Category Archives: Cell Therapy

Francisco Hernandez-Ilizaliturri, MD

As bispecific antibodies gain traction in the diffuse large B-cell lymphoma (DLBCL) treatment paradigm, patient characteristics such as frailty, fitness, and disease risk influence how Francisco Hernandez-Ilizaliturri, MD, selects and sequences treatment with bispecific antibodies and CAR T-cell therapies.

Version 2.2024 of the NCCN Clinical Practice Guidelines in Oncology for B-Cell Lymphomas, which were released in April 2024, include axicabtagene ciloleucel (Yescarta) and lisocabtagene maraleucel (Breyanzi) as recommended second-line therapies, and bispecific antibodies, such as epcoritamab-bysp (Epkinly), are recommended in the third- and subsequent-line settings.1

Bispecific antibodies are another form of T-cell engager therapy, and their activity has been proven in clinical trials not only in relapsed/refractory large-cell lymphoma, but also in follicular lymphoma, [and] to a lesser degree in other types of lymphomas, Hernandez-Ilizaliturri said in an interview with OncLive. Some of them are approved for patients with relapsed/refractory large-cell lymphoma, so in this context we are trying to weigh the choice of CAR T-cell therapy [vs a] bispecific antibody.

In the interview, Hernandez-Ilizaliturri detailed how he selects and sequences treatments for patients with DLBCL, and also provided insights into the multiple myeloma space regarding how the FDA approvals of the CAR T-cell therapies ciltacabtagene autoleucel (cilta-cel, Carvykti) and idecabtagene vicleucel (ide-cel, Abecma) have provided more options for patients in earlier lines of treatment. Hernandez-Ilizaliturri is the director of Lymphoma Research, head of the Lymphoma Translational Research Laboratory, a professor of oncology, and an associate professor in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Hernandez-Ilizaliturri: The approval of CAR T-cell therapy in multiple myeloma highlights the principle that these novel forms of immunotherapy can be applied to cancers beyond B-cell lymphomas. They provide therapeutic strategies for patients who are youngwhen they have good kidney function[and] need to have disease control.

The activity [observed] in the 2 clinical trials with each of the CAR T-cell therapy products also highlights the need to develop new treatments because in contrast with what we see with B-cell lymphoma, the duration of the activity is not as long. Sometimes we should not wait too long to implement these treatments because the more damaged the immune system is in a patient from prior treatments, the less likely it is that these kinds of immunotherapies are going to [be effective] for a long time.

[The data] also stressed the need to learn how those myeloma cells may be further affecting CAR T-cell function, so we can develop a better way to apply this technology to have better clinical activity. [These are] encouraging data that are going to change the way that we practice, but it opens a lot of questions and is forcing industry to partner with academic centers to develop better CAR T-cell products for myeloma.

In general, we have longer follow-[up] data with CAR T-cell therapy; we can be comfortable assuming that CAR T-cell therapy can cure [approximately] 30% to 40% of patients with relapsed or refractory LBCL. Whereas the follow-up of patients treated with bispecific antibodies is not long enough to see if patients are being cured with this intervention. For a patient who is younger and fit, it may be better to start with a CAR T-cell therapy product because there is longer follow-up data and we have become more proficient in treating acute toxicitiesthat mitigates some of the concerns about that treatment.

If a patient is frailer, a bispecific antibody may be more suitable. [Treatment selection] also has to do with the geographic location of the patient and their access to CAR T-cell therapy. One of the benefits of bispecific antibodies is that they can be administered close to the patients home, as long as the physician is comfortable using the bispecific antibody and monitoring the adverse effects.

Its encouraging that bispecific antibodies have shown activity in patients previously treated with CAR T-cell therapy. A way to sequence these treatments would be to first start with CAR T-cell therapy and then [administer] a bispecific antibody in patients with high-grade lymphoma. This may change, as there are some interesting emerging data [regarding] combining bispecific antibodies with rituximab [Rituxan] or CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] in patients with high-risk DLBCL or large cell lymphoma.

