Expanding the Therapeutic Reach of Chimeric Antigen Receptor T-Cells and Bispecific T-Cell Engagers Across Solid Tumors

The introduction of T-cell-based therapeutics in hematologic malignancies has led to improvements in outcomes for patients with acute leukemia, lymphoma, and multiple myeloma. To date, the Food and Drug Administration (FDA) has approved seven chimeric antigen receptor-T (CAR-T) cell therapies and seven bispecific T-cell engagers (BiTEs) across a variety of hematologic malignancies; however, the extension of CAR-T therapies and BiTEs to the solid tumor arena has been somewhat limited. In this review, we discuss the landmark data that led to the commercialization of four novel FDA-approved T-cell-based therapeutics in solid malignancies, including tarlatamab for small cell lung cancer, afamitresgene autoleucel for synovial sarcoma, lifileucel for metastatic melanoma, and tebentafusp for metastatic uveal melanoma. We discuss the targetable antigen landscape of CAR-T therapies and BiTEs under investigation in solid malignancies. We explore the translational potential for various CARs under active investigation, including human epidermal growth factor receptor 2-directed CARs in breast cancer, prostate stem cell antigen-directed CARs for prostate cancer, epidermal growth factor receptor (EGFR)-IL13Ra2 and EGFR-vIII CARs for glioblastoma, and GD2-directed CARs for neuroblastoma. We glean from lessons learned for existing CAR-T therapies and BiTEs for hematologic malignancies and emphasize solutions toward facilitating the clinical rollout of T-cell-based therapies in solid tumors, including scalability to meet the growing needs of clinical oncology. Some solutions include addressing on-target, off-tumor toxicity; improving the manufacturing of CARs; optimizing the tissue-specific tumor microenvironment by combating immune desert tumors; and discovering natural tumor neoantigens and non-self-epitopes generated by tumor-specific mutations. These concepts can help provide transformative benefits for patients with solid malignancies in the coming years.