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Topic

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

Corey Cutler, MD, MPH, FRCP(C); Carrie L. Kitko, MD

BURST Expert Illustrations and Commentaries™: Exploring the Mechanistic Rationale for CSF-1R– Directed Treatment in Chronic GVHD

Asim V. Farooq, MD; Joann Kang, MD; Nita Lee, MD, MPH

(CME) Optimizing Management of Ocular Toxicity in Cancer Patients: The Role of Ophthalmologists in the Spectrum of Care

(COPE) Optimizing Management of Ocular Toxicity in Cancer Patients: The Role of Ophthalmologists in the Spectrum of Care

Andre H. Goy, MD; Monique Hartley-Brown, MD, MMSc (Guest Co-Chair); Chiara Battelli, MD, PhD; Marios Giannakis, MD, PhD; Shail Maingi, MD; Aparna Parikh, MD

Community Practice Connections™: 6th Annual Precision Medicine Symposium – An Illustrated Tumor Board

™ 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.

In Episode 2 of ImmunoLogic, Bruce Levine, PhD, discussed the current the risk-benefit-ratio for CAR-T therapy.

ImmunoLogic, Episode 2: "Charting New Frontiers in CAR T-Cell Safety" With Bruce Levine, PhD

We're excited to introduce another episode of the 

an assistant professor of microbiology and the director of the Fraietta Lab at the University of Pennsylvania! Fraietta is joined by cohost 

, a clinical fellow in oncology (MSTR Program) at the University of Pennsylvania. Our hope is that this show will serve as a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions

 the Barbara and Edward Netter Professor in Cancer Gene Therapy at the Perelman School of Medicine at the University of Pennsylvania, about the black box warnings for secondary malignancies that were issued by the FDA with regard to the autologous chimeric antigen receptor T-cell (CAR-T) therapies approved by the agency, and the implications of the findings that informed these warnings for the risk-benefit ratio of these therapies. Levine, Fraietta, and Minehart covered topics including risk and informed consent, genetic modification as it relates to safety, epitope spreading and T-cell stimulation, and the importance of the National Institutes of Health (NIH) to CAR T-cell research.

 is tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility. This podcast is an essential resource for those driving the future of immunotherapy.

Interested in co-hosting an episode or being a guest? Have feedback to share? 

If you'd like to get in touch to talk about the show, contact our editorial director, Matt Hoffman: 

Podcasts

In Episode 1 of ImmunoLogic, Stephen J. Schuster, MD, discussed the potential of treating lymphoma without chemotherapy.

ImmunoLogic, Episode 1: "Chemo-Free Lymphoma? Seriously?" With Stephen J. Schuster, MD

, a clinical fellow in oncology (MSTR Program) at the University of Pennsylvania. Our hope is that this show will become a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions

, the director of the Lymphoma Program at Penn Medicine, about the changing role of chemotherapy in lymphoma treatment, and the potential for its elimination. Schuster covered topics including trials for chimeric antigen receptor T-cell (CAR-T) therapy without lymphodepletion, using AI to predict CAR-T treatment outcomes, the importance of T-cell fitness, and the role of persistence in CAR-T success.

Joseph Fraietta, PhD, previews his new podcast, ImmunoLogic

ImmunoLogic Episode 0

an assistant professor of microbiology and the director of the Fraietta Lab at the University of Pennsylvania! Our hope is that this show will become a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions.

In this short preview episode, Fraietta outlines the podcast’s mission to scrutinize the critical milestones shaping immunotherapy today and discuss how episodes will analyze the journey from bench to bedside—focusing on the real-world implementation of clinical data and the impact of regulatory achievements on patient outcomes. Topics will include discussions on chimeric antigen receptor (CAR) T-cell therapies, tumor-infiltrating lymphocyte (TIL)-based approaches, antibody-driven treatments, and the latest advances in gene editing technologies such as CRISPR, with a goal of expanding the conversation outside of the field of oncology.

 will be tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility. With its first full episode launching in early 2025, this podcast promises to be an essential resource for those driving the future of immunotherapy.

Hosted by Joseph Fraietta, PhD, ImmunoLogic will be tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility.

