CAR T-Cell Therapy for Hematologic Malignancies: Toxicities, Efficacy, and Opportunities
Dr. Mark Geyer delivered an outstanding presentation, which was a remarkable tour de force, as he examined the toxicities and outcomes associated with both current and future CAR T-cell therapies. CAR T cells involve the genetic engineering of T cells for HLA-independent cytotoxicity. This strategy allows T cells to target tumor cells effectively, even when tumors attempt to evade elimination by downregulating HLA class I molecules and dysfunctional antigen processing. Notably, Diffuse Large B Cell Lymphoma (DLBCL) alone boasts three FDA-approved CAR T-cell therapies, each featuring distinct combinations of co-stimulatory (CD28 vs. 4-1BB), transmembrane, and hinge domains. Furthermore, additional CAR T-cell products have gained approval for the treatment of follicular lymphoma, mantle cell lymphoma, and multiple myeloma.
Lymphodepletion is a prerequisite before administering any of the commercially-approved CAR T-cell infusion, conferring numerous advantages including the removal of suppressive regulatory T-cells, suppression of initial host responses to murine components of CAR T cells, provision of an anti-tumor effect, and depletion of homeostatic cytokine sinks before introducing millions of CAR T cells on treatment day. It is worth noting that different dosages of CAR T-cell products have been infused in various clinical trials. For example, the ZUMA-1 trial used a dose of 2 million CAR T-cells per kilogram, whereas the TRANSFORM trial used a fixed dose of 100 million CAR-T cells with an equimolar ratio of CD4+ to CD8+ T-cells.
The primary initial toxicity associated with CAR T cells is cytokine release syndrome (CRS), with fever being the sine qua non. Treatment for this syndrome warrants the use of the FDA-approved IL-6 inhibitor known as tocilizumab. Another significant toxicity is immune effector cell-associated neurotoxicity syndrome (ICANS) representing a complex pathophysiology involving cytokines that induce vascular permeability, inflammation, and glial injury. Additional toxicities are being investigated, such as cardiac injury which has been retrospectively noted in more than 15% of patients within a large cohort comprising over 200 patients with B cell non-Hodgkin’s lymphoma.
Numerous clinical trials are currently exploring avenues for improving CAR T-cell design and mitigating toxicities. For example, the FELIX trial is investigating obecabtagene autoleucel, which uses a single-chain variable fragment (scFv) with lower CD19 affinity, resulting in faster disassociation when compared to commercial CAR T cells. This modification may reduce toxicities and enhance durability. Additionally, another CAR T-cell product incorporates a humanized scFv with a mutated ITAM, demonstrating reduced exhaustion and improved persistence. Allogeneic CAR T cells are developed using genome editing technologies like ARCUS or CRISPR to disrupt the T-cell receptor alpha constant (TRAC) locus. This approach effectively prevents graft-versus-host disease while offering the potential for an easily accessible ‘off-the-shelf’ product, compared to the few weeks required for autologous productmanufacturing. Concerns with T-cell fratricide and graft-versus-host responses need to be addressed in targeting T-cell malignancies, but several CD7-targeted CAR T cells (including GC027) have demonstrated early evidence of clinical activity.
Finally, innovative strategies preceding or following CAR T-cell infusion are under investigation to mitigate toxicities and maximize outcomes. One such approach involves the use of the anti-CD45 antibody, apamistamab, labeled with 131-iodine (131-I apamistamab). This treatment specifically targets monocytes, macrophages, and myeloid-derived suppressor cells, among other immune cells implicated in the pathophysiology of CRS and ICANS. Patients receiving CAR Tcells with high risks of exhaustion and low rates of persistence may warrant consolidation with allogeneic stem cell transplantation as part of curative intent therapy.
Immune effector cell therapies have now become an established approach for patients withseveral relapsed or refractory hematologic malignancies and the future is bright as we broaden the approved indications and further optimize novel technologies.