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Ajai Chari, MD; Alfred Chung, MD; Adriana Rossi, MD

Applying New Evidence in Multiple Myeloma Care from Frontline to R/R Disease

Andre H. Goy, MD; Sandra M. Swain, MD, FACP, FASCO Associate Dean for Research; Carolina Bernabe Ramirez, MD; Jonathan E. Rosenberg, MD; David H. Vesole, MD, PhD, FACP Director, Myeloma Program; Isabel Preeshagul, DO, MBS  
 

Community Practice Connections™: 5th Annual Precision Medicine Symposium – An Illustrated Tumor Board

Annual Hematology Meeting: Preceding the 66th ASH Annual Meeting and Exposition

Joseph R. Mikhael, MD, MEd, FRCPC, FACP; Ajai Chari, MD; Caitlin Costello, MD; Krina Patel, MD, MSc

Translating New Evidence into Treatment Algorithms from Frontline to R/R Multiple Myeloma: How the Experts Think & Treat

George M. Rodgers III, MD, PhD; Patricia A. Ford, MD; Sidharth Anand, MD, MBA

Medical Crossfire: How Has Iron Supplementation Altered Treatment Planning for Patients with Cancer-Related Anemia?

Nicole Lamanna, MD; William Wierda, MD, PhD; Jennifer A. Woyach, MD

Medical Crossfire®: The Experts Bridge Recent Data in Chronic Lymphocytic Leukemia With Real-World Sequencing Questions

Andre H. Goy, MD; Marco L. Davila, MD, PhD; Ajay K. Nooka, MD, MPH, FACP

Community Practice Connections™: Pre-Conference Workshop on Immune Cell-Based Therapy

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

™ Oncology specialty topic page highlights the latest clinical care news related to the development of cell therapies, gene therapies, and engineered and regenerative medicines for various cancers. It also houses video interviews with key opinion leaders in the field of oncology speaking to the related FDA actions, clinical guideline updates, and clinical trial findings in the field of gene and cell therapy for oncologic diseases.

The company also discontinued its other clinical programs as well, which included small molecule and monoclonal antibody modalities.

Oncternal Therapeutics Axes B-Cell Lymphoma Trial for CAR-T Therapy ONCT-808

Review top news and interview highlights from the week ending September 13, 2024. 

CGTLive®’s Weekly Rewind – September 13, 2024 

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – September 11, 2024

Xandra Breakefield, PhD, an investigator of neurology at Mass General Research Institute, discussed research from her grad student, Lisa Nieland, presented at the ASGCT 2024 meeting.


Trying New Approaches to AAV Therapy for Glioblastoma

Lisa Nieland, a PhD candidate from Lieden University Medical Center and Breakefield Lab at Mass Gen, discussed her work presented at the ASGCT 2024 meeting.


Slowing Tumor Growth in Glioblastoma With Novel AAV Therapy

The chief executive officer of Tessera Therapeutics discussed ongoing research into developing its platform for sickle cell disease, CAR T-cell therapy, and more. 

Michael Severino on In Vivo Gene Editing With RNA Gene Writers 

“Our programs are based on a platform that we call our RNA gene writers. So, our RNA gene writers modify DNA, but they do it using all RNA constructs. So, the protein that does the work is delivered as an mRNA, and the template which contains the instructions is an RNA, and that enables a number of advantages.”

Tessera Therapeutics is aiming to develop effective and safe in vivo, nonviral gene and cell therapies, which could eliminate issues inherent with current modes of approved gene therapies such as ex vivo chimeric antigen receptor (CAR) T-cell therapies and adeno-associated virus (AAV) therapies. The company presented on a number of these programs at 

the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting

, held May 7 to 10, 2024, in Baltimore, Maryland.

spoke with Michael Severino, chief executive officer, Tessera, while at ASGCT to learn more about the company’s RNA gene writing platform and the promising advantages it might offer for a variety of different fields and indications. He overviewed research Tessera is conducting into using its platform for sickle cell disease and for in vivo generation of CAR T-cell therapies for oncologic indications. He also shared validation data on the platform in mouse models that were presented at the meeting.

1. Palchaudhuri R, Gupta M, Monte MT, et al. In Vivo RNA Delivery to T Cells and Hematopoietic Stem Cells in Humanized Mice and Non-Human Primates Using Targeting Lipid Nanoparticles. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #132
2. Stein KT, Rodriguez J, Johnson L, et al. A Same-Day Manufacturing Platform Leveraging an RNA-Based Lipid Nanoparticle (LNP) Gene Writer System to Generate Chimeric Antigen Receptor (CAR) T Cells. ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #379
3. Schiroli G, Heshmati Y, Cao Y, et al. In Vivo HSC Gene Editing for Correction of Sickle Cell Mutation Using RNA Gene Writers. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #280

Videos

The Don and Marilyn Anderson Professor of Oncology at University of Wisconsin – Madison discuss the state of cell and gene therapy development. 

Jacques Galipeau, MD, on Exponential Progress With Cell and Gene Therapy 

"Ten years ago, we were starting clinical trials. There was really no meaningful number of approved cell therapies in international jurisdictions. Fast forward a decade, now we have at least 6 key products that are approved, gene engineered stem cells have been approved. TILs have been approved, and the regulators are telling us that they anticipate that the number of approvals is going to grow every year. So now we have approved therapies and it’s not theoretical, and that's expanding. And there's this whole pipeline behind it.”