There are data looking at combining the bispecific antibody [epcoritamab] with R-CHOP [rituximab plus CHOP] and the ORR [was] 100% [in 31 patients with high-risk DLBCL treated in the phase 1/2 EPCORE NHL-2 (NCT04663347) trial]. There are ongoing randomized trials in the first-line setting combining a bispecific antibody with R-CHOP vs R-CHOP in DLBCL [as well].

We dont know if bispecific antibodies will move into the first-line setting at [some] point, but in the relapsed/refractory setting the most logical treatment sequence will be to do CAR T-cell therapy followed by a bispecific antibody; that thought process may be different in follicular lymphoma because patients tend to be elderly, have medical problems, and, in general, the disease is not pacing too aggressively. [Therefore], patients may be more suited to receive a bispecific antibody first and followed by CAR T-cell therapy, but this is a moving field. We have to be open-minded [with] the capacity of these 2 technologies to see how were going to learn to sequence them better in the future.

NCCN. Clinical Practice Guidelines in Oncology. B-Cell Lymphomas, version 2.2024. Accessed July 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

Link:
Sequencing of Bispecific Antibodies vs CAR T-Cell Therapies is Dependent on Several Factors in DLBCL, Multiple Myeloma - OncLive

Six months after winning fast track status for multiple sclerosis, Kyverna Therapeutics KYV-101 has secured another US Food and Drug Administration (FDA) designation; this time, a regenerative medicine advanced therapy (RMAT) tag for the treatment of stiff-person syndrome.

An RMAT designation includes those benefits included in the fast track and breakthrough therapy pathways such as a priority review, along with early and enhanced FDA interactions. The RMAT tag also permits the use of surrogate endpoints in clinical trials studying the therapy, which can lead to accelerated approval.

Shares in the US biotech rose 9.5% at market open compared to a pre-announcement 15 July market close. Kyverna has a market cap of $427m.

Kyvernas KYV-101 is a CD19 chimeric antigen receptor (CAR)-T cell therapy designed for B cell-driven autoimmune disorders. It is currently being evaluated in a Phase II trial in patients with treatment-refractory stiff-person syndrome. The study, named KYSA-8, received the FDA greenlight last month.

The RMAT applications success was based on the positive clinical outcomes of KYV-101 in patients treated in Germany under a named patient treatment option, according to a 16 July press release.

Kyverna has not revealed further information about the US trial, with the biotechs CEO Peter Maag saying we are eager to begin generating data.

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Stiff-person syndrome is a progressive autoimmune disorder that causes muscle stiffness and spasms in the torso and limbs. Many patients can break bones from falling as they lack the necessary muscle reflexes for correction. It is not known what causes the disease.

Kyverna is considering cell therapy treatments beyond blood cancers, the space in which many CAR-T treatments are currently approved to treat. KVY-101 is being evaluated in sponsored Phase I/II and Phase II trials in the US and Germany in indications such as refractory lupus nephritis (NCT05938725), multiple sclerosis, and myasthenia gravis. The biotech reported positive Phase I results for the cell therapy in multiple sclerosis patients in April this year, the indication for which the drug has fast track status from the FDA.

In total, Kyverna says that 50 patients with cancer or autoimmune conditions have been treated with KYV-101 so far.

Kyverna went public earlier this year, raising $319m in the process. The initial public offering (IPO), which was larger than expected, saw the company sell 14.5 million shares for $22 each.

Cell & Gene Therapy coverage on Pharmaceutical Technology is supported byCytiva.

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Kyverna wins RMAT designation for stiff-person syndrome for cell therapy candidate - Pharmaceutical Technology

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Originally posted here:
Exploring treatment options in cancer: Tumor treatment strategies - Nature.com

The FDA has granted priority review of the biologics license application (BLA) for tabelecleucel (tab-cel) as a monotherapy to treat adult and pediatric patients two years of age and older with Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). The Prescription Drug User Fee Act (PDUFA) target action date is Jan. 15, 2025.

