Can checkpoint inhibitor therapy improve response to chemotherapy?

Excerpt

The emergence of novel therapies has substantially changed the treatment landscape in advanced melanoma. Disrupting the MAPK pathway in BRAF mutant patients with targeted therapies and enhancing antitumor immunity with immune checkpoint inhibitors have shown unique clinical benefit and superseded the era of chemotherapy in melanoma. Randomized clinical trials showed response rates of 12–19% for the anti-cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) antibody ipilimumab, 33–44% for anti-programmed death 1 (PD-1) antibodies, and 57–62% for combined ipilimumab and nivolumab treatment (Larkin et al. 2015; Robert et al. 2015) with only rare responses to combined checkpoint inhibitor therapy after progression upon sequential antibody monotherapy (Kirchberger et al. 2016). Serum biomarkers can be used to monitor clinical response and enrich for populations with clinical benefit. However, predictive markers to guide therapy decisions are still missing in melanoma. Despite these results only a subset of patients achieves long-term stable disease. One factor that is associated with clinical response is the abundance of CD8+T cells in the tumor microenvironment. Thus, transforming immunologically “cold” tumors into cytotoxic T-cell rich “hot” tumors is assumed to have the potential to boost tumor response rates. In murine lung adenocarcinoma models, the combination of oxaliplatin and cyclophosphamide induced CD8+T cell infiltration and thus sensitized tumors to anti-PD-1 and anti-CTLA-4 checkpoint inhibitor treatment (Pfirschke et al. 2016). Our clinical experience indicates that patients could benefit from chemotherapy after failure of checkpoint inhibitor therapy and the response rates of second-line chemotherapy need further investigation. …