Somatic Tumor Neoepitopes as Basis for Response to CTLA-4 Inhibition in Melanoma


Key Points

  • High mutational load alone did not account for long-term benefit.
  • A signature of somatic tumor neoepitopes was significantly associated with long-term benefit and increased overall survival.

The molecular determinants of benefit from immune checkpoint inhibitor treatment have not been characterized. In a study reported in The New England Journal of Medicine, Snyder et al found that benefit of the anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies ipilimumab (Yervoy) and tremelimumab, which activate T cells, is associated with a large number of somatic tumor neoantigens in patients with melanoma.

The study involved 25 discovery set patients (11 with long-term benefit and 15 with no or minimal benefit from ipilimumab) and 39 validation set patients (25 with long-term benefit and 14 with no/minimal benefit from ipilimumab or tremelimumab). Whole-exome sequencing was performed on tumors and matched blood samples.

Effect of Mutational Load

Higher mutational load was associated with degree of clinical benefit in both the discovery set (P = .01) and validation set (P = .009); in the discovery set, patients with > 100 mutations had significantly longer overall survival than those with fewer mutations (P = .04), with a trend toward improved survival observed in the validation set. However, absence of response to therapy was observed in tumors with high mutational load, indicating that mutational load alone was not sufficient for response.

Tumor Neoepitope Signature

Candidate tumor neoantigens were identified for each patient using genome-wide somatic neoepitope analysis and patient-specific HLA typing. In the discovery set, a predictive signature for long-term benefit was identified that consisted of 101 tetrapeptide neoepitopes shared exclusively among the patients with long-term benefit, with the finding being independently observed in the validation set; in five models tested, P values for the association were < .001 in four and .002 in one. The neoepitope signature derived in the discovery set was strongly associated with increased overall survival in both the discovery and validation sets (P < .001 for both).

The shared neoepitopes did not appear to be a consequence of high mutational load alone. For example, the patient in the discovery set with the greatest number of mutations (1,028) among patients with little or no benefit from treatment shared none of the neoepitope signatures with patients who had long-term benefit. Overall, a high mutational load appeared to increase the likelihood of but not guarantee presence of a neoepitope signature associated with benefit.

In testing in vitro, the predicted neoantigens activated T cells from patients treated with ipilimumab.

The investigators concluded: “These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti–CTLA-4 agents are being considered.”

Timothy A. Chan, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine Dr. Chan and Jedd D. Wolchok, MD, PhD, and Alexandra Snyder, MD, Vladimir Makarov, MD, Taha Merghoub, PhD, and Jianda Yuan, MD, PhD, all of Memorial Sloan Kettering Cancer Center, contributed equally to the article.

The study was funded by the Frederick Adler Fund, National Institutes of Health, Swim across America, Ludwig Trust, Melanoma Research Alliance, Stand Up to Cancer-Cancer Research Institute Immunotherapy Dream Team, Hazen Polsky Foundation, STARR Cancer Consortium, and a Ruth L. Kirschstein National Research Service Award. Bristol-Myers Squibb, the employer of two authors, did not provide funding for the study. For full disclosures of the study authors, visit

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