Jacques Galipeau, MD, Don and Marilyn Anderson Professor of Oncology at University of Wisconsin – Madison, and president, International Society for Cell and Gene Therapy (ISCT), chaired the presidential plenary of this year’s meeting, held in Vancouver, Canada, from May 29 - June 1. The plenary brought together leaders of sister scholarly societies to discuss cell and gene therapy development including Anna Sureda, MD, PhD, president of European Society for Blood and Marrow Transplantation; Amander Clark, PhD, president, International Society for Stem Cell Research; and Corey Cutler, MD, MPH, FRCP(C), president, American Society for Transplantation and Cellular Therapy. The speakers discussed challenges with cell and gene therapies and their current state of development, within each country and internationally.

® spoke with Galipeau to learn morethe state of gene and cell therapy investigations and development. He emphasized the progress in the field over the last 10 years, and how the number of novel approvals is expected to keep growing. Accordingly, he noted that the ISCT meeting is growing in attendance every year, and this year’s meeting, which was the 30th anniversary meeting, broke the record for attendance so far.

Galipeau J, Sureda A, Clark A, Cutler C. La présidentielle. Presented at: ISCT 2024 Meeting, held in Vancouver, Canada, from May 29 – June 1.

The Don and Marilyn Anderson Professor of Oncology at University of Wisconsin – Madison discussed the state of cell and gene therapy development. 

The associate professor of medicine at University of Colorado discussed data presented at ASCO 2024. 

Manali Kamdar, MD, on Liso-Cel's Ongoing Benefit in the Treatment Lanscape for LBCL 

“Especially with follicular lymphoma, the response rates are just stellar. The median follow up is a little under 3 years right now, but at this point in time, the median duration of response and responders [are great]. Personally, for the people I enrolled on the trials, they're all in a complete remission, they've gone back to life, they have not relapsed. They're young patients and older patients across all age groups. It's really gratifying as a clinical trial to see just the power of the construct.”

Lisocabtagene maraleucel (liso-cel), approved under the name Breyanzi for patients with primary refractory/relapsed (r/r) large B-cell lymphoma (LBCL) based off of data from the phase 3 TRANSFORM (NCT03575351) and TRANSCEND trials (NCT02631044), continues to demonstrate deep and durable responses in patients with r/r LBCL and superiority over standard of care.

Manali Kamdar, MD, associate professor of medicine – hematology, University of Colorado School of Medicine - Anschutz Medical Campus, and UCHealth Blood Disorders and Cell Therapies Center, investigator on TRANSCEND, TRANSFORM, and other investigations on liso-cel, presented updated, 3-year data from TRANSFORM at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 31 to June 4, in Chicago, Illinois. CGTLive® spoke with Kamdar to learn more about liso-cel's ongoing benefit in the treatment landscape of LBCL. She also shared her enthusiasm for data presented on liso-cel for treating Richter transformation.

Click here to view more coverage from the 2024 ASCO meeting.

1. Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagenemaraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7013
2. Winter AM, Bharadwaj S, Herrera AF, et al. Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR). Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7010

The associate professor of medicine at University of Colorado discussed findings from subgroup analyses of liso-cel.  

Manali Kamdar, MD, on The Importance of Bringing Liso-Cel to Earlier Lines of Lymphoma Treatment 

"We see, based on these subgroup analysis, that patients do really well, but for patients who are heavily treated with5 or more lines of prior treatment, I think, given that the liso-cel efficacy goes slightly lower, it's really important to keep bringing these constructs ahead in the algorithm for managing management of mantle cell lymphoma, because so far, it remains a fairly heterogeneous disease. It is certainly treatable but there are definitely not many cures out there, so I do believe that it's important that constructs like liso-cel, if brought early on, will show better efficacy and thus better duration of remission, thus better progression free survival, and then hopefully better overall survival.”

Lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T-cell therapy FDA-approved for patients with heavily pretreated mantle cell lymphoma, has demonstrated its ability to yield durable complete responses for this indication.

 Subgroup analyses of outcomes after liso-cel in these patients were presented at the 

, held May 31 to June 4, in Chicago, Illinois.

 The subgroup analyses were conducted according to prior lines of therapy and prior Bruton tyrosine kinase inhibitor treatment.

 spoke with study coauthor Manali Kamdar, MD, to learn more about the findings from the subanalyses. She emphasized that given the lower efficacy seen in patients with 5 prior median lines of therapy, it is important to bring liso-cel to earlier lines of treatment.

1. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s Breyanzi as a New CAR T Cell Therapy for Relapsed or Refractory Mantle Cell Lymphoma. News release. FDA. May 30, 2024. Accessed May 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma
2. Palomba ML, Siddiqi T, Gordon LI, et al. Lisocabtagenemaraleucel (liso-cel) in patients (pt) with R/R mantle cell lymphoma (MCL): Subgroup analyses by number of prior systemic lines of therapy (LOT) and by response to prior Bruton tyrosine kinase inhibitor (BTKi) from the TRANSCEND NHL 001 MCL cohort (TRANSCEND-MCL). Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7016

The PhD candidate from Lieden University Medical Center and Breakefield Lab at Mass Gen discussed her work presented at the ASGCT 2024 meeting. 

Lisa Nieland on Slowing Tumor Growth in Glioblastoma With Novel AAV Therapy 

“I think in that window, we would be able to combine current available therapies to target the tumor at the same time, so with a combinational treatment to hopefully then have a better outcome and better effect because until now, the chemo is just not doing its job, unfortunately. So maybe we can create this kind of niche window that we then can have an improved outcome, hopefully. That's the whole aim.”

