Genomic correlates of response to CTLA-4 blockade in metastatic melanoma

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.

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

“…To test this, we applied our method to a dataset consisting of 42 pre-treatment melanoma biopsies from patients that received anti-CTLA-4 therapy. 10 As in the PD-1/PD-L1 data, we observed significantly higher MBL scores in patients experiencing clinical benefit within 6 months (P = 0.05) and long-term survival with no clinical benefit (P = 0.05) relative to patients experiencing no clinical benefit following treatment (Figure 2A). Furthermore, high-MBL patients exhibited significantly prolonged overall survival compared to low-MBL patients, with high-MBL patients having a median overall survival time of 853 days compared to 160 days in low-MBL patients (P = 0.01; Figure 2B).…”

“…6 Early immune-related biomarkers that have been identified for anti-PD-1/anti-PD-L1 include CD8 + T cell density 7 and intratumoral PD-L1 expression, 8 while the expression of immune-related genes has been associated with response to anti-CTLA-4. 9,10 In addition to markers of immune infiltration, a higher tumor mutation burden (TMB) has been associated with response to both therapies, implicating the neoantigen-driven immune reaction as a common factor involved in immune checkpoint blockade response. 10–14 Interestingly, somatic copy number alterations (SCNAs) have been shown to be more strongly correlated with tumor immune activity and response to anti-CTLA-4 than TMB, with lower SCNA levels associated with higher immune activity and improved response rates.…”

“…9,10 In addition to markers of immune infiltration, a higher tumor mutation burden (TMB) has been associated with response to both therapies, implicating the neoantigen-driven immune reaction as a common factor involved in immune checkpoint blockade response. 10–14 Interestingly, somatic copy number alterations (SCNAs) have been shown to be more strongly correlated with tumor immune activity and response to anti-CTLA-4 than TMB, with lower SCNA levels associated with higher immune activity and improved response rates. 15 The pre-treatment transcriptome of patients receiving immune checkpoint inhibitors is one area that has yet to be fully explored.…”

“…Recent studies have released transcriptomic data and identified expression-based correlates of response for small cohorts of patients receiving immune checkpoint blockade therapy. 10,12,13 However, no studies have examined whether common and reproducible correlates exist that are associated with response to drugs targeting the PD-1/PD-L1 axis and CTLA-4.…”

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…While being an adverse prognostic marker, a nonsynonymous NF1 mutation can be a favorable treatment‐predictive marker, by virtue of its association with increased mutational load. In particular, tumors with high mutational burden (or deficiency in the DNA mismatch repair pathway leading to such an increase) have recently been shown to respond better to immune checkpoint blockade agents (Le et al ., 2015; McGranahan et al ., 2016; Rizvi et al ., 2015; Van Allen et al ., 2015). Furthermore, NF1 ‐mutant melanomas have been found to be dependent on MAPK signaling and to respond to inhibitors targeting key players of this pathway (MEK, ERK) (Maertens et al ., 2013; Nissan et al ., 2014; Whittaker et al ., 2013).…”