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Updated: Apr 4, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
Eliezer M Van Allen1,2,3, Diana Miao1,2, Bastian Schilling4,5
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Abstract:
Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Insights
Predicting response to ipilimumab in metastatic melanoma is challenging. While tumor mutational and neoantigen load correlate with benefit, specific neoantigen sequences do not reliably predict patient responders to immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitors like ipilimumab targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) offer clinical benefits for metastatic melanoma.
- Predictors of response to CTLA-4 blockade therapy are not fully understood.
- Understanding the role of tumor neoantigens and the tumor microenvironment is crucial for predicting treatment outcomes.
Purpose of the Study:
- To investigate the association between tumor-specific neoantigens, tumor microenvironment alterations, and clinical response to ipilimumab in metastatic melanoma patients.
- To identify molecular determinants of response and resistance to immune checkpoint inhibitors.
Main Methods:
- Whole-exome sequencing of pretreatment melanoma tumor biopsies and matched germline DNA from 110 patients.
- Transcriptome analysis of pretreatment tumor samples from 40 of these patients.
- Analysis of overall mutational load, neoantigen load, and immune microenvironment markers.
Main Results:
- Overall mutational load, neoantigen load, and expression of cytolytic markers were significantly associated with clinical benefit.
- No specific recurrent neoantigen peptide sequences were identified as predictors of patient response.
- Integrated molecular analysis of larger patient cohorts may be necessary.
Conclusions:
- While tumor neoantigen load and immune microenvironment markers correlate with response to ipilimumab, they are insufficient for predicting responders.
- Identifying robust determinants of response and resistance to immune checkpoint inhibitors requires comprehensive molecular characterization of extensive patient cohorts.