Glioma, and specifically the most aggressive typeglioblastoma, have historicallyvery poor outcomes, with a 1-year survival rate of 40% and a 2-year survival rate of 17%. The disease occurs inthe inherently challenging environment of the brain and is a difficult one to treat, with investigations into targeted therapies often running into obstacles with the blood brain barrier and potential neurotoxicity.

Lisa Nieland, a PhD candidate from Lieden University Medical Center, is doing her PhD on interactions between the healthy brain cells and the tumor in the glioma tumor microenvironment. She presented some of her research, being conducted at the lab of Xandra Breakefield, PhD, investigator of neurology, Mass General Research Institute, and professor of neurology, Harvard Medical School, at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, Maryland.

Nieland investigated adeno-associated virus (AAV) delivery of Staphylococcus aureus Cas9 (saCas9) guided by a single-guide RNA to target microRNA-21 (miR-21) coding sequences in the genome in vivo and found reduced tumor growth and improved survival in mouse models. miR-21 is highly expressed in glioma cells responsible for tumor progression.

spoke with Nieland to learn more about the background behind her research and the potential impact she foresees this work may lead to in the glioma field.

1. Glioblastoma Multiforme. Webpage. 2024. American Association of Neurological Surgeons. https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme
2. Nieland L, Vrijmoet AB, Jetten IW, et al. All-in-One Adeno-Associated Virus Delivery for Therapeutic miR-21 Editing by saCas9 In Vivo. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #113

The associate professor of medicine at University of Colorado discussed how the field has shifted to support the growing use of CAR Ts and progress to come. 

Manali Kamdar, MD, on Acclimating to Routine CAR T Practice in the Field 

“I think experience is very important. I will say that academic centers, where I practice, we have a well-oiled machinery in terms of resources, staffing, in order to successfully take patients through CAR-T cell therapy, so the wariness around toxicities, finagling logistics, especially payer authorization, and all of that, I think we have ways to circumvent the delays. So, it's certainly very important to build around this experience with regards to the uptake of CAR T-cell therapy. In the community setting, I feel liso-cel is an excellent choice because it's a very manageable CAR-T cell therapy, wherein we feel comfortable after giving the initial CAR T cell therapy and initial observation period to transfer patients back to the community physicians, because the majority of patients don't experience cell therapy related toxicities.”

Lisocabtagene maraleucel (liso-cel), approved under the name Breyanzi for patients with refractory/relapsed (r/r) large B-cell lymphoma (LBCL), has continued to demonstrate deep responses and superiority over standard of care.

Updated, 3-year data from TRANSFORM were presented at the 

, held May 31 to June 4, in Chicago, Illinois, by Manali Kamdar, MD, associate professor of medicine – hematology, University of Colorado School of Medicine - Anschutz Medical Campus, and UCHealth Blood Disorders and Cell Therapies Center. 

® spoke with Kamdar to learn more about her experience administering chimeric antigen receptor (CAR) T-cell therapies in an academic center. She stressed that as the field gets more used to CAR T-cell therapies, their administration has become more routine and streamlined for patients, with better education and community access.

Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7013

The associate professor of medicine at University of Colorado discussed a post hoc analysis study on subgroup analyses of liso-cel response. 

Manali Kamdar, MD, on Evaluating Liso-Cel in Mantle Cell Lymphoma by Lines of Therapy, Prior BTKi 

“We got to present the subgroup analysis of the Transcend-NHL-001 mantle cell lymphoma cohort study. This is a study that investigated lisocabtagene maraleucel in patients with relapsed refractory mantle cell lymphoma. And this is actually a post hoc analysis of patients based on number of prior lines of therapy, as well as by response to prior Bruton tyrosine kinase inhibitor.”

Lisocabtagene maraleucel (liso-cel) has demonstrated its ability to yield durable complete responses in patients with heavily pretreated mantle cell lymphoma and was FDA-approved for this indication in May 2024.

Subgroup analyses of outcomes after liso-cel in these patients according to prior lines of therapy and prior Bruton tyrosine kinase inhibitor treatment were presented at the 

CGTLive spoke with study coauthor Manali Kamdar, MD, to learn more about the subanalyses and its goal. She went over the different stratified groups, their treatment history, and disease characteristics.

The associate professor of medicine at University of Colorado discussed data in the primary relapsed LBCL setting. 

Manali Kamdar, MD, on Bringing Liso-Cel to Earlier Lines of Treatment 

“Investigating liso-cel even earlier, besides just waiting for the patients to relapse, and then give it to them makes a lot of sense. But I feel it absolutely needs to be tested with scientific rigor within a clinical trial setting. There is some data that's emerging where we could bring liso-cel if interim PET scans are partial response or stable disease. And I think that may be the next opportunity to showcase the strength of liso-cel in terms of bringing it to earlier line settings.”

Lisocabtagene maraleucel (liso-cel) has continued to demonstrate deep responses in patients with primary refractory/relapsed (r/r) large B-cell lymphoma (LBCL) and superiority over standard of care. The therapy is approved under the name Breyanzi for patients with r/r LBCL based off of data from the phase 3 TRANSFORM (NCT03575351) and TRANSCEND trials (NCT02631044).

Updated, 3-year data from TRANSFORM were presented by Manali Kamdar, MD, associate professor of medicine – hematology, University of Colorado School of Medicine - Anschutz Medical Campus, and UCHealth Blood Disorders and Cell Therapies Center at the 

, held May 31 to June 4, in Chicago, Illinois. 

