Nivolumab in combination with ipilimumab for the treatment of melanoma

Abstract

Melanoma patients develop resistance to most therapies, including chemo- and targeted-therapy drugs. Single-agent therapies are ineffective due to the heterogeneous nature of tumors comprising several subpopulations. Treatment of melanoma with immune-based therapies such as anti-cytotoxic T-lymphocyte activation-4 and anti-programmed death-1 antibodies has shown modest but long-lasting responses. Unfortunately, only subsets of melanoma patients respond to antibody-based therapies. Heterogeneity in lymphocyte infiltration and low frequency of anti-melanoma-reactive T-cells in tumor lesions are partly responsible for a lack of response to antibody-based therapies. Both antibodies have same biological function but they bind to different ligands at various phases of T-cell activity. Thus, combination therapy of antibodies has shown superior response rates than single-agent therapy. However, toxicity is a cause of concern in these therapies. Future identification of therapy-response biomarkers, mobilization of tumor-reactive T-cell infiltration using cancer vaccines, or non-specific targeted-therapy drugs will minimize toxicity levels and provide long-term remissions in melanoma patients.

Keywords:

• antibody therapy
• anti-CTLA-4
• anti-PD-1
• immune-checkpoint inhibitors
• Melanoma

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Approval of targeted therapy drugs and immune-based therapies has revolutionized the treatment of advanced melanoma patients.

• Therapy resistance and immune non-responsiveness to immune checkpoint blockade antibodies is a major issue.

• Combination therapy approach of debulking tumor followed by immune checkpoint blockade may effectively overcome immune non-responsiveness to immunological therapies.

• Toxicity to targeted- and immune-based therapies is a major concern with combination therapies.

• Modern imaging techniques to monitor immune cell trafficking into tumor lesions will help in predicting therapy response and reduce toxicity issues when immune-based therapies are used for treatment.

• Mobilization of anti-tumor specific T-cells by cancer vaccines or by non-specific means by use of BRAF and MEK inhibitors will reduce toxicity and provide better OS in patients.

• Enhancement and prolongation of T-cell infiltration into tumor lesions by using VEGF inhibitors.