Yamamoto et al. review the status of T cell-based adoptive cell transfer (ACT) for the treatment of solid tumors. Current, mostly unsatisfactory, approaches include CARs, engineered TCRs, and TIL therapies. Challenges of ACT include: identifying tumor-specific neoantigens; identifying and expanding neoantigen-reactive T cells and determining their in vivo antitumor reactivity; and maintaining the appropriate T cell phenotype during extensive expansion. The efficacy of ACT could be improved by recruiting patients soon after initial diagnosis, creating individualized TCRs, using iPSCs, reducing T cell apoptosis, and combining ACT with ICB and/or vaccines.
Stimulating an immune response against cancer through adoptive transfer of tumor-targeting lymphocytes has shown great promise in hematological malignancies, but clinical efficacy against many common solid epithelial cancers remains low. Targeting 'neoantigens'-the somatic mutations expressed only by tumor cells-might enable tumor destruction without causing undue damage to vital healthy tissues. Major challenges to targeting neoantigens with T cells include heterogeneity and variability in antigen processing and presentation of targets by tumors, and an incomplete understanding of which T cell qualities are essential for clinically effective therapies. Finally, the prospect of targeting somatic tumor mutations to promote T cell destruction of cancer must contend with the biology that not all tumor-expressed 'neoepitopes' actually generate neoantigens that can be functionally recognized and provoke an effective immune response. In this Review, we discuss the promise, progress and challenges for improving neoantigen-targeted T cell-based immunotherapies for cancer.