® spoke with Kamdar to learn more about moving liso-cel and other chimeric antigen receptor (CAR) T-cell therapies to earlier lines of therapy.

Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagenemaraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #7013


The professor from Cedars Sinai discussed further research being conducted in the field after lifileucel’s approval. 

Omid Hamid, MD, on Assessing TIL Combination Therapies, Expanding Past Melanoma 

“The message here is that we've made major discoveries that give benefit to our patients. And we've moved past the idea that these are standalone therapies. Our current clinical trials are looking at not only combinations, but combinations of different modalities together. So, the future is bright in the care of patients with advanced melanoma of any type, uveal, mucosal, acral, and for all solid tumors.”

The FDA took a big leap forward in the field of cell therapy with the February 2024 approval of Iovance Biotherapeutics’ lifileucel for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, or treated with a BRAF inhibitor with or without a MEK inhibitor in the instance that the patient is if BRAF V600 positive. The tumor-infiltrating lymphocyte (TIL) therapy, marketed under the name Amtagvi, is the first cell therapy approved for solid tumors and comes with a price tag of $515,000 yearly.

® spoke with Omid Hamid, MD, professor and director, Melanoma Program, Cedars-Sinai and chief, Translational Research and Immunotherapy, The Angeles Clinic and Research Institute, who served as a principal investigator on the pivotal trials (NCT02360579; NCT05727904) of lifileucel that supported the accelerated approval. Hamid spoke about the landmark approval of lifileucel as well as other trials that his center is involved in dealing with TIL therapies for other indications including non-small cell lung cancer. He also discussed further research looking into combinations of TILs with natural killer cells and bispecific antibodies. He shared his excitement that more research will likely expand and lengthen already encouraging responses seen with lifileucel alone for patients with melanoma and other solid tumors.

FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed February 16, 2024.

The scientist from Krembil Research Institute shared takeaways from the session she chaired. 

Sowmya Viswanathan, PhD, on Translating Cell Therapies to the Clinic at ISCT 2024 

“It was a really nice session, because it showed this kind of progression from a simpler product and design to sort of more and more complex products, and what that means in terms of challenges for the companies, how to raise money and how to get return on investment, so from a commercial perspective, but also on the clinical side, what it means to follow patients for long term, and what it means from kind of manufacturing and the process development, and how complex that is to generate these products.”

The Translation to Clinic plenary of the International Society for Cell and Gene Therapy (ISCT) 2024 Meeting, held in Vancouver, Canada, from May 29 - June 1, brought together sponsors developing cell and gene therapies in the clinical stage and earlier research stage, including Sai Kiang Lim, PhD, from A*Star Institute of MolecularBiology in Singapore; Marcus Yountz, MD, FAAN, from BlueRock Therapeutics, and Bob Velamehr, PhD, from Fate Therapeutics, with Sowmya Viswanathan, PhD, scientist, Osteoarthritis Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Krembil Research Institute, University Health Network) andAssociate Professor, Institute of Biomedical Engineering and, Division of Hematology, Department of Medicine, University of Toronto chairing the session, to discuss the development process.

® spoke with Viswanathan to learn more about the plenary. She shared the perspectives that each speaker brought to the discussion, including Lim’s early work with extracellular vesicles, BlueRock’s experiences with developing its cell therapy for the potential treatment of Parkinson disease, and Fate Therapeutics’ work with gene-edited cell therapies.

Viswanathan S, Valamehr B, YountzM, Lim SK. Translation to Clinic Plenary. Cell Therapies: Coming of Age, No Longer Just a Concept. Presented at: ISCT 2024 Meeting, held in Vancouver, Canada, from May 29 – June 1.

The last thing that I might add is something that’s decidedly nonimmunologic and that’s that I think we really have to make sure, as a field, and I think this has to be a collaboration between developers and physicians and even payers, both government and private payers, is to make sure that we have access to these therapies.

One of the things that I’ve seen and have been increasingly thinking about is systems and how we succeed is a troubling trend that, first, not everybody has equal access in this country. That’s dictated by racial and socioeconomic and structural features as well as in part by the cost of these therapies and the difficulty of getting them to people. And as we look at individuals, for example, who have received all T-cell therapies including giving CAR T therapies, you start to see more skewing; in other words, traditional factors that affect access, whether it’d be racial or socioeconomic, tend to be exaggerated as we have these high-cost complex technologies that require not being treated in the rural center where you live but getting to an expert like you or me at the H. Lee Moffitt Cancer Center, Tampa, Florida or UCSF [University of California, San Francisco] where you have to take some effort to get there. And it’s going to be harder. Individuals who historically had access barriers whether culturally, educationally, or economically are less likely to get to us.

I would say you’re absolutely right. I don’t think I can add to your thoughtful summary of the immunologic issues, but I want to make sure as we move forward that we do everything we can to make sure that these therapies, which are breakthrough therapies, are keeping people alive longer, already in clinical trials, and will do so even more once they’re approved, get to everybody, and that we work as hard as we can in a collaborative way to make that happen.

I think that’s a great way to end this session. I’d like to thank 

®for having afforded us the opportunity to get TIL [tumor-infiltrating lymphocyte] cell therapy to the forefront. And I’d like to thank my colleague, Krishna Komanduri MD, for sharing his excellent expertise.

Thank you. My brilliant pleasure, and I want to join you in thanking the 

® group and our audience for paying attention this long. Thanks so much.

