Immunotherapy strategies for mesothelioma – the role of tumor specific neoantigens in a new era of precision medicine

ABSTRACT

Introduction: Immunotherapy has long been considered a potential therapy for malignant mesothelioma and is currently being pursued as such. Some of the early phase clinical trials involving immunomodulators have demonstrated encouraging results and numerous clinical trials are underway to further investigate this treatment approach in various treatment settings and larger patient cohorts.

Areas covered: This review summarizes the current and emerging clinical evidence for checkpoint blockade and other immunotherapeutic strategies in mesothelioma. The mesothelioma tumor immune microenvironment and mutational landscape are also discussed, including their impact on treatment strategies. We also provide an evaluation of the current evidence for neoantigen targeted personalized immunotherapy.

Expert opinion: Immune checkpoint inhibitors work by unleashing the host immune response against probable neoantigens. Despite impressive activity in a small subset of patients and the potential for prolonged responses, most patients experience treatment failure. Neoantigen vaccines provide a potential complementary therapeutic strategy by increasing the immunogenic antigen load, which can lead to an increased tumor specific immune response. Further research is needed explore this treatment option in mesothelioma and technological advances are required to translate this concept into clinical practice.

KEYWORDS:

• Mesothelioma
• neoantigens
• immunotherapy
• immune checkpoint blockade
• vaccines

Article highlights

• Mesothelioma is an aggressive cancer with significant morbidity and quality of life burden, and limited effective therapeutic options.

• Immunotherapy aims to induce, boost and/or reinvigorate anti-tumor immunity through various mechanisms.

• The role of checkpoint inhibitors such as pembrolizumab, nivolumab, atezolizumab and tremelimumab, alone and in combination with other immunotherapy and chemotherapy agents is currently being investigated in clinical trials. Results from early phase clinical trials show response rates of 4–30% and median overall survival of 7 to 17 months in pretreated patients.

• A number of other immunotherapeutic strategies such as anti-mesothelin therapies, cancer vaccines directed against tumor associated antigens, dendritic cell based therapy, immune gene therapy, CAR T cell therapy have been investigated with mixed results and multiple studies are ongoing.

• High binding affinity neoantigens have been predicted in mesothelioma tissue and may provide a potential therapeutic target.

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Declaration of interest

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 relationships or otherwise to disclose

Additional information

Funding

The authors were supported by the Australian Government Research Training Program Scholarship, Douglas Peter Swift Scholarship, NHMRC of Australia, Insurance Commission of Western Australia, iCARE Foundation, Sir Charles Gairdner Research Advisory Committee, and the Cancer Council of Western Australia.