To develop better animal models for adoptive T cell transfer (ACT) targeting neoantigens, Hanada and Yu et al. engineered B16 melanoma cells to express native gp100 or a mutated (neoantigen) gp100. Both versions of gp100 were recognized by pmel-1 T cells, but the neoantigenic version induced a much stronger IFNγ response in vitro and complete and durable regression of established tumors in vivo. The stronger antitumor response in the gp100 neoantigen model created the opportunity to effectively explore less toxic regimens (e.g. ACT without lymphodepletion) and T cell functional modifications (e.g. enforced CD25 expression).
The adoptive cell transfer (ACT) of T cells targeting mutated neoantigens can cause objective responses in varieties of metastatic cancers, but the development of new T cell-based treatments relies on accurate animal models. To investigate the therapeutic effect of targeting a neoantigen with ACT, we used T cells from pmel-1 T cell receptor-transgenic mice, known to recognize a WT peptide, gp100, and a mutated version of the peptide that has higher avidity. We gene-engineered B16 cells to express the WT or mutated gp100 epitopes and found that pmel-1-specific T cells targeting a neoantigen tumor target augmented recognition as measured by IFN-gamma production. Neoantigen expression by B16 also enhanced the capacity of pmel-1 T cells to trigger the complete and durable regression of large, established, vascularized tumor and required less lymphodepleting conditioning. Targeting neoantigen uncovered the possibility of using enforced expression of the IL-2Ralpha chain (CD25) in mutation-reactive CD8+ T cells to improve their antitumor functionality. These data reveal that targeting of "mutated-self" neoantigens may lead to improved efficacy and reduced toxicities of T cell-based cellular immunotherapies for patients with cancer.
Author Info: (1) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA. (2) Surgery Branch, National Ca
Author Info: (1) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA. (2) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA. (3) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA. Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, United Kingdom. (4) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA. Harvard University, Cambridge, Massachusetts, USA. (5) Surgery Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA. Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland, USA.