Closing out their discussion on TIL therapy, Drs Sarnaik and Komanduri identify existing barriers to TIL use in clinical practice and how the field might optimize patient access to these regimens.

Overcoming Barriers to TIL Use in Patients With Solid Tumors

Well, that’s a great segue into our final topic, and that involves future directions. Are there any interesting ongoing either trials or data or concepts that you look forward to seeing with regards to the TIL [tumor-infiltrating lymphocyte] space?

I would say the first thing is that we shouldn’t underestimate the importance of this moment. I mean, it’s been a long time coming. We’ve been talking about cell therapies and gene therapies for a long time, axi-cel [axicabtagene ciloleucel], tisagenlecleucel, and ide-cel [idecabtagene vicleucel] have been absolutely transformative in the setting of CD19 diseases. And lately, we have really remarkable successes in the context of BCMA [B-cell maturation antigen] approaches and now we have TIL therapies. I do think one of the things that we’re going to have to look for is how therapies that require bespoke manufacturing like CAR [chimeric antigen receptor] T-cells and TIL therapy are going to compete with therapies that can quite easily be manufactured at scale like bispecific antibodies that may not have quite the success that TIL therapies or CAR T-cell therapies have, but are a lot easier to manufacture and might not have or won't have, I think, the downside associated with treatment delays.

I think that we’re in a setting and we’re starting to see this in areas like myeloma where we’ve just had a number of dramatic advances. We went from immunomodulatory therapies to proteasome inhibition therapies. Now, we have bispecifics and CARs all competing with other pharmacologic agents. In melanoma, of course, we still have targeted agents that can interfere with MAP [mitogen-activated protein] kinase and MEK [mitogen-activated protein] signaling, for example. I think one of the curious things that we’re going to have to see is how do we as a field come together, sequence therapies, use combination therapies generally as immunologists.

I think that we’re going to be moving further toward combination therapies. And yet those trials are hard to do. These agents are expensive individually, and they’re even more expensive together. So how do we do that and appropriately ask questions as a field in ways that we’re not stepping on each other’s toes and competing with each other as we do these trials? I think that’s going to be a real challenge. I know that that’s not a direct answer to where are we going but I think in a way we have amazing successes and new approved therapies coming and that’s going to create challenges for us as academicians to figure out how to do that. I’m curious if you have any thoughts on that topic or if you can see other obvious directions that we’re going to go in.

I think one of the interesting points you raised is that there’s going to be a lot of competition between agents and how to sequence. I think also how to attribute biological response to the actual agent in question and what I mean by that is it’s good news that our patients are now living much longer with advanced melanoma than 10 years ago. But what you notice is that some of the efficacy may be additive. Somebody gets a PD-1 antibody, and they progress, there still may be a lingering biological effect of that PD-1 antibody because it’s not the PD-1 antibody that’s exerting the response, it’s the effect of the PD-1 antibody on the immune cell. So unlike chemotherapy, where it’s a nonspecific poison and it only works for as long as the drugs in the patient system, immunotherapy is not like that at all.

And I think one of the things that we do need to develop are surrogates for response, readout assays that are beyond just scanning the patient or functional path, or immunologic assays to detect and track a specific antitumor immunologic response from your treatment. And I think if we’re able to do that, we should be able to logically sequence our patient treatment. And we may be able to do that in a patient-specific way. I think we’re still a bit primitive in our clinical trial design where we take a group of 100 patients and treat them not really understanding that well maybe some portion of that patient population would respond to one treatment better than another. If we’re able to build better readout assays to predict which treatment modality would give the best biological effect, that’ll come a long way for us.

The last thing I wanted to mention, tying it back into some of these preclinical abstracts that we’ve discussed, I do think that improving the efficacy of cell therapy on a per cell basis may have a couple of advantages. Number 1, we may not need to treat patients with such large number of TILs that we’re doing now. I think that is one distinction between CAR T and TIL is that CAR T uses a much smaller number of cells and TIL does and in part it could be the target of your CAR T is a lot more amenable than it is for melanoma or non-small cell lung cancer because you need the TIL to traffic outside of the blood supply which you don’t need for CAR T-cell therapy.

And secondly, the need for such intensive lymphodepletion. If we have more potent T cells, we may be able to attenuate or even do away with the lymphodepletion and that would result in our being able to treat more patients and possibly also give repeated cycles of therapy. Right now, we’re limited in our cycles of therapy because the lymphodepletion can cause some permanent bone marrow fibrosis and bone marrow failure. But if we get tumor-specific TIL, we won’t get the on-target off-tumor effect and then we’ll also get the ability for improved efficacy. What are your thoughts about that?

Well, first I’d say, no I consider myself card-carrying immunologist. I don’t think I could do much better than you just did, so I won’t try and riff on what you just said. I think all those things are really critical.

Experts Amod Sarnaik, MD, and Krishna Komanduri, MD, consider lessons learned about TILs and CAR T-cell therapy in hematologic cancers, and how they anticipate TILs fitting into treatment paradigms for solid tumors.

TIL Therapy: Lessons Learned and Potential Future Directions in Care

I think the field also had a bit of a setback in the last few weeks. Another abstract that was reported on was about the design of the DELTA-1 trial, which was another TIL [tumor-infiltrating lymphocyte] trial, in patients who had failed primary therapy with checkpoint inhibitors, and MEK inhibition if BRAF associated. Unfortunately, we got the news just a couple of weeks ago that Instil Bio, the sponsor of that trial, is suspending its lead product, ITIL-168, and has had a significant commercial setback. We don’t know to what extent that will affect the development of other products that are competing. I certainly think it’s always good from my perspective, from an academic perspective, to have healthy competition driving success and providing more options for patients. I think we’re all not yet cognizant of what the factors were, but that’s a bit sad.