Lymphoproliferative disease is a rare but life-threatening complication after organ or stem-cell transplants. Many cases are associated with Epstein-Barr virus, accounting for more than 75% of post-transplant lymphoproliferative disease, according to one estimate. Most people have been infected with Epstein-Barr at some point in their lives. The immune suppression used after a transplant can reactivate the virus, causing B cells to grow uncontrollably.

There is no treatment available specifically for Epstein-Barr virus related post-transplant lymphoproliferative disease, but Rituxan (rituximab) and chemotherapy are often used to treat the disease.

Developed by Atara Biotherapeutics, tab-cel is an allogeneic, T-cell immunotherapy designed to target and eliminate cells infected with Epstein-Barr virus. If approved, it would be indicated for those patients who been treated with at least one other therapy.

The FDAs granting of priority review highlights the high unmet need in EBV+ PTLD, which is a devastating disease with limited treatment options and a poor overall survival rate, Pascal Touchon, president and CEO of Atara, said in a news release.

The BLA is supported by data from more than 430 patients treated with tab-cel across multiple life-threatening diseases, including the pivotal ALLELE study that met its primary endpoint. Interim data from this study found that 22 of 43 (51.2%) Epstein-Barr virus related post-transplant lymphoproliferative disease patients achieved an objective response rate (ORR). The median duration of response was 23 months and the median overall survival was 18.4 months.

Tab-cel was well tolerated with no reports of tumor flare reaction, cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, and there were no events of graft-versus-host disease or solid organ transplant rejection related to treatment. These data werepreviously presentedat the 2022 American Society of Hematology (ASH) Annual Meeting.

An updated analysis from the October 2023 data cut off of the ALLELE study continued to demonstrate a statistically significant 49% ORR. These data were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Tab-cel is approved in Europe with the brand name Ebvallo.

Atara has partnered with Pierre Fabre Laboratories for development, manufacturing, and commercialization rights in Europe and the United States. The FDAs BLA acceptance has triggered a $20 million milestone payment from Pierre Fabre Laboratories to Atara, with an additional $60 million milestone payment if approved by the FDA.

See original here:
FDA Sets Review Date for Cell Therapy for Post-Transplant Complication - Managed Healthcare Executive

Pluri Inc., a biotechnology company, has signed a tech transfer and manufacturing agreement with KadimastemLtd., a clinical stage biotechnology company developing therapeutic cells for ALS and diabetes treatments. PluriCDMO, launchedearlier this year, leverages Pluris 47,000 sq.-ft. GMP cell production facility to manufacture cell-based products for life science companies.

PluriCDMO will manufacture two cell therapy candidates for Kadimastem: AstroRx, clinical grade human astrocytes (nervous system supporting cells) for the treatment of ALS for an upcoming U.S. FDA Phase 2a study; and IsletRx, clinical grade pancreatic islet cells which produce and secrete insulin and glucagon in response to blood glucose levels, for the treatment of diabetes.

PluriCDMO offers experience in developing and manufacturing cell-based products in GMP grade for clinical use, from initial clinical trial batches to mass scale commercial production.

"Working with Pluri marks a pivotal milestone, enhancing Kadimastem's capacity to manufacture our products under GMP conditions, said Ronen Twito, Executive Chairman & President of Kadimastem, This collaboration is integral to our strategy as we prepare for clinical trials and expand into the US market with our AstroRx product candidate."

We are excited to work with Kadimastem and support their development of cell therapies, potentially improving the lives of patients with ALS and diabetes, said Yaky Yanay, Chief Executive Officer and President of Pluri. This collaboration underscores the versatility of our PluriCDMO platform and our commitment to aiding innovative companies in advancing their life-saving therapies. We look forward to a successful collaboration with Kadimastem as they progress their clinical development programs.

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Pluris CDMO To Manufacture Kadimastems Cell Therapy Candidates - Contract Pharma

Theres a frustrating fact about todays immunotherapies for cancer. While sometimes they work beautifully completely eliminating or greatly reducing cancer in particular patients other times they dont work at all. Its a mystery.

