Melanoma immunotherapy: strategies to overcome pharmacological resistance

ABSTRACT

Introduction: Although checkpoint inhibitors have provided a breakthrough in how melanoma is treated, about half of patients still do not respond due to primary or acquired resistance. New strategies are, therefore, required to increase the number of patients benefiting from immunotherapy. This systematic review investigates novel combinations that may overcome immune resistance in patients with melanoma.

Areas covered: We provide an overview of immune-related resistance mechanisms and the various therapeutic strategies that can be considered in attempting to overcome these barriers, including combined immunotherapy approaches and combinations with chemotherapy, radiotherapy, and targeted therapy.

Expert opinion: The immune response is a dynamic process in which the tumor microenvironment and immune cells interact in a variety of ways. New treatment approaches aim to enrich the tumor microenvironment with immune-infiltrate and increase response to immune checkpoint inhibitors.

KEYWORDS:

• Melanoma
• immunotherapy
• combination treatment
• immune resistance
• tumor microenvironment

Article highlights

• Despite the improved long-term outcomes seen with checkpoint inhibitors, nearly 40-50% of tumours are not responsive to single-agent immune checkpoint blockade, and those that do respond can develop resistance over time.

• Immuno-resistance can be clinically categorized as primary resistance if the tumour does not respond to immunotherapy with progression during the first 3-4 months of therapy, or acquired resistance (secondary), if progression occurs after stable disease on therapy.

• Three models of cancer immune phenotype have been described: the inflamed tumour (‘immune-hot’), in which the TME is enriched by immune infiltrate and the tumour shows a significant response to immune checkpoint inhibition; the immune-excluded tumour (‘immune-cold’), in which immune cells in the TME are peripheric due to stromal or vascular factors, driving resistance to immunotherapy; and the immune desert tumour, without evidence of immune infiltrate in the TME.

• The most important mechanisms of resistance may include an immune desert or immune-excluded tumour phenotype, an increase in the number of regulatory cells into the tumour microenvironment, an increase in the production of immunosuppressive cytokines (e.g. TGF-β, IL-8, VEGF), and upregulation of inhibitory receptors expressed on T cells (e.g. PD-1, CTLA-4, LAG3, TIM3, BTLA, VISTA, CD160).

• In order to overcome resistance to single-agent immune checkpoint inhibition, combination strategies have been suggested and multiple trials of different combinations are currently being conducted, including with chemotherapy, radiotherapy, targeted therapy and other immunotherapies with complementary modes of action.

Declaration of interest

Paolo A Ascierto has served in a consultant or advisory role for Bristol Myers Squibb, Roche-Genentech, Merck, Sharpe & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, 4SC, and Alkermes; has received research funding from Bristol Myers Squibb, Roche-Genentech, and Array; and has received travel funding from Merck, Sharpe & Dohme. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This manuscript has not received any funding.