Autologous T Cells Targeting Four Neoantigens Induce Tumor Regression

Immunotherapy including immune checkpoint blockade or adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL) has demonstrated clinical efficacy in tumors with a high mutation burden but has not been as successful in treating tumors with lower mutation rates. Adoptive transfer of autologous TILs that target the expressed proteins of somatically mutated cancer genes may improve therapeutic efficacy and have induced tumor regression in patients with metastatic bile duct, colon, and cervical cancers. Zacharakis and colleagues assessed autologous TILs from a patient with ER-positive metastatic breast cancer treated with adoptive transfer of mutant protein–specific TILs in combination with IL2 and the anti–PD-1 antibody pembrolizumab. Whole-exome and RNA sequencing identified 62 nonsynonymous somatic mutations in the tumor, and TILs isolated from the patient harbored two mutant tumor antigens—SLC3A2 and KIAA0368. The patient was treated with these mutant SLC3A2 and KIAA0368 TILs and 6 months after cell transfer achieved a 51% reduction in tumor burden. At 22 months after cell transfer all target and nontarget lesions had radiographically resolved. T-cell receptor (TCR)–focused deep sequencing revealed dominant TCR pairs that also recognized the mutant tumor antigens CADPS2 and CTSB. Overall, there were 11 TCR clonotypes that recognized all four neoantigens (SLC3A2, KIAA0368, CADPS2, and CTSB). Only two of these were detectable at low frequency in peripheral blood prior to treatment (0.002%–0.003% of TCRβ variable regions), but 3–12 weeks after cell infusion, the median cumulative frequency was 2.83%. Further, 8 of the 11 neoantigen-reactive TCRs persisted in the peripheral blood, making up 0.81% of the TCR repertoire 17 months after infusion. Altogether, these findings suggest that autologous TILs that target multiple tumor neoantigens may better overcome tumor immune escape mechanisms to induce durable tumor regressions, and these results may aid the engineering of more effective autologous TILS for adoptive transfer to treat patients with cancer.

Zacharakis N, Chinnasamy H, Black M, Xu H, Lu YC, Zheng Z, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med 2018;24:724–30.

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