Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer

ABSTRACT

Introduction: Immunotherapy has revolutionized the treatment of cancer. Given this growing success, at the same time, there are significant limitations and unanswered questions concerning response rates, duration of therapy, why some patients respond and others do not, and if combining different immune-agents would overcome this lack of response, increase the chance of success and postpone acquired resistance.

Areas covered: The comprehension of how to properly modulate the immune pathways, the molecular and the immunological bases of the disease, will be fundamental to guide the development of therapeutic interventions and combinations that will be more suitable for treatment of cancer patients. In this review, we discuss the strategies of immunotherapy combinations in order to develop more effective immunotherapy programs, with a particular focus on melanoma and renal cancer patients, as well as the combination of immunotherapy and chemotherapy.

Expert Opinion: Given the complexity of immune activation, combinatorial approaches are needed, and due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored. In summary, combined therapies have shown promising success, but additional and continuous research to identify the safety, efficacy, optimal combination, dosage and timing are still required.

KEYWORDS:

• Immunotherapy
• drug combinations
• checkpoint blockade
• combination therapies

Article highlights

• Combination of drugs has the rational of potentially increase the immunogenicity of the tumor, enhancing the effects of immunotherapy.

• Increased response rates have been identified with combination immunotherapy, although combination treatment is associated with increased iAEs and higher cost.

• Given the complexity of immune activation and the physiologic homeostatic mechanisms controlling immune responses, combinatorial approaches are needed to efficiently mobilize the immune system against cancer.

• Due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored.

• A better understanding and characterization of tumor biology and the interactions between cancer and immune system will help to stratify patients by tumor type, target expression on tumor and T cells, and the likelihood of success of combining immunotherapy agents.

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Declaration of interest

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.

Reviewer Disclosures

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

Additional information

Funding

This paper was not funded.