Scientists have posed several hypotheses to explain the disparity. Perhaps its the number of mutations present in a tumor, with more mutations leading to better responses. Or maybe its the tissue environment surrounding the tumor, with some environments supporting and others suppressing effective immune responses. But so far, none of these explanations has proved definitive or applicable in all cases.

Researchers at Memorial Sloan Kettering Cancer Center (MSK) and Baylor College of Medicine in Houston, Texas, now think they have a better explanation.

It turns out that in order for immune cells to effectively kill the cells of a tumor, they need to take on a specific spatial configuration, says Andrea Schietinger, PhD, a tumor immunologist and member of the Immunology Program in MSKs Sloan Kettering Institute. They need to form a triad.

Triad meaning three cells. But not just any three cells will do. What you need, she explains, is three different immune cells all collaborating together at the same time and in the same spot: one dendritic cell, one cytotoxic (killer) T cell, and one helper T cell.

These cells arent rare or unusual, immunologically speaking. Theyre the standard actors described in any immunology textbook. But up until now, no one knew that these cells needed to be physically present together in tumors in order to generate an effective immune response against cancer cells.

The discovery, which was published in the journal Cancer Cell on July 8, 2024, has immediate therapeutic implications and could alter the way doctors administer immunotherapies.

The main implication of our findings is that it's not the absolute numbers of cells that matters, it's their spatial configuration.

Dr. Andrea Schietinger, immunologist, Sloan Kettering Institute

Dr. Gabriel Espinosa-Carrasco

A postdoctoral fellow in the Schietinger lab, Gabriel Espinosa-Carrasco, PhD, is the first author on the new paper. What sparked Dr. Schietingers and Dr. Espinosa-Carrascos curiosity about this line of research was the abundant and frankly discouraging data from human clinical trials of adoptive T cell therapies. These are therapies in which researchers take a sample of cytotoxic T cells from a patient, identify ones that recognize the cancer, then expand those to billions of copies in the lab and return them to the patient. (Alternatively, scientists can engineer T cells in the lab to recognize specific targets and then expand and infuse those.)

The approach sounds logical; it should work, but it often doesnt.

How is this possible that we can generate the most perfect cytotoxic T cells in the lab, give patients billions of these cells, and yet they still fail to eliminate the cancer? Dr. Schietinger asks. There seems to be something so fundamental that we are missing about what cytotoxic T cells need to kill effectively.

In retrospect, she says, the answer seems obvious.

Scientists have known for a long time that cytotoxic T cells dont operate on their own. They need the assistance of helper T cells to become armed and activated. This is textbook knowledge, Dr. Schietinger points out.

Thats why, as she explains, every existing protocol where cytotoxic T cells are being activated and prepared for adoptive T cell therapy adds important chemicals made by helper T cells. At that point, the thinking goes, the cytotoxic T cells should be ready to fight cancer when they are infused back into the body.

A triad made of a killer T cell (red), helper t cell (green), and dendritic cell (yellow) unite to form a strong fighting force against cancer cells.

But what if cytotoxic T cells need the assistance of helper T cells not only early on to become armed and activated, but also to carry out their kill mission? Do cytotoxic T cells like James Bond need a license to kill? Dr. Schietinger wondered.

To find out, she and her team devised a mouse model of cancer that she could treat with a form of adoptive T cell therapy similar to those currently used with people. She set up two contrasting situations. In one case, she gave the mice with cancer only cytotoxic T cells. In the other case, she gave the mice both cytotoxic T cells and helper T cells. The results were clear and dramatic: only the mice that had received both types of T cells saw their tumors regress.

What this implies is that just having the cytotoxic machinery up and running is not really enough to do the actual killing, Dr. Schietinger says. You need to actually license them to kill the target cell.

How that licensing may occur became clearer when they looked at the tumor tissues from the mice under the microscope. Thats when they saw that in the mice that had responded to the treatment, their cells had formed the distinctive immune cell triads. The cells were physically nestled together. Somehow, Dr. Schietinger says, that spatial arrangement allows cytotoxic T cells to finally get the message: time to take action.

