be such a therapy that could potentially benefit ALS patients who have a loss of STMN2 due to TDP-43 pathology," said Merit Cudkowicz, M.D., M.Sc., director of the Sean M. Healey & AMG Center for ALS, chief of neurology at Massachusetts General Hospital, director and the Julieanne Dorn Professor of Neurology at Harvard Medical School, and member of QurAlis' Clinical Advisory Board.

ANQUR (NCT05633459) is a first-in-human global, multi-center, randomized, double-blind, placebo-controlled multiple-ascending dose Phase 1 clinical trial designed to evaluate the safety, tolerability, and pharmacokinetics of QRL-201 versus placebo in patients with ALS. The primary objective of the study is to determine the safety and tolerability of multiple doses of QRL-201 in people living with ALS. The ANQUR clinical trial is expected to include 64 study participants with ALS across sites in Canada, the U.S., the United Kingdom, Belgium, the Netherlands, Italy, Germany, and Ireland.

Visit http://www.clinicaltrials.gov for more information about the ANQUR study.

About STATHMIN-2 and TDP-43STATHMIN-2 (STMN2) is a well-validated protein important for neural repair and axonal stability, the expression of which is significantly decreased in nearly all ALS patients. Also known as SCG-10, STMN2 is a protein essential for the stabilization of microtubules which form an important component of the cytoskeleton of cells and axons. STATHMIN-2 is highly expressed in human motor neurons, the cells that primarily degenerate in patients suffering from ALS. In animal models, STMN2 deletion was found to cause axonal degeneration and loss of muscle innervation, which is the primary functional deficit that leads to paralysis in ALS patients.

Using human neuronal stem cell models from ALS patients, QurAlis co-founder and former Harvard professor Kevin Eggan, Ph.D.,discovered in 2019 that the expression of STMN2 is regulated by TDP-43. The Eggan Lab showed that loss of normal TDP-43 function leads to a highly significant decrease in expression of STMN2 and an impairment in neuronal repair which could be rescued by restoring STMN2 levels. These results were published in Nature Neuroscience.

In addition to nearly all ALS patients, TDP-43 pathology is also associated with approximately 50 percent of patients with frontotemporal degeneration (FTD), the second most common form of dementia; about a third of Alzheimer's Disease patients; and up to seven percent of Parkinson's disease patients.

There are currently no cures for ALS or FTD. Limited therapeutic options are available for ALS and FTD patients who are in desperate need for effective therapies.

About QurAlis CorporationQurAlis is trailblazing the path to conquering amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases with genetically validated targets with next-generation precision medicines. QurAlis' proprietary platforms and unique biomarkers enable the design and development of drugs that act directly on disease-causing genetic alterations. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a deep pipeline of antisense oligonucleotides and small molecule programs including addressing sub-forms of ALS that account for the majority of ALS patients. For more information, please visit http://www.quralis.com or follow us on Twitter @QurAlisCo.

SOURCE QurAlis

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QurAlis Announces First Patient Dosed With QRL-201, a First-in ... - PR Newswire

Allogeneic CAR T-Cell Therapy Potentially Reduces GVHD Risk – Targeted Oncology

Michael Tees, MD, a hematologist-oncologist at Colorado Blood Cancer Institute, discusses the preliminary safety outcomes observed for an allogeneic chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma.

CAR T-cell therapies made with donor cells can potentially be given more quickly and affordably than autologous therapies that are currently available, but allogeneic CAR T-cell therapies, like allogeneic hematopoietic stem cell transplants, can cause graft-vs-host disease (GVHD).

ALLO-501A, which was studied in this trial, has a disrupted TCR gene meant to reduce the likelihood of transplanted immune cells harming the host. Tees says that in early trials of this product, there was only 1 documented case of GVHD, which was a patient with possible low-level GVHD of the skin.

Tees notes that this is not the only safety signal to be concerned with, as cytokine release syndrome (CRS) and neurotoxicity can also limit the use of CAR T-cell therapies. As trials of this agent continue, he hopes that a donor-derived CAR T-cell product will also help reduce the incidence of CRS.

TRANSCRIPTION:

0:08 | What ALLO-501A is, is a genetically reengineered product to reduce the likelihood of an argument between the donor and the recipient. One of the initial concerns was using someone else's T cells to fight the malignancy is that potential risk of GVHD, and that's what we see in [patients with] allogeneic stem cell transplant where donor hematopoietic stem cells grow into an immune system that can potentially argue with the recipient. In early ALLO-501 trials, I want to say that there was 1 patient with low-level, cutaneous GVHD, and its a question on whether that was a true [adverse event]. That risk has really been demonstrated to not be an issue. We can safely infuse these T-cell products from a different donor into a recipient.

1:09 | The next phase of this is efficacy and safety. There are other safety signals that we need to be looking at for CAR T-cell therapies such as cytokine release syndrome [CRS] and neurotoxicity. The current products that are available for patients commercially do have a high incidence of CRS and neurotoxicity. I am hopeful that perhaps having a donor-derived product can reduce the severity of CRS.