We do think the trial you did, and the work that’s happening should lead to an approval sometime. Again, being optimistic and having no idea of what the FDA is exactly thinking, but we’re hopeful that there will be an approved TIL therapy in 2023 for patients who have failed prior melanoma therapies.

Excellent. I think time permits a couple more abstracts to be discussed, and you as an immunologist should be uniquely poised to answer them. There was an abstract at SITC [Society for Immunotherapy of Cancer annual meeting] by Carmela Passaro, PhD, et al, involving TILs expressing IL-15 [interleukin-15] along with other cytokines. Please comment.

So a couple of things. I think one of the other abstracts we were going to talk about is the interaction between natural TIL expansion and things like checkpoint inhibitors that regulate how T cells respond. We know that checkpoint inhibitors obviously have a role broadly in human cancers across the solid tumor spectrum. Some pioneering work by Arlene Sharpe, MD, PhD, looked at the role of PD-1 signaling in the TILs, which was also reported at the SITC meeting, and the idea that perhaps if we modulated PD-1 signaling in TILs as they’re being expanded, that could lead to optimized expansion approaches. So this abstract by and colleagues; we talked about the role of IL-2 administered in patients to lead to the survival and expansion of the TILs following an infusion of the patient. But it’s also important to note that IL-2 is used to expand almost all categories of T cells that are in commercial therapies. IL-2 is used in CAR [chimeric antigen receptor] T cell manufacture, it’s used in antivirus-specific T-cell manufacturing. And it is one of the things that is used to expand T cells outside the body in the TIL manufacturing process.

What this group did was use some genetic transduction methods to express other molecules that are also important in T-cell expansion, and that included IL-15 and IL-18, and they had an undisclosed member of the TNF [tumor necrosis factor] receptors family that was also used. All these approaches in conjunction with interferon alpha were used to basically optimize the expansion of the TIL product.

Now, I would say none of this from my perspective is quite ready for prime time, but it tells us, and you thoughtfully mentioned earlier, that the TIL is not common from person to person. The T cells that are around my tumor might be different from the T cells around your tumor. They might have different ratios of CD4 to CD8 cells, regulatory T cells, or other cells. By optimizing the manufacturing environment, it’s very likely that we’ll over time improve the speed of manufacturing, the reliability of manufacturing, and I think the subsets of T cells. You mentioned, for example, in the preclinical analysis that you had done, that if you had more TILs at the end of the product manufacturing time, that was likely something that should theoretically affect clinical responses in vivo.

I think this is an interesting look forward into ways we could use better engineering approaches to generate a better TIL product. I think associated with that, there were a couple of other interesting abstracts where, again, we’ve talked about the interplay between checkpoint inhibitors, not only in patients that relate to their prior responses, but the notion that checkpoint inhibitors on the TILs themselves might be modulated in vitro to get better expansion. Another abstract by Colin Thalhofer, PhD, looked at silencing using an RNA [ribonucleic acid] interference approach of PD-1, which again led to better expansion and potentially the function of those T cells in a more rich and functional product that can be infused.

I think these are some exciting approaches. For all of us who are both clinically and scientifically oriented in this field, as you and I both are, we want to see an approved product go to patients, and we want to see that effectively manufactured and reach patients, and provide a treatment alternative. But I think it’s clear once we have that, there are a number of things that are iterative that can be done in the pipeline to manufacture better products. To more reliably manufacture products, it could be that some patients won’t have a product that’s manufactured, and some of these theoretical approaches might lead to more reliable or successful product manufacturing in a shorter period of time. All of the factors that you talked about are going to be critical for us as we move forward.

Shared insight from Amod Sarnaik, MD, and Krishna Komanduri, MD, on the halted DELTA-1 clinical trial of ITIL-168 in melanoma, followed by a focused discussion of SITC 2022 data on emerging TIL design and manufacturing strategies.

Data from Additional Clinical Studies on Tumor-Infiltrating Lymphocyte Therapy

The next abstract we would like to discuss is a multicenter, single-arm, phase 2 study involving TILs [tumor-infiltrating lymphocytes] in the treatment of advanced treatment-refractory melanoma. This was a study that was sponsored by Iovance [Biotherapeutics]. The study had 153 patients, so it’s the largest study of TILs in melanoma that we’re aware of. The patients were heavily pretreated with 3 median lines of prior therapy. The reported response rate was 31%.

All patients had metastatic melanoma that was refractory to PD-1 antibody-based therapy. And the median duration of response was not reached at a median follow-up of 36 months. The 12-month overall survival rate was 54%. And there was a plateau of the Kaplan-Meier curve very commonly seen with immunotherapy. The trial was a massive undertaking. It involved tumor harvest from around North America with centralized manufacturing.

The benefit of this study is it demonstrates the feasibility that we can harvest cells from patients at local cancer centers that do not have manufacturing capabilities of TIL on site. The tumor can be shipped centrally where manufacturing occurs and then shipped back to the originating center for patient treatment. This is convenient for the patient as they don’t have to travel as far. They can go to a regional cancer center that’s able to treat patients with the lymphodepletion, with TIL, and IL-2 [interleukin-2] as we discussed, but they don’t have to go all the way to a cancer center that has a manufacturing facility on site, which as you know can be quite expensive. The data from the study are being reviewed by the FDA, and we’re cautiously optimistic that we’ll get regulatory approval, but that’s still under scrutiny.