It was an interesting and exciting finding. But would it hold beyond the particular mouse model they used?

To answer that question, Dr. Schietinger and her team reached out to colleagues at Baylor College of Medicine, surgeons Hyun-Sung Lee, MD, PhD, and Bryan M. Burt, MD. That group had unpublished data on a group of patients with pleural mesothelioma, a type of lung cancer, who had been treated with a form of immunotherapy called immune checkpoint blockade. Within that group, some of the patients had responded well to the treatment, seeing their tumors shrink, while others did not.

When the surgeons at Baylor went back to look at tissue samples they had collected as part of the trial, they found that those patients who had responded to the therapy had the distinctive triads in their tumors. The ones who didnt respond did not have them.

That was pretty compelling evidence that the immune triads were indeed important, and not just a coincidence. The three types of immune cells interact in such a way that makes them a stronger fighting force against cancer cells.

What are the implications of all this? First, says Dr. Schietinger, there is the possibility that these triads could be used as a biomarker for identifying which individuals are likely to respond to immunotherapy. So far, doctors do not have good biomarkers to make that distinction.

Second, the results imply that doctors should rethink how they administer adoptive T cell therapies. Instead of giving predominantly killer T cells, perhaps they should include helper T cells too; and maybe much fewer killer T cells would be enough if there were helper T cells in the mix as well.

Lastly, the results have implications for the design of cancer vaccines, where fragments of cancer-associated proteins are designed to boost patients killer T cells.

Dr. Schietingers team is working to advance research in all these directions. For example, one member of her team, a bioengineer, is designing tools to connect one killer T cell to one helper T cell, to encourage their formation of a triad with a dendritic cell (the cell type responsible for presenting fragments of cancer proteins to T cells).

Theyre also experimenting with new formulations of cancer vaccines and are partnering with other leaders in the field to bring this work to clinical trials.

The main implication of our findings is that its not the absolute numbers of cells that matters, its their spatial configuration, Dr. Schietinger says. The three cell types need to be on the battlefield together, and building therapeutics which do that is our next big goal.

Additional authors on the study include: Edison Chiu and Asim Dave of MSK; Matthew Hellmann of MSK and Weill Cornell College of Medicine (now at AstraZeneca); Aurora Scrivo of the Albert Einstein College of Medicine; Paul Zumbo and Doron Betel of Weill Cornell Medicine; and Sung Wook Kang and Hee-Jin Jang of Baylor College of Medicine.

This work was supported by NIH grants DP2CA225212 and R01CA269733, a Lloyd Old STAR Award of the Cancer Research Institute, an AACR-Bristol-Myers Squibb Midcareer Female Investigator Award, the Pershing Square Sohn Award, the Josie Robertson Young Investigator Award, the Weill Cornell Medicine Core Laboratories Center, a Ludwig Cancer Center Postdoctoral Fellowship, NIH Merit Award R37CA248478, Cancer Prevention and Research Institute of Texas Grant CPRIT RP200443, Department of Defense Peer Reviewed Cancer Impact Award CA210522, NIH R21AI159379, the Helis Medical Research Foundation, the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (NCI P30CA125123 and NCRR S10RR024574) and CPRIT (RP180672), the MSKCC-Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Jose and Henry R. Kravis Center for Molecular Oncology.

Dr. Hellmann is currently an employee and shareholder at AstraZeneca. Dr. Burt received funding from AstaZeneca for the clinical trial related to this project, clinical trial funding from Momatero-Gene, and clinical trial funding from Novartis.

Read the study: Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors, Cancer Cell. DOI: 10.1016/j.ccell.2024.05.025

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Better Together: Spatial Arrangement of Three Immune Cells Is Key to Attacking Tumors - On Cancer - Memorial Sloan Kettering

Through its Myeloma Investment Fund, the Multiple Myeloma Research Foundation (MMRF) has invested $1 million in novel CAR T-cell technology from Dynamic Cell Therapies (DCT) that aims to better treat multiple myeloma.

