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.
Author Info: (1) Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, MD, USA.
Author Info: (1) Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, MD, USA. Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA. (2) Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, MD, USA. (3) Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. restifon@mail.nih.gov. Center for Cell-Based Therapy, NCI, NIH, Bethesda, MD, USA. restifon@mail.nih.gov. Lyell Immunopharma, South San Francisco, CA, USA. restifon@mail.nih.gov.