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Allogeneic CAR T-Cell Therapy Potentially Reduces GVHD Risk - Targeted Oncology

Maintenance Therapies Needed to Prevent Relapse After Transplant – Targeted Oncology

Oncologists are on the cusp of helping to prevent relapse patients with cancer after transplant with the use of maintenance therapies. For patients with hematologic malignancies like acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), one type of therapy making headway is tyrosine kinase inhibition.

Prior to transplant, clinicians also utilize immunotherapy conjugates for their patients. Now, these agents are starting to be assessed in the post-transplant setting.

Years ago, when I started in transplantation, we viewed a transplant as the last gasp [or] what we do at the end of a patient's treatment course to try to save them and try to cure them of their malignancyThese days, however, transplant is much better tolerated. We have the opportunity to combine transplantation with a variety of agents, both chemotherapy agents, immunotherapy agents, cellular therapy approaches, to actually treat relapse, or even better, prevent relapse using these agents in a maintenance setting, Robert J. Soiffer, MD, said in an interview with Targeted OncologyTM.

According to Soiffer, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, and a presentation he gave at the 4th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies, researchers must now focus their efforts on maintenance therapies and the prevention of relapse.

By further understanding which patients are most likely to relapse, which therapies to use, and how to provide patients with those treatments, patients with many hematologic malignancies, including leukemia, lymphoma, myeloma, etc., will have improved outcomes and less of a chance for relapse after transplant.

In the interview, Soiffer discussed relapse after transplant for patients with cancer and what is important to note moving forward with research.

Targeted Oncology: Can you discuss the current role of transplantation? Why is it important to discuss relapse after transplant for patients with cancer?

Soiffer: Oftentimes, when we consent patients for transplant, we concentrate on complications, like organ toxicity, infection, graft-vs-host disease, but we often don't address the elephant in the room, which is relapse after transplant, which is, of course, the real reason we're doing the transplant in the first place. Indeed, in patients who are beyond day 100 of relapse represents the primary reason for cause of death. We really have to make a concerted effort to address the issue of relapse.

Years ago, when I started in transplantation, we viewed a transplant as the last gasp [or] what we do at the end of a patient's treatment course to try to save them and try to cure them of their malignancy. It usually wasn't much to do after transplant or in conjunction with transplant because transplant itself was so toxic. These days, however, transplant is much better tolerated. We have the opportunity to combine transplantation with a variety of agents, both chemotherapy agents, immunotherapy agents, cellular therapy approaches, to actually treat relapse, or even better, prevent relapse using these agents in a maintenance setting.

Are there any ongoing trials or recent research that has caught your eye in this space?

There are a number, and they largely revolve around maintenance efforts to try to prevent patients from relapsing. These include the use of targeted agents and tyrosine kinase inhibitors that are now becoming much more popular and have become a standard of care in the treatment of many patients with AML and ALL, as well as immunotherapy conjugates that are used to treat patients prior to transplant. They're now being looked at in the post-transplant setting as maintenance.

Can you discuss the role of stem-cell transplant for hematological malignancies prior to the availability of CAR T-cell products?

Prior to the advent of CAR T-cell or immune effector cell approaches allogeneic transplant or autologous transplant represented the main cellular therapy for patients with blood cancers. They could be employed in a variety of circumstances, either in the autologous transplant setting in patients with non-Hodgkin lymphoma or Hodgkin lymphoma, and multiple myeloma, or the allogeneic setting for these very same diseases or those individuals with acute leukemia, MDS, or myelofibrosis.

They were used quite frequently in many circumstances. We didn't use them in all patients, as there were patients who were considered good risk patients by their biologic characteristics or their clinical characteristics. We wouldn't expose those patients to transplant because of the potential toxicity of transplant, hoping that standard therapy would be sufficient to cure them. Those individuals who were high-risk patients by their clinical or genomic characterization or those individuals who had not responded to primary therapy with those individuals are those individuals who we employ hematopoietic stem cell transplant for.

What unmet needs still exist regarding transplants?

We have been doing transplants for 50-60 years at this point. I've been doing it for just about 40 years, and we've made some good progress, but we have a long way to go. Transplant is still too toxic. There is a mortality associated with it, particularly with allogeneic transplants. Even if we've improved substantially, we want to have a therapy that we can offer patients that doesn't put their life at jeopardy. We need to continue to improve the safety of transplant. As I said, we've come a long way there.

The topic of my talk from Miami discussed relapse after transplant. There we have to cooperate. Those who work with allogeneic transplants have to collaborate with disease focused colleagues, whether it be leukemia, lymphoma, myeloma, or other diseases, to work together to try to bring down that risk of relapse, first by getting patients more ready for transplant and at a better minimal disease state going into transplant, and then working on ways to continue that therapy after transplant to try to suppress the risk of relapse.

What is important to note about relapse after transplant?

The real focus needs to be on maintenance therapies and the prevention of relapse. We must understand who is likely to relapse, how to deploy those therapies, and work together with our disease experts in leukemia, lymphoma, myeloma, and more, to combine the best of non-transplant therapies with transplants.

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Maintenance Therapies Needed to Prevent Relapse After Transplant - Targeted Oncology