CGTLive® Presents: ImmunoLogic, A Video Podcast With Joseph Fraietta, PhD

In observance of National Colorectal Cancer Awareness Month, held annually in March, we took a look back at news in cell therapy for colorectal cancer indications.

National Colorectal Cancer Awareness Month 2025: Looking Back at Progress for Cell Therapy

Review top news and interview highlights from the week ending March 21, 2025.

CGTLive®’s Weekly Rewind – March 21, 2025

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 – March 19, 2025

CGTLive® took a closer look at the single-center, open-label study, which aims to assess the safety and efficacy of the CAR-T therapy.

Shanxi Bethune Hospital Evaluating CAR-T for R/R Hematological Tumors in Phase 2/3 Clinical Trial

Review top news and interview highlights from the week ending March 14, 2025.

CGTLive®’s Weekly Rewind – March 14, 2025

This video originally appeared on our sister site,

The director of the Autologous Hematopoietic Cell Transplantation, Cell Therapy and Transplant Program at the Hospital of the University of Pennsylvania discussed data from the phase 2 BMT CTN 1902 trial.

Bhagirathbhai R. Dholaria, MD, on Evaluating P-BCMA-ALLO1 in R/R Myeloma

“We set a bar for ourselves to see if we could increase [the proportion of patients who converted to a complete response (CR)] to at least 30%, and what we found actually was that we did even better than that by a good amount. Sixty-three percent of patients converted to CR, and another 24% upgraded their response in some other way. A total of 87% of patients improved their response to some extent.”

Bristol Myers Squibb and 2seventy bio's idecabtagene vicleucel (ide-cel, marketed as Abecma), an FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy, is currently being evaluated in conjunction with subsequent lenalidomide (Revlimid) maintenance in the phase 2 BMT CTN 1902 clinical trial (NCT05032820) for the treatment of patients with multiple myeloma (MM) who had a suboptimal response following upfront autologous stem cell transplant (ASCT) and maintenance lenalidomide. Data from this study were recently presented at 

the 2025 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR

, held in Honolulu, Hawaii, February 12 to 15, 2025, by Alfred L. Garfall, MD, MS, the associate professor of medicine (hematology-oncology) and director of the Autologous Hematopoietic Cell Transplantation, Cell Therapy and Transplant Program at the Hospital of the University of Pennsylvania.

, spoke with Garfall to learn more. In an interview with 

, Garfall explained that, historically, patients who do not achieve a complete response (CR) following ASCT and lenalidomide maintenance do not typically convert to a CR down the line, and noted that for BMT CTN 1902, the investigators projected that this happens in approximately 10% of patients. As such, the primary end point for the study was set as the CR rate at 6 months following ide-cel infusion, with the goal of increasing that rate to at least 30%.

 that 63% of patients (n =38) achieved a CR, and an additional 24% of patients experienced an upgraded response without reaching a CR, leading to an overall response improvement rate of 87%.

With regard to safety, cytokine release syndrome (CRS) was observed in 81.6% of patients, with all cases limited to grade 1 (68.4%) or grade 2 (13.2%). The median time to CRS onset was 1 day (range, 0-4), with resolution occurring at a median of 2.5 days (range, 0-6). Tocilizumab was administered in 77% of cases, and corticosteroids were used in 23% of patients with CRS. Notably, there were no cases of immune effector cell–associated neurotoxicity syndrome observed.

Click here for more coverage of Tandem 2025.

Videos

Canonical

Alfred L. Garfall, MD, MS, on Ide-Cel and Lenalidomide Maintenance in MM Following Suboptimal ASCT Response

This article originally appeared on our sister site,

The associate professor of medicine at Medical College of Wisconsin discussed efficacy data presented at the 2025 Tandem Meetings.

Nirav Shah, MD, on Evaluating Zamto-Cel in R/R DLBCL

"Despite some of these poor prognostic indicators, we were happy to report that the overall response rate was [72.8%,] with [50.8%] of patients achieving a complete remission. Many of these remissions were durable."

Zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1), a dual CD19- and CD20-directed noncryopreserved chimeric antigen receptor T-cell (CAR-T) therapy, is currently being evaluated in the 

 for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Interim data from this study were recently presented at 

, held in Honolulu, Hawaii, February 12 to 15, 2025.