Backed by this investment, DCT remains on track to move a new CAR T-cell therapy into clinical testing in people with relapsed and refractory multiple myeloma over the next two years.

The support of the MMRF & the Myeloma Investment Fund provides key expertise that will enable us to hasten the development of novel and best-in-class CAR-T cell therapies for patients with relapsed and refractory multiple myeloma, Fred Mermelstein, PhD, DCTs CEO, said in a company press release.

According to the release, DCT is developing technology platforms that will allow CAR-T cells to attack unique tumor targets that will allow for durable responses to treatment.

Multiple myeloma is a blood cancer in which abnormal plasma cells a type of immune cells that produce antibodies grow out of control in the bone marrow and crowd out normal immune cells that help fight infection, causing the diseases symptoms.

Despite the therapeutic options available, multiple myeloma can be difficult to treat because it often is refractory, meaning it does not respond well to therapy or becomes resistant to it. Additionally, the cancer often is relapsing, meaning it returns after treatment.

CAR T-cells have emerged as a therapeutic option for many types of blood cancer, including multiple myeloma. This type of therapy involves modifying a patients immune T-cells with a chimeric antigen receptor, or CAR, that can recognize specific cancer proteins.

These modified T-cells are then infused back into the patients blood, where they travel toward cancer cells and destroy them.

But despite the benefits seen with the recently approved CAR T-cell therapies Carvykti (ciltacabtagene autoleucel) and Abecma (idecabtagene vicleucel), many patients with multiple myeloma still relapse after therapy, Mermelstein said.

In addition, overactive CAR T-cells often lead to side effects and dose-limiting toxicities.

To overcome these issues, DCT developed a CAR T-cell technology in which cancer cell targeting is uncoupled from CAR T-cell activation. These CAR T-cells recognize a chemically inactive small molecule that is conjugated, or bound, to an antibody that targets a specific cancer molecule.

When they bind to the small molecule-antibody conjugate bound to cancer cells, CAR T-cells release proteins that form holes in the cancer cells membrane, leading to their death. At the same time, activated CAR T-cells release immune signaling molecules that recruit other immune cells to fight the cancer.

By controlling the amount of the small molecule-antibody conjugate that is given to a patient along with CAR T-cells, physicians are expected to be better able to control the cells activity, reducing the risk of side effects.

For example, administering higher doses of the antibody conjugate will boost the immune attack against cancer, while lower doses will minimize harm to normal cells.

Further, the same small molecule can be conjugated to different antibodies targeting other cancer molecules, which could improve CAR T-cells ability to kill cancer cells, even when mutations arise as a mechanism to escape the effects of CAR T-cell therapies.

At the MMRF, we are deeply committed to advancing novel treatments intended to improve patient outcomes and get us closer to cures. We are energized by DCTs cutting-edge cell therapy approach as a potentially transformative answer to patients with relapsed or refractory myeloma.

Preclinical work led by researchers from DCT showed that small molecule-activated CAR T-cells expanded more rapidly in number, produced more immune molecules, and were better at killing cancer cells. In a mouse model of multiple myeloma, these CAR T-cells showed better long-term cancer control than did Carvykti and Abecma alone.

At the MMRF, we are deeply committed to advancing novel treatmentsintended to improvepatient outcomes and get us closer to cures, said Michael Andreini, MMRFs president and CEO.

We are energized by DCTs cutting-edge cell therapy approach as a potentially transformative answer to patients with relapsed or refractory myeloma, Andreini added.

The Myeloma Investment Fund is a philanthropy fund that provides financial and strategic support to advance new potential therapies for multiple myeloma. All of its profits are reinvested into ongoing research until a cure is found.

