Combining immunotherapies to treat non-small cell lung cancer

ABSTRACT

Introduction: In recent years, immunotherapy has become an integral part of the treatment of many cancers, including non-small cell lung cancer (NSCLC). Precious therapeutic weapons impacting survival are monoclonal antibodies directed against the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint.

Areas covered: Unfortunately, not all patients treated with checkpoint inhibitors have durable clinical responses. However, a better understanding of the complexity of interactions between the immune system and cancer, the latter capable of adopting evasion mechanisms, indicates different opportunities to enhance anti-tumor immunity.

Expert opinion: In this paper, we review multiple strategies of combining immunotherapies that exploit not only additional immune checkpoint receptors and ligands but also other synergistic approaches such as vaccines or indoleamine 2,3-dioxygenase (IDO) inhibitors with the potential to extend the number of NSCLC patients achieving successful outcomes.

KEYWORDS:

• Combination immunotherapies
• durvalumab
• IDO inhibitors
• ipilimumab
• nivolumab
• NSCLC
• tremelimumab
• tumor mutational burden
• vaccines

Article Highlights

• Immunotherapy is a major breakthrough of the last years in treating advanced NSCLC. Anti-PD-(L)1 immune checkpoint antibodies boost the antitumor T cell response resulting in a survival gain by patients.

• Actually, tumor cells can escape from the immune system through different mechanisms and not all treated patients have the same benefit from immunotherapy.

• Tumour and the surrounding microenvironment actively interact with the immune system. This led to the development of a number of combining immunotherapies with synergistic effects.

• Phase III clinical studies using combinations of antagonistic PD-(L)1 and CTLA-4 antibodies, as first-line treatment for advanced NSCLC, are ongoing.

• TMB failed to be an independent biomarker influencing the benefits of the immunotherapy combos.

• Apart from enhancing T cell activation, current research is aiming to revert inhibitory signals and augment the release of tumor antigens, for example through the development of IDO inhibitors and cancer vaccines, respectively.

• The need for prospectively validated prognostic and predictive biomarkers remains to better select patients responders to immunotherapy and its combinations.

• Rational combination immunotherapy strategies, also associated with chemotherapy, represent the future of immuno-oncology with a view to improving efficacy and reducing resistance.

Declaration of interest

One author has received honoraria as speaker bureau and advisory board member for BMS, MSD, Roche, and Astra Zeneca. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

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

Additional information

Funding

This paper was not funded.