, interviewed Nirav Shah, MD, MSHP, an associate professor of medicine at Medical College of Wisconsin, about the analysis, which included 59 evaluable patients in the modified intention-to-treat population. Shah pointed out that many of these patients had elevated International Prognostic Index (IPI) scores and lactate dehydrogenase (LDH) levels at enrollment, indicating high-risk disease. Although, the overall response rate (ORR) was 72.8%, including a complete remission (CR) rate of 50.8%, despite the adverse prognostic factors. Furthermore, an 11.4 month median duration of response was recorded, and for patients achieving a CR, the median duration of CR was not yet reached as of the data cut-off.

At 6 months, the progression-free survival (PFS) rate was 55%, and the median PFS was 9.0 months. The median overall survival (OS) had not been reached.

Shah explained that continued follow-up will be vital to obtain more mature data. Future analyses will examine the 1- and 2-year outcomes for patients treated during the study.

The safety profile of zamto-cel was favorable, with no cases of grade 3 or higher cytokine release syndrome reported. Immune effector cell–associated neurotoxicity syndrome of grade 3 or higher occurred in 4.3% of patients.

Notably, dual CD19/CD20 targeting was associated with a potential mitigation of antigen loss as a resistance mechanism. Among 27 patients who had disease progression, no antigen loss was observed in 22 patients. CD19 loss and CD20 loss were experienced by 2 patients each, and 1 patient had dual CD19/CD20 loss.

Nirav Shah, MD, MSHP, on Evaluating Zamto-Cel in R/R DLBCL

The associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center discussed results from a phase 1 clinical trial.

“We did not report any grade 3 or [higher] cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome.”

Poseida Therapeutics is currently evaluating P-BCMA-ALLO1, an allogeneic BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy, in an ongoing phase 1/1b clinical trial (NCT04960579) for the treatment of relapsed/refractory (r/r) multiple myeloma (MM). Data from the trial were recently presented at 

, held in Honolulu, Hawaii, February 12 to 15, 2025. The presentation focused on findings from the study's optimized lymphodepletion cohort (Arm C).

Arm C included patients with r/r MM who had been previously treated with at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an antiCD38 monoclonal antibody. The arm allowed for inclusion patients who had previously received a BCMA-directed therapy. In an interview with 

, Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, discussed the results presented at the conference.

The study included 32 evaluable patients in Arm C, and findings demonstrated an overall response rate (ORR) of 88%. Among specific subgroups, patients who were naive to BCMA-directed therapy (n = 16) achieved an ORR of 100% . Those who previously had received 1 or more BCMA-targeted therapies (n = 12) experienced an ORR of 75%, and patients with prior exposure to both BCMA- and GPRC5D-directed therapies (n = 9) achieved an ORR of 78%. Notably, responses were rapid, with a median time to response of 16 days for patients across cohorts A, B, and C. In cohorts A and B, the median duration of response was 214 days; most patients in arm C had been enrolled within 6 months of data cutoff.

Safety data for P-BCMA-ALLO1 in cohort C showed that no cases of grade 3 or higher cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS) were reported. Additionally, no patients experienced Parkinsonism, movement disorders, or hemophagocytic lymphohistiocytosis. The overall incidence of CRS was 42%, with all cases limited to grade 1 or 2 in severity. ICANS occurred in 14% of patients, but all events were grade 1 and resolved with minimal steroid intervention.

The hematology-oncology and BMT cell therapy fellow at Stanford University discussed implications of his institution’s findings on treatment-related secondary malignancies.

Mark Hamilton, MD, PhD, on Analyzing PostCAR Myeloid Neoplasms

“One question that we're often asked is whether we should avoid therapy in patients with clonal hematopoiesis mutations, since they can be detected. We don't see any evidence, at least so far, that patients with lymphoma should be denied a life-saving therapy because they have the presence of these mutations prior to infusion. Of course, more work is certainly needed to better define and understand these processes, but as of right now, we find that they're kind of what we would expect.”

 for all chimeric antigen receptor T-cell (CAR-T) therapy products that had been approved by the agency at that time.

 The warnings were related to the potential risk for the development of secondary T-cell malignancies occurring in relation to treatment with BCMA- and CD19-directed genetically modified autologous CAR-T therapy.