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MMRF invests $1M to advance DCTs new CAR T-cell therapy - Myeloma Research News

In November 2023, the FDA first warned about the risk of T cell malignancies after treatment with CAR T cell therapies, which are used to treat patients with lymphoma and leukemia. In April 2024, regulators concluded that T cell malignancies may present soon after treatment and may be fatal. The FDA began requiring approved CAR T therapies to have a boxed warning about this risk.

Now a new study, published last month in The New England Journal of Medicine, highlights work from researchers at Stanford Medicine. They analyzed patients at Stanford Health Care who were treated with a CAR T-cell therapy between 2016 and 2024.

They found that the risk of secondary blood cancers after treatment with a CAR-T cell therapy is low and may not be related to the CAR T-cells. In their study of 724 patients just 6.5% patients had a secondary malignancy in the three years after therapy. One patient died.

Stanford researchers said this was likely due to the immunosuppression caused by CAR-T cell therapy, rather than the CAR-T cells themselves. They theorize that the compromised immune system allowed preexisting, but not previously detected, cancer cells to grow.

Ash Alizadeh, M.D., Ph.D.

We compared protein levels, RNA sequences and DNA from single cells across multiple tissues and time points to determine that the therapy didnt introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels, professor of medicine Ash Alizadeh, M.D., Ph.D., a member of the Stanford Cancer Institute, said in a news release.

Currently, there are six approved CAR T-cell therapies:

For these therapies, a patients own immune T cells are engineered to seek out cancer cells. These T cells encode for the protein chimeric antigen receptor, which binds to cancer cells.

In the Stanford study, the person who died was treated with Yescarta for diffuse large B-cell lymphoma. Researchers profiled both the original and the secondary lymphoma and found that each were molecularly and genetically distinct. Both lymphomas, however, were positive for EpsteinBarr virus, a virus known to cause cancer. The patient also had a history of autoimmune disease.

These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy, David Miklos, M.D., Ph.D., professor of medicine and chief of bone marrow transplantation and cellular therapy at Stanford, said in the news release. Understanding how it contributes to cancer risk is particularly important as the CAR-T cell field pivots from treating high-risk, refractory blood cancers to lower risk, but clinically important, disorders including autoimmune diseases.

Read more from the original source:
Stanford Study Finds Low Risk of Secondary Cancer with CAR T Therapy - Managed Healthcare Executive

Stiff person syndrome a rare, progressive disorder that causes painful muscle spasms can be treated with a therapy typically used for cancer, a new case report suggests.

In stiff person syndrome (SPS), the immune system attacks a key protein in the nervous system. The condition is rare, affecting fewer than 5,000 people in the U.S., but it recently gained attention when Canadian singer Cline Dion announced she had SPS.

Those most severely affected by SPS develop progressively worse muscle stiffness, eventually leaving them bedbound, while chest spasms can sometimes hinder their breathing. There is currently no cure for SPS, only treatments to subdue the symptoms but these don't always help.

Now, a case study published in June in the journal PNAS highlights a potential new treatment for people with SPS.

Related: Women have 4 times men's rate of autoimmune disease. The X chromosome may be to blame.

One of the greatest challenges people with SPS deal with is getting a diagnosis, because the disease is rare and its symptoms resemble those of other disorders. In 2014, Dr. Simon Faissner, a neurologist in the St. Josef Hospital at the Ruhr University of Bochum, met the patient featured in the case report. She reported stiffness and pain when moving, but her case notes said that previous physicians thought her symptoms were psychosomatic brought on by a psychological condition.

Faissner performed a lumbar puncture test, revealing that the patient's cerebrospinal fluid, which circulates through the spinal cord and the brain, was packed with antibodies against a protein called glutamic acid decarboxylase (GAD). GAD is needed to make GABA, a chemical messenger that helps tamp down neuron activity. Without it, the brain fires off signals at an excessive rate, leading to the muscle cramps and stiffness seen in SPS.

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Following her diagnosis, the patient started therapies that dampened these GAD-targeting antibodies and stabilized her condition for several years. However, by 2023, her condition had deteriorated, leaving her unable to walk for a time.

