Medline ® Abstract for Reference 1
of 'Immunotherapy of advanced melanoma with immune checkpoint inhibition'
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA
N Engl J Med. 2014;371(23):2189. Epub 2014 Nov 19.
BACKGROUND: Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.
METHODS: We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.
RESULTS: Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.
CONCLUSIONS: 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. (Funded by the Frederick Adler Fund and others.).
From the Department of Medicine (A.S., T.M., M.A.P., J.D.W.), Human Oncology and Pathogenesis Program (A.S., V.M., A.D., L.A.W., K.K., T.A.C.), Swim across America-Ludwig Collaborative Research Laboratory (T.M., Y.L., C.E., C.L., J.D.W.), Department of Radiation Oncology (T.A.C.), Department of Pathology (T.J.H.), and Immunology Program, Ludwig Center for Cancer Immunotherapy (J.Y., P.W., T.S.H., J.D.W.), Memorial Sloan Kettering Cancer Center; Weill Cornell Medical College (A.S., M.A.P., J.D.W., T.A.C.); and Department of Mathematics, Columbia University (C.B.) - all in New York; the Department of Molecular and Medical Pharmacology (J.M.Z., A.R.) and the Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center (A.R.), University of California, Los Angeles, Los Angeles; and Bristol-Myers Squibb, Princeton, NJ (C.T.H., L.W.).