To understand why TIL therapy is less effective in anti-PD-1-experienced, compared to naive patients, Levi et al. studied TMB, neoantigen number/quality, neoantigen TIL repertoire, and TIL therapy response in these patients. Overall, TMB, neoantigen number, and breadth of neoantigen TIL repertoire positively correlated with response. Anti-PD-1-naive patients showed a higher TMB and a larger pool of neoantigen-specific TIL than anti-PD-1-experienced patients. This TIL difference persisted even for a TMB-equivalent set of patients, suggesting that other factors, such as clonality, immunoediting, or T cell phenotypic changes also contribute to reduced response.
Contributed by Ed Fritsch
Purpose: Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the National Cancer Institute (NCI) demonstrated decreased responses in patients previously treated with anti PD-1 agents. We aimed to find a basis for the difference in response rates between anti PD-1 naïve and experienced patients.
Experimental design: We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti PD-1 naïve and 69 anti PD-1 experienced patients.
Results: Anti PD-1 naïve patients were found to have higher TMBs (352.0 vs. 213.5, p = 0.005) and more neoantigens (2 vs. 1, p = 0.003) compared to anti PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT non-responders in both anti PD-1naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, patients naïve to anti PD-1 therapy were more likely to have identifiable neoantigens and tumor specific lymphocytes in their treatment products (2.5 vs. 1, p = 0.02).
Conclusions: These results indicate that decreases in TMB and targeted neoantigens only partially account for the difference in response to ACT and that additional factors likely influence responses in these patients.
Author Info: (1) National Institutes of Health, Bethesda, United States. (2) University of California, Los Angeles, Los Angeles, CA, United States. (3) National Institutes of Health, Bethesda,
Author Info: (1) National Institutes of Health, Bethesda, United States. (2) University of California, Los Angeles, Los Angeles, CA, United States. (3) National Institutes of Health, Bethesda, United States. (4) University of Miami Miller School of Medicine, Miami, FL, United States. (5) National Cancer Institute, Bethesda, MD, United States. (6) Amgen, Inc, South San Francisco, CA, United States. (7) Baylor College of Medicine, Houston, TX, United States. (8) National Institutes of Health, Bethesda, United States. (9) National Institutes of Health, Bethesda, United States. (10) National Cancer Institute, Bethesda, MD, United States. (11) National Institutes of Health, Bethesda, United States. (12) National Cancer Institute, Bethesda, MD, United States. (13) National Cancer Institute, Bethesda, MD, United States. (14) NCI/NIH, Bethesda, MD, United States. (15) National Cancer Institute, Bethesda, MD, United States. (16) National Cancer Institute, Bethesda, MD, United States. (17) National Institutes of Health, Bethesda, United States. (18) National Institutes of Health, Gaithersburg, MD, United States. (19) National Cancer Institute, United States. (20) National Cancer Institute, BETHESDA, Maryland, United States. (21) National Cancer Institute, Bethesda, MD, United States. (22) National Cancer Institute, Bethesda, MD, United States. (23) National Cancer Institute, Bethesda, United States. (24) National Cancer Institute, Bethesda, MD, United States.