To try and alleviate some of the patient's symptoms, Faissner and Dr. Jeremias Motte, another St. Josef Hospital neurologist, decided to use a new treatment: an adapted CAR T-cell therapy.

This treatment uses immune cells called T cells, which hunt down and kill abnormal and diseased cells in the body. The therapy involves removing some of a patient's T cells and tweaking them to take aim at a specific target typically cancer.

However, in the new case report, the researchers aimed CAR T cells' crosshairs at antibody-producing immune cells, called B cells. This approach had previously been tried as a treatment for an autoimmune condition called lupus nephritis, but Faissner and Motte wanted to see if it could help their SPS patient.

Existing SPS therapies also target B cells but less thoroughly. "It's not such a deep depletionof B-cells," Motte told Live Science. "Not so deepin the lymph nodes and not so deep in the organs, muscles or in the bone marrow."

The idea is that CAR T-cell therapy eliminates the disease-driving B cells but leaves behind a population of "baby B cells," Motte said. These then repopulate the body without making harmful antibodies.

"It's like a rebooting of a computer system," Faissner told Live Science. "Theproblematic immunological system should be erased [following the therapy]."

The treatment had a rapid effect, the team revealed in the case report. The patient had recovered some ability to walk prior to getting the therapy, and within six months of the one-time treatment, her walking speed doubled. She was still fatigued and stiff, but she went from walking only several yards to around 4 miles (6 kilometers) a day.

The patient was also able to discontinue all other immunotherapies and reduce her use of benzodiazepines, which help make up for lost GABA function.

"It's an impressive improvement," Marinos Dalakas, a neurologist at Thomas Jefferson University who developed one of the first immunotherapies for SPS back in 2001, told Live Science.

Dalakas, who was not involved in the case, pointed out that the new treatment remains experimental. Future trials will have to expand on the limited data offered by a single case study. He also noted that there's a mid-stage clinical trial of a different CAR T-cell therapy for SPS happening, although it will be some time before any results are available.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to community@livescience.com with the subject line "Health Desk Q," and you may see your question answered on the website!

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Rare 'stiff person syndrome' treated with reconfigured cancer therapy - Livescience.com

Alexandra Gomez Arteaga, MD, hematologist/oncologist in the bone marrow transplant and cellular therapy program at Weill Cornell Medicine in New York, New York, discusses the rationale behind a retrospective study comparing Orca-T with posttransplant cyclophosphamide-based hematopoietic cell transplantation using data from existing studies that involved similar patient populations.

Arteaga also discusses the mechanism of action of Orca-T, a novel cell therapy under investigation. The agent works by leveraging regulatory T cells from allogeneic donors to control graft-vs-host disease (GVHD).

Transcription:

0:09 | Our field in allogeneic stem cell transplantation is changing, and we now have new ways of doing GVHD prophylaxis. The posttransplant cyclophosphamide studies and the platform have shown significant reduction in chronic GVHD. There might be other ways that we can improve outcomes by reducing other important things such as toxicities and relapse.

0:31 | Orca-T is a high precision immunotherapy that is a more organized fashion to create immune reconstitution. Based on the new changes in post transplant cyclophosphamide, we wanted to compare Orca-T [with] posttransplant cyclophosphamide since we currently are doing a study with Orca-T against the standard of care.

0:52 | With the current allografts, there are over 50 cell types that are infused together, and we have no control over how these cells interact for engraftment. Orca-T immune reconstitution, on the other hand, is the high-precision immunotherapy where the cells are in manufacture and divided into 3 main components. The first component is hematopoietic stem cells. The second component is highly purified T regulatory cells. The third component is the conventional cells.

1:20 | With this high precision immunotherapy, we can give the patient the exact number of cells at the exact time. On day 0, the patients get the stem cells from the T regulatory cells and these the regulatory cells are going to have an optimal immunomodulatory environment so that there's less GVHD. There is more organization of how the immune reconstitution happens.

Read the rest here:
Advancements in Stem Cell Transplantation: Comparing Orca-T With PTCy - Targeted Oncology