In light of these warnings, interest has continued in gaining a better understanding a better understanding of these risks, including the mechanisms behind them and their similarity to other treatment-related risks in oncology. One such study on this topic was presented at at the

 66th American Society of Hematology (ASH) Annual Meeting and Exposition

, held December 7-10, 2024, in San Diego, California, by Mark Hamilton, MD, PhD, a hematology-oncology and bone marrow transplant (BMT) cell therapy fellow at Stanford University.

 The single-institution study evaluated data from a cohort of patients treated with CAR-T therapy for nonHodgkin lymphoma (NHL) at Stanford University.

 held shortly after the conference, Hamilton described the key results of the study and their implications. He pointed out that postCAR myeloid neoplasms seem to derive from preexisting clonal hematopoeisis and occur in patients with high treatment burdens that often have 

 mutations. Hamilton also discussed some of the challenges and limitations of the study, and emphasized that more research on this topic is needed.

REFERENCE
1. FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. April 18, 2024. Accessed February 5, 2025. News release. FDA. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-boxed-warning-t-cell-malignancies-following-treatment-bcma-directed-or-cd19-directed
2. Hamilton M, Phillips N, Lee D, et al. Single institution analysis of lymphoma treatment related post-CAR myeloid neoplasms. Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract #704

The medical director of the Immune Effector Cell Therapy Program at UCLA discussed initial data from a phase 1/2 trial.

Sarah Larson, MD, on Evaluating Lyell’s CAR-T IMPT-314 in LBCL

“I'm excited to see what the duration of response and progression-free survival are. The follow-up at this point is too short for that to have been presented... I'll be excited to see that [because] the CD62L-selected cells we would expect to have better persistence, which we would hope then translates into a longer duration of response and progression-free survival.”

Currently, a number of chimeric antigen receptor T-cell (CAR-T) therapies are commercially available for the treatment of large B-cell lymphoma (LBCL). Although, a number of companies and academic institutions are continuing to develop new CAR-T products for this indication, with innovations intended to provide new alternatives and overcome limitations of the current treatment options. One such product is Lyell Immunopharma’s IMPT-314, a CD19/CD20 dual-targeted autologous CAR-T therapy, which is currently being evaluated in a phase 1/2 clinical trial (NCT05826535) for the treatment of relapsed/refractory LBCL in patients who have not previously received CAR-T therapy. Initial results from patients treated in this trial were recently presentedat the

, held December 7-10, 2024, in San Diego, California, by Sarah Larson, MD, the medical director of the Immune Effector Cell Therapy Program in the Division of Hematology/Oncology at David Geffen School of Medicine at University of California, Los Angeles (UCLA).

Shortly after the close of the conference, 

 interviewed Larson to learn more. Larson discussed the rationale behind the design of IMPT-314, and then went over the key results that were presented, highlighting that among 17 patients evaluable for efficacy, the overall response rate was 94% (16/17), with a complete response rate of 71% (12/17) by 3 months posttreatment. In terms of safety, she noted that the toxicity profile was favorable, with no grade 3 or higher cytokine release syndrome reported, and cases of immune effector cell-associated neurotoxicity syndrome (ICANS) predominantly being grade 1 to 2. Larson also spoke about potential future plans for IMPT-314, and pointed out that the clinical trial is currently recruiting patients.

REFERENCE
1. Lyell presents positive initial clinical data from the phase 1-2 clinical trial of IMPT-314 for the treatment of B-cell lymphoma at the 2024 ASH annual meeting. News release. Lyell Immunopharma, Inc. December 9, 2024. Accessed January 23, 2025. https://ir.lyell.com/news-releases/news-release-details/lyell-presents-positive-initial-clinical-data-phase-1-2-clinical

This is the third part of an interview with Manali Kamdar, MD. For the second part, 

The clinical director of lymphoma services at the University of Colorado discussed the importance of referring patients who are transplant ineligible for CAR-T treatment.

Manali Kamdar, MD, on Transplant Eligibility Versus CAR-T Eligibility

“Please if you think of a [patient with] refractory, diffuse LBCL in the second line setting or third line setting, please refer them to a CAR-T academic center or a community site capable of doing CD19 CAR-T ASAP because it is really of the essence to get the patient to a CAR-T physician. As you know, manufacturing time has to be accounted for, and for now, I can say the only cure I know of, which is the new standard of care, would be a CD19 CAR in the second line as well as in the third line setting.”

