Since the advent of CD19-directed chimeric antigen receptor T cells (CAR-Ts), we have been left wondering how these products will change our current standards of care and what the next generation of cellular therapy products will look like. Will cytokine release syndrome (CRS) and neurotoxicity become a thing of the past or remain a necessary evil? Do these cells need to be autologous and manufactured for the individual or can off-the-shelf products provide similar, or even better, results? The best and brightest minds are postulating ways around current toxicities of CAR-T therapies in lymphoid neoplasms, and when to use what.
This year, we will not only get updates about “known” CAR-T therapies and bispecific antibodies, but we will also be introduced to new constructs and new settings (i.e., earlier lines of therapy) for cellular therapies.
Moving CAR-T Therapy to Earlier Lines of Treatment
Dr. Manali Kamdar of the University of Colorado will present promising data from the phase III TRANSFORM (abstract 91) study. This trial compared liso-cel to standard-of-care (SOC) salvage chemotherapy followed by autologous transplantation in the second-line setting for patients with large B-cell lymphoma (LBCL) who were primary refractory or had relapsed less than 12 months after initial therapy. TRANSFORM met its primary endpoint — improvement in event-free survival compared to SOC. Of note, ZUMA-7, the results of which will be presented during the Plenary Scientific Session (abstract 2), looks at the use of another autologous CAR-T product, axi-cel, in a similar population. Given the poor outcomes in this patient population with current standard therapy, this is an area of unmet need, and these favorable results are highly anticipated.
Stratifying Response to CAR-T Therapy in Lymphoma
With CAR-T achieving such remarkable responses in heavily pretreated patients, and now in even earlier lines of treatment, a reasonable question is who will respond and who are the unfortunate patients who will be resistant. How can we manage our patients’ expectations? Should everyone get CAR-T?
Dr. Brian T. Hill of the Cleveland Clinic will present data on molecular signatures in diffuse LBCL (DLBCL) and their correlations with outcomes in patients who received axi-cel or tiso-cel. Certain high-risk subgroups or “clusters” of DLBCL and driver mutations are associated with more favorable outcomes with commercial CAR-T therapy. These features are distinct from predictors of response to chemoimmunotherapy standard treatments (abstract 165). Dr. Hua-Jay J. Cherng of MD Anderson Cancer Center will present the use of low-pass whole-genome sequencing for cell-free DNA (cfDNA) to generate a risk score that correlates with outcomes after CD19–CAR-T therapy in LBCL (abstract 38). Zachary Jackson of Case Western will present on using single-cell RNA sequencing and protein surface marker profiling to create a novel prognostic biomarker, that may identify risk of CAR-T exhaustion (abstract 164). Dr. Katelyn Burleigh of Seattle Children’s Research Institute will present findings showing that overactivation of IL-18 signaling appears to be associated with poor outcomes in pediatric patients receiving CAR-T therapy for B-cell acute lymphoblastic leukemia (abstract 168).
Toxicities of CAR-T Therapy
There are many ways in which we can improve our current CAR-T therapies. In addition to determining the optimal time for CAR-T therapy and looking to better predict who will benefit, we also strive to decrease the toxicities associated with currently available CAR-T approaches.
Dr. Jae H. Park of Memorial Sloan Kettering Cancer Center will present a phase II study of prophylactic anakinra to prevent CRS and neurotoxicity in relapsed/refractory (R/R) lymphomas, which showed fairly low use of tocilizumab with this strategy (abstract 96). In a poster session, Dr. Anna Barata of H. Lee Moffitt Cancer Center will present on using several tools including cognition questionnaires and quality-of-life assessments to understand the longitudinal effects of CAR-T therapy on cognition and physical functioning (abstract 3052).
Improving Responses to CD19–CAR-T Therapy
CAR-T products targeting CD19 are becoming more refined. Dr. Nirav N. Shah of Medical College of Wisconsin will present data from a phase I/II study of CD19–CAR-Ts cultured with IL15 and IL17 for R/R B-cell non-Hodgkin lymphoma; this was inspired by pre-clinical data showing that culturing CAR-T cells with these cytokines can improve cell expansion, in vivo CAR-T persistence, tumor cytotoxicity, and increase frequency of a memory T-cell phenotype (abstract 95). Dr. Bijal D. Shah of H. Lee Moffitt Cancer Center will present an allogeneic CD19-targeted CAR-T therapy. Editing of the T-cell receptor alpha constant (TRAC) and an “enhanced” lymphodepleting regimen were used to decrease the risk of graft-versus-host disease (GVHD) from use of an allogeneic product (abstract 302).
Update on Bispecific Antibodies
Due to the expense, need for aphaeresis, and manufacturing time for CAR-T therapy, there is a limited ability to provide CAR-T treatments to all patients, particularly in community practices. Thus, bispecific antibodies are appealing, and more constructs are being developed to treat lymphoid malignancies. There has been particular excitement about the efficacy seen to date for CD20-CD3 bispecific antibodies in follicular lymphoma (FL). Dr. L. Elizabeth Budde of City of Hope will present updated data from the phase I/II study of mosunetuzumab for the treatment of R/R FL showing high response rates, even in typically difficult-to-treat populations, such as those who progress within 24 months of initial therapy (abstract 127). This year’s program is diverse and exciting, and it was rather difficult to pick which abstracts to preview here! We hope you will join us today, Saturday, December 11, to learn even more about the ways CAR-T and cellular therapies are changing for the betterment of our patients. You can also view these sessions on-demand via the virtual platform.
Dr. Blackmon and Dr. Brem indicated no relevant conflicts of interest.
