CAR T-Cell Therapy for Solid Tumors: Leveraging Lessons From Hematologic Malignancies

Zhubin Gahvari, MD, MS

There are still no FDA-approved autologous chimeric antigen receptor (CAR) T-cell therapies available for solid tumors, with many constructs to date showing minimal efficacy.1 Comparatively, there are 7 commercial anti-CD19 and anti–B-cell maturation antigen (BCMA) CAR T-cell products currently available for the treatment of patients with hematologic malignancies, with dozens of others in active development.2-9 Challenges faced in the development of CAR T-cell agents for solid tumors include selecting appropriate target antigens while mitigating antigen escape, ensuring adequate CAR T-cell expansion, augmenting localization of the CAR T cells to tumor sites, minimizing exhaustion of CAR T cells in the setting of an immunosuppressive tumor microenvironment, and prolonging persistence of CAR T cells.10,11 Recent clinical trials, including those of anti-CLDN18.2 CAR T-cell therapies for patients with CLDN18.2-expressing gastrointestinal cancers and anti-GD2 CAR T-cell agents for patients with neuroblastoma, have provided reasons for optimism that some of these challenges are being overcome.12,13

As we plan for a future when solid tumor CAR T-cell therapy becomes available, we should be mindful of lessons learned from the introduction of CAR T-cell agents for hematologic malignancies. The first lesson is to recognize that timely access to therapy can be a significant barrier. Unsurprisingly, delays in access to anti-CD19 and anti-BCMA CAR T-cell agents have been shown to worsen survival, as patients who are waiting for treatment may die from their cancer.14,15 The impact of delays on patient outcomes will likely be more detrimental in solid tumors, as there are typically fewer options for effective systemic therapy to maintain disease control compared with hematologic malignancies.

Psychosocial factors including geography and socioeconomic status are potential barriers to timely access.16 CAR T-cell therapy is typically only available at tertiary academic centers; many patients live a significant distance away and also need referrals. The need to travel, stay an extended period away from home, and have a caregiver as well as associated financial costs may prevent patients with disadvantages from receiving CAR T-cell therapy. Although insurance coverage can be a limitation, patients with private insurance may have longer “decision to vein” time than those with government insurance.17 Analyses from patients receiving anti-CD19 CAR T cells highlight the effect of disparities: patients with disadvantages may experience shorter survival18 and are less likely to receive CAR T-cell therapy.19

Production capacity can also contribute to delays in receiving CAR T-cell therapy.20 The rollouts of idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) were hampered by limited numbers of manufacturing slots, forcing patients onto waiting lists at multiple institutions and leading to difficult decisions about which patients to allocate slots to.21 Manufacturing-related delays could be a much bigger challenge for solid tumors than hematologic malignancies on the basis of sheer number of patients alone. In 2024, it was estimated there were more than 2 million new cases of cancer, of which less than 10% were myeloma, lymphoma, or leukemia.22 Additionally, a certain percentage of CAR T-cell products will not conform to FDA requirements, leading to “out-of-specification” designations and a need to recollect and/or remanufacture or to proceed on a research basis using an expanded access protocol.23 Either choice will lead to a delay in cell therapy infusion, and it is critical to inform patients considering CAR T-cell therapy about this possibility.

Another lesson is the importance of being cognizant and transparent about risks of CAR T-cell therapy. Although the risk of CAR T-cell toxicity such as cytokine release syndrome and immunoeffector cell (IEC)–associated neurotoxicity syndrome may be associated with increased tumor burden at the time of infusion, there are other risks as well.24,25 These other risks are not trivial: findings from a meta-analysis of real-world and clinical trial data estimated a CAR T-cell treatment–related mortality up to 15% depending on the product used.26 Years after the initial commercial approvals of CAR T-cell agents, we are still learning about potential CAR T-cell–related toxicities such as secondary primary malignancies, IEC-associated hemophagocytic syndrome and colitis, and parkinsonism.27-30 Infection has been the primary driver of morbidity and mortality in CAR T-cell therapy so far, requiring providers to be vigilant about using appropriate antimicrobial prophylaxis, growth factors, and intravenous immunoglobulin as needed.26 Although infection and other toxicities such as IEC-associated hematotoxicity may be less common if the CAR T-cell target does not reside in the bone marrow or lymphoid compartments, there will likely be hitherto undescribed emerging toxicities given the use of new targets that will have different off-tumor specificity.31,32

The final lesson is that even an effective CAR T-cell construct for a specific solid tumor will not be effective for all patients with that disease. It remains important to continue development of other forms of systemic therapy, including medical and cellular immunotherapy. For example, bispecific antibodies and antibody-drug conjugates can be effective in treating lymphoma or myeloma even when a CAR T-cell therapy directed toward the same target is not.33,34 Fortunately, in 2024, the FDA approved 2 other types of adoptive T-cell therapies for solid tumors: lifileucel (Amtagvi), a tumor-infiltrating lymphocyte therapy for metastatic or unresectable melanoma, and afamitresgene autoleucel (Tecelra), a T-cell receptor cell therapy for advanced synovial sarcoma and myxoid round liposarcoma. Several bispecific antibodies for solid tumors have recently been approved as well.35-37

When CAR T-cell therapies are approved for solid tumors, a greatly increased number of patients will become eligible. We can use our experience with CAR T-cell therapy thus far to refine our current approaches and incorporate promising new techniques in order to make sure the maximum number of patients benefit. The most important step will continue to be ensuring that our patients are adequately informed and prepared for this new landscape (Figure).23,38-43

Figure. Future Directions to Optimize CAR T-Cell Therapy As It Expands to Solid Tumors23,38-43

Zhubin Gahvari, MD, MS, is an assistant professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, the University of Wisconsin Carbone Cancer Center in Madison.

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