One of the key early line treatment options for patients with hematologic malignancies such as large B-cell lymphoma (LBCL) is allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although allo-HSCT has the potential to be curative, unfortunately some patients are ineligible to receive it, because of factors such as advanced age or a frail constitution that may put them at too high of a risk to endure the potentially serious adverse events (AEs) associated with allo-HSCT. In the second and third line settings for relapsed/refractory (r/r) LBCL, autologous chimeric antigen receptor T-cell (CAR-T) therapy, such as the CD19-directed lisocabtagene maraleucel (liso-cel, marketed as Breyanzi by Bristol Myers Squibb), can serve as another potentially curative option for patients. Because CAR-T also has certain potentially serious AEs associated with its use, some healthcare providers are inclined to equate allo-HSCT ineligibility with CAR-T ineligibility.

, Manali Kamdar, MD, the associate professor of medicine–hematology and clinical director of lymphoma services at the University of Colorado, argued against this trend as an addendum to a larger discussion about results from the TRANSCEND-NHL-001 clinical trial (NCT02631044) evaluating liso-cel that were presented at the

, held December 7-10, 2024, in San Diego, California. Kamdar emphasized her view that some patients traditionally deemed ineligible for allo-HSCT are perfectly capable of receiving CAR-T safely, and that such patients should be referred to a center capable of providing CAR-T as soon as possible in order to ensure better treatment outcomes.

REFERENCE
1. Abramson JS, Palomba ML, Gordon LI, et al. Five-year survival of patients (pts) from Transcend NHL 001 (TRANSCEND) supports curative potential of lisocabtagene maraleucel (liso-cel) in relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract 3125

The clinical director of lymphoma services at the University of Colorado discussed the importance of referring patients with r/r LBCL who are transplant ineligible for CAR-T treatment. 

This is the second part of an interview with Manali Kamdar, MD. For the first part, 

The clinical director of lymphoma services at the University of Colorado discussed the choice between treating patients with liso-cel or bispecific T-cell engagers.

Manali Kamdar, MD, on Sequencing of Treatment in Third-Line R/R LBCL

“I think that is potentially the main question: Based on the 5-year follow-up of the TRANSCEND-NHL-001 study demonstrating a curative potential of liso-cel, how [do we] pitch it against CD20 BiTEs?”

Current treatment options for patients with third-line relapsed/refractory (r/r) large B-cell lymphoma (LBCL) include Bristol Myers Squibb’s lisocabtagene maraleucel (liso-cel, marketed as Breyanzi), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, and CD20-bispecific T-cell engagers (BiTEs), such as epcoritamab (Epkinly) and Glofitamab (Columvi). Liso-cel was approved by the FDA for treatment in this setting based on results from the TRANSCEND-NHL-001 clinical trial (NCT02631044). Notably, 5-year survival data from patients treated in the LBCL cohort in TRANSCEND-NHL-001 were recently presented by Jeremy S. Abramson, MD, the director of the Lymphoma Program and the Jon and Jo Ann Hagler Chair in Lymphoma at the Massachusetts General Hospital Cancer Center, at the

, held December 7-10, 2024, in San Diego, California.

 spoke with Manali Kamdar, MD, the associate professor of medicine–hematology and clinical director of lymphoma services at the University of Colorado, about the implications on this newly reported data for the treatment landscape in third-line r/r LBCL. Kamdar pointed out that now one of the major questions facing treating physicians is the sequencing of treatment options: whether patients in the third-line should be treated with liso-cel or CD20 BiTEs first? Kamdar weighed the pros and cons of each of these 2 options, noting that liso-cel has longer-term follow-up data available than do CD20 BiTEs. She pointed out that that currently, data indicates that liso-cel has curative potential, and that it has the advantage of being a one-time, one-and-done treatment. On the other hand, Kamdar emphasized that CD20 BiTEs are able to be used off-the-shelf, without a lengthy manufacturing time, unlike CAR-T, and that caregiver requirements for CD20 BiTEs may be less stringent in the future because of the lower risks of cytokine release syndrome and neurotoxicity associated with CD20 BiTEs in comparison to CAR-T.