This is really important, and I think barring something unexpected, many of us in the field are recognizing that this is not the end of a long road, but I would say a major milestone in a long road. It started with work in Steven Rosenberg’s MD, PhD, laboratory to develop and commercialize cellular therapies that are not engineered but come from the patient’s own tumors. I thought it was exciting that not only did you show the ability to broadly do this, because I think the logistic feats of scale in a trial like this are not insignificant. Manufacturing has been something that’s quite important in the ability to do this at scale, and it’s significant. We’ve seen this again in the context of other very promising therapies, even approved therapies for CARs [chimeric antigen receptor] T-cell therapies, that we’re having a hard time getting those therapies to patients. So, the fact that it was feasible is something that you and the other study authors should be commended for.

I thought that significantly you also had a good follow-up. You had a median follow-up that was over 2 years, the median duration of response was not reached, and there were very significant fractions of patients who had responses for a long time, greater than 18 months. I think that not only was this a breakthrough in terms of potential and feasibility, but I was quite impressed by the frequency of the responses with really good follow-up. I don’t know if you want to comment further on what you think about what this means for patients. And where would this go in, I think that’s the other key question for our audience. Are these going to be upfront therapies for melanoma, or where are they going to come in? Do you want to talk about that for a second?

Yes, absolutely. There’s no question that PD-1 antibody-based therapy has revolutionized the treatment of melanoma as well as non–small cell lung cancer. I think using it as frontline therapy sets the bar pretty high. The same sponsor does have a clinical trial of concurrent TIL plus PD-1 antibody in the frontline setting. The logistic issues are No. 1. At least in this country, most patients do get PD-1 antibody-based therapy in the community upon diagnosis and are then referred to the regional cancer center. So, we tend to see patients who have already had frontline therapy, and it makes a combination PD-1 plus TIL trial in the treatment-naïve setting logistically challenging in terms of accrual.

It turns out there was a clinical trial conducted in Europe, where PD-1 antibodies are a bit more restricted, that was published by John Haanen, MD, PhD, et al, and recently published in the 

, and they found a 49% response rate of TILs compared to a 20%-range response rate with ipilimumab. Some of those patients were in the second line, but some of them were either in the front line or recently progressed on adjuvant PD-1. So, I think the earlier line of therapy you get TIL into, the higher the responses. But whether TILs for melanoma can really reach the frontline is still in question.

The other issue to think about is the time it takes for the TILs to manufacture. The sponsor of this trial, Iovance, has shortened the manufacturing to 22 days, and adding a week of lymphodepletion, the patients are being treated around 30 days from the TIL harvest. That’s a relatively short period of time, but unfortunately, sometimes we do see patients progress while they’re waiting for therapy. Other more traditional TIL manufacturing strategies have taken 6 weeks or longer, and that’s a lot more of a challenge to have a patient wait for their treatment when they can get something off the shelf like PD-1 antibody. So, the jury’s still out. There can be modifications to TILs that may boost efficacy so it surpasses PD-1 antibody-based therapy, and shortening the time to treat, as was done by Iovance, is certainly another breakthrough of this trial that should be highlighted.

Expert perspectives on results from C-144-01, which utilized the TIL therapy lifileucel in the setting of metastatic melanoma, and situations in which the regimen might be used in clinical practice.

Results From the C-144-01 Trial and Potential Impact on Clinical Practice

To wrap up this session, we’ve selected a couple of e-abstracts from SITC [Society for Immunotherapy of Cancer] Annual Meeting to discuss. The first abstract involves CD4 polarization on TIL [tumor-infiltrating lymphocyte] therapy. Let’s start with that 1.

When we do apheresis for a CAR [chimeric antigen receptor] T-cell product, we’re just getting T cells, which are then genetically modified. You were part of this abstract, so I’d love to hear your thoughts about it. To me, it talks about the characteristics of the T-cell product as harvested, what we learned from the numbers of TILs that were expanded and infused into the patient, and the correlations between subsets of TILs or T cells in the harvested product and outcomes. I’d love to hear your thoughts, and then I can tell you my thoughts as somebody who’s been a translational immunologist for a long time.

This was a collaboration between myself at Moffitt Cancer Center, David Woods and his team at the University of Colorado, and Jeff Weber at New York University. It adds to a body of knowledge that the TIL contained within the TIL products are not uniform but are polarized, and we believe that this polarization may be exploited to improve responses.

There’s no question that we need to do more work on T-cell biology to tease out the details, but there are unique aspects, especially with the CD4 TIL, where some expression or epigenetic modifications may lead to lower TIL numbers in the TIL product. We all know that a lower TIL count in the product is associated with lower responses. Ways of polarizing the TIL during the TIL propagation may improve the TIL yield, tumor reactivity, persistence, and ultimately lead to long, durable patient outcomes. However, I suspect that there’s a lot more complexity to the T-cell phenotype as it affects antitumor biology. We’re working hard to expand on this knowledge.

One cool thing you did in that paper was look at different subsets of T cells that are known to be polarized with different functions, and you also looked at regulatory T cells. Regulatory T cells are a subset of the CD4 T cells, or healthy T-cell response, that are important in preventing our immune response to cause autoimmunity. We might get a crazy immune response responding to a virus, but we don’t get autoimmunity after getting the flu or COVID-19. The reason is that we expand these regulatory T-cell subsets, which are natural breaks to our immune response.

