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Genetic basis for clinical response to CTLA-4 blockade in melanoma
Alexandra Snyder1, Vladimir Makarov1, Taha Merghoub1
1Department 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.).
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.).
Insights
Identifying tumor neoantigens is key to predicting response to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade in melanoma. This study reveals a genetic basis for CTLA-4 therapy benefit, guiding future treatment strategies.
Area of Science:
- Immunogenomics
- Cancer immunology
- Melanoma research
Background:
- Immune checkpoint inhibitors, such as ipilimumab and tremelimumab targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), are effective cancer treatments.
- However, the molecular factors determining clinical benefit from anti-CTLA-4 therapy remain largely unknown.
- CTLA-4 blockade activates T cells, enhancing their tumor-cell-destroying capabilities and prolonging survival in melanoma patients.
Purpose of the Study:
- To investigate the molecular determinants of clinical benefit in melanoma patients treated with CTLA-4 blockade.
- To identify specific tumor neoantigens associated with response to ipilimumab and tremelimumab.
- To establish a genetic basis for predicting efficacy of anti-CTLA-4 therapies.
Main Methods:
- Whole-exome sequencing of tumor and matched blood samples from 64 melanoma patients treated with ipilimumab or tremelimumab.
- Characterization of somatic mutations and identification of candidate neoantigens.
- Testing of neoantigen peptides for T-cell activation in lymphocytes from treated patients.
Main Results:
- Mutational load correlated with clinical benefit but was insufficient for prediction.
- Genomewide neoantigen analysis identified a distinct neoantigen landscape in tumors responding strongly to CTLA-4 blockade.
- Predicted neoantigens successfully activated T cells from ipilimumab-treated patients, validating the findings in an independent cohort.
Conclusions:
- The study defines a genetic basis for benefit from CTLA-4 blockade in melanoma.
- The identified neoantigen signature provides a rationale for exome analysis in patients considered for anti-CTLA-4 therapy.
- These findings support the use of neoantigen profiling to guide treatment decisions for melanoma.
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