The clinical director of lymphoma services at the University of Colorado discussed 5-year follow-up data from the TRANSCEND-NHL-001 clinical trial.

Manali Kamdar, MD, on the Curative Potential of Liso-Cel in Third-Line R/R LBCL

“This goes on to show that liso-cel demonstrates a curative potential of 38% at the 5-year mark in the patients who have received it in the third-line setting.”

Bristol Myers Squibb’s lisocabtagene maraleucel (liso-cel, marketed as Breyanzi), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, was approved by the FDA for the treatment of third-line relapsed/refractory (r/r) large B-cell lymphoma (LBCL) based on results from the TRANSCEND-NHL-001 clinical trial (NCT02631044). Following the approval, the study continued to collect data on the treated patients, before it finally completed in 2024. At the

, held December 7-10, 2024, in San Diego, California, Jeremy S. Abramson, MD, the director of the Lymphoma Program and the Jon and Jo Ann Hagler Chair in Lymphoma at the Massachusetts General Hospital Cancer Center, presented 5-year survival data from patients treated in the LBCL cohort in TRANSCEND-NHL-001.

 got in touch with Manali Kamdar, MD, the associate professor of medicine–hematology and clinical director of lymphoma services at the University of Colorado, to learn more about the data Abramson presented and its implications. Kamdar went over the key results, highlighting that the median overall survival at 5 years was 27.5 months with an estimated overall survival rate at 5 years of 38%. She also pointed out that that the median disease-specific survival at 5 years was 68 months and that the estimated disease-specific survival rate at 5 years was 52%. Kamdar emphasized that these results support the curative potential of liso-cel for r/r LBCL in the third-line setting, having noted that patients with diffuse LBCL who remain in remission at 5 years of follow-up are typically considered to have been cured. Kamdar also discussed the 5-year safety data, pointing out that there were no new toxicity signals since the 2-year follow-up.

The associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center discussed interim data from the phase 1/1b clinical trial evaluating Poseida's CAR-T.

Bhagirathbhai R. Dholaria, MD, on Evaluating Allogeneic CAR-T P-BCMA-ALLO1 in R/R Multiple Myeloma

“Given the fact that this is an allogenic product, it's readily available. There is no leukapheresis needed. There is no waiting for manufacturing, which is a huge issue in autologous BCMA-targeted CAR T-cell therapy, which is takes anywhere from 4 to 6 weeks from the time of leukapheresis to actual cell infusion. Many of our high-risk patients are not able to wait that long, and they end up requiring bridging therapy, which none of the patients on this trial needed because P-BCMA-ALLO1 was available right away.”

Patients with relapsed/refractory (r/r) multiple myeloma (MM) have several treatment options, from chemotherapy regimens to several FDA-approved autologous chimeric antigen receptor T-cell (CAR-T) therapies. Despite these options, however, substantial unmet need remains, and many new treatment options are currently in development to address gaps in eligibility and shortcomings in safety and efficacy of current treatment options. One such new treatment option currently in development is Poseida Therapeutics’ P-BCMA-ALLO1, an allogeneic BCMA-directed CAR-T therapy, which is being evaluated in an ongoing phase 1/1b clinical trial (NCT04960579) in r/r MM. Notably, 

 were recently presented at the 21st International Myeloma Society (IMS) Annual Meeting, held September 25 to 28, in Rio de Janeiro, Brazil.

 got in touch with trial investigator Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, to learn more about the data. Dholaria explained what differentiates P-BCMA-ALLO1 from current FDA-approved CAR-T therapies for MM, pointing out that it is allogeneic rather than autologous and that it is engineered with a nonviral gene-editing approach. Afterwards he spoke about the promising safety and efficacy results, highlighting the nonoccurrence of graft versus host disease in the treated patients and the 91% overall response rate in the enhanced lymphodepletion arm.

REFERENCES
1. Poseida Therapeutics garners FDA RMAT designation for allogeneic CAR-T P-BCMA-ALLO1 in r/r multiple myeloma. News release. Poseida Therapeutics, Inc. September 27, 2024. Accessed October 10, 2024. https://investors.poseida.com/news-releases/news-release-details/poseida-therapeutics-reports-positive-interim-phase-1-results

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

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.

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.

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