One thing this study showed is that there may be natural regulatory populations within the TIL subset that may decrease the expansion of that. Obviously, we don’t have a choice. We have the T cells that come from the patient, and those are the ones that are expanded. But if we learn what aspects of that composition are associated with better expansion and better in vivo activity, then we might be able to manipulate that product or expansion process to yield a more effective product, which is less likely to be suppressed. We’re going to talk a little later in our discussion about other abstracts that are more actively trying to achieve that as well, but I thought it was a very good study. Congratulations.

Thank you. For a final word on this abstract before we move forward, in the past, NCI [National Cancer Institute] did a study in which all the CD4 was depleted from the TIL product. In fact, this got lower responses. There are subsets of CD4 that clearly are deleterious, but there are also subsets of CD4 that are quite beneficial for tumor response.

A focused discussion on clinical trial data presented at SITC 2022 elucidating the biologic activity of tumor-infiltrating lymphocyte therapies.

Tumor-Infiltrating Lymphocyte Therapy: Clinical Data on Biologic Activity

The next item to discuss is our experience with TILs [tumor-infiltrating lymphocytes] in clinical trials, and how to improve communication with clinicians outside the clinical trial when using TIL.

The key thing is understanding how to coordinate routes of care. We learned a lot in the CAR [chimeric antigen receptor] T-cell setting. As we move from third-line therapy in the setting of lymphoma to second-line therapy, where we need the patient to be referred to a tertiary center, we need to think about whether CAR T-cell therapy is important. Some of those rules will also apply to the TIL setting. We need to develop areas of crosstalk. In the CAR T-cell setting, we developed approaches to have pulmonologists, neurologists, and ID [infectious disease] doctors working closely with medical oncologists or hematologists to administer CAR T-cell therapies. Here there’s the added complexity of making sure that we have coordination between the surgical team and the medical oncology team, and these are things that are unique.

We’d like to make sure we have broad utilization of these therapies for the patients who deserve to have access to them. I applaud the companies in this space for working on approaches to proactively educate individuals about infrastructure outside the clinical trial setting. We don’t want to get to a situation in which we have therapies approved for patients—especially those who failed frontline therapies—that are available, and then we have issues of suboptimal referral or suboptimal coordination within centers. You and I are fortunate to work in centers that have broad experience in immunotherapies, not only commercial immunotherapies but also therapies being developed in house. We’re further along the learning curve, and it’s important that we continue to do things to make sure individuals are comfortable. That’s largely the case.

The good thing is that we have a great cohesive and collaborative milieu in which we work—melanoma and dermatology and surgical oncology, as well as medical oncology and hematology. It’s going to take some effort. One lesson we learned from CAR T-cell therapy is that too few patients who can benefit from these therapies are getting them. Even 5 years after of approval of breakthrough CARs, less than half the individuals who qualify according to the label are getting them. We want to make sure we don’t see the same underutilization of these therapies when it comes to TILs, knowing that there are unique aspects of coordination of team building that are required.

I’m proud to say that you and I are members of this TIL working group. It’s a national consortium of individuals in academia. Sometimes it’s hard to get all of us to play together in the same sandbox. It’s an excellent collegial environment that helps get the word out and improve awareness, as well as forums such as this 1. 

® is watched by many individuals, and this is going to improve awareness of this promising treatment modality.

That’s absolutely true. We’re learning from each other as we go along. That’s critical as we help our patients.

Amod Sarnaik, MD, and Krishna Komanduri, MD, share their clinical experience with, and practical advice on, tumor-infiltrating lymphocyte therapy for their patients with solid tumors.

Clinical Experience With TIL Therapy for Solid Tumors

Krishna, tell us a little about the safety and efficacy of TILs [tumor-infiltrating lymphocytes] in patients with advanced solid tumors based on the data presented in recent years?

You highlighted it well. Obviously, there are some unique aspects of coordination. I’ve heard that the oldest CAR [chimeric antigen receptor] T-cell therapy patient was 92 years old, which is remarkably high. There are some modest, age-related limits. Age 75 is probably the reasonable upper limit. This looks a lot like our current landscape for autologous and allogeneic transplant therapies. There can be patients with comorbidities, and there can be patients who are older. Extremely old patients might be contraindicated. In the early trials of CAR T-cell therapy, the median age in the 3 pivotal trials of CD19 CAR therapies was under age 60. That age has been pushed forward as we understand how to do management and optimize characterization of early signs and problems and we get better at managing them. I’m confident that that will happen in the context of TIL therapy as well.

As you noted, 1 advantage of TIL therapy is that we don’t have to know about the target antigen. These are T cells that we already know in the context of a human immune response. They’ve gotten to the tumor and are around the tumor, so presumably they have learned to recognize the tumor and have already expanded, albeit in relatively modest numbers. These are interesting potential advantages.

In terms of toxicities, you highlighted them well. There’s the need for a moderate dose of cyclophosphamide. In some patients who are older or have significant impairment in performance status, that may be an issue. There’s the need to give IL-2 in a supportive care setting. This is not a therapy that would be administered in a community setting, at least not in the…foreseeable future, because of the need for hospitalization and specialized coordination—the collection of the tumor, cell therapy laboratories, and the clinical competency to infuse the cells, administer IL-2, and watch and support patients until they get out of trouble. Those are the key elements.

Shared insight on the benefits and drawbacks of using tumor-infiltrating lymphocyte therapy for treatment of solid tumors, as compared to chimeric antigen receptor (CAR) T-cell therapy.

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