Molecular mechanisms of response and resistance to immunotherapy in mesothelioma

Anagnostou V, Nowak AK, Forde P, Cook AM, Lesterhuis JL, Brahmer J, Scharpf R, Velculescu V, Smith K.

Funding: US Department of Defense; Team Award (2020).

Synopsis (lay): We recently completed a clinical trial testing the combination of chemotherapy and a type of immunotherapy, known as ‘checkpoint blockade’, to treat malignant mesothelioma. During this study, we collected blood and tissue samples from over 50 participants. We are working with another group in the USA who have completed a similar study. Both trials worked well, so we have jointly instigated a third, bigger study of this treatment. We will use data from all three of these clinical trials to examine how the tumour’s genetics and also the cells of the immune system change in response to treatment. This information can help us make the therapy even more effective.

Synopsis (scientific): Immune checkpoint blockade (ICB) has shown promise in malignant pleural mesothelioma (MPM) and pre-clinical studies have shown that chemotherapy may enhance T cell responses in MPM suggesting a potential synergy between chemotherapy and immunotherapy.  Recent successes with immune targeted agents and combination chemo-immunotherapy in MPM highlight the importance of understanding the underlying mechanisms of response and resistance to these therapies.

Unlike melanoma or lung cancer, therapeutic responses do not seem to be driven by a high tumour mutation burden, as mesotheliomas typically harbor a low number of somatic sequence genomic alterations. Recent studies have identified an increased rate of structural chromosomal abnormalities, including inter- and intra-chromosomal rearrangements in MPM; such alterations may generate immunogenic neoantigens capable of triggering an effective anti-tumour immune response. Overall, the molecular and cellular features driving response to immunotherapy in MPM remain largely unknown. Therefore, harnessing immunotherapy approaches to improve outcomes of MPM patients and predict those most likely to respond is an urgent unmet clinical need.

Together with our collaborators at Johns Hopkins University, USA, we will first perform an integrative genomic and immune repertoire characterization of mesotheliomas with differential responses to combined chemo-immunotherapy to determine the molecular features of responding and resistant tumours. We will then study clonal evolution through analyses of the genomic, neoantigen, transcriptomic and immune repertoire in order to map the evolutionary trajectories under selective pressure of ICB, leveraging serially obtained tissue and blood specimens from a cohort of resectable MPM patients treated with neoadjuvant ICB.

In parallel, we will employ non-invasive molecular assays to capture peripheral clonal dynamics as they relate to response to these therapies. Our approach leverages biospecimens from three cohorts of unresectable MPM treated with combination immuno-chemotherapy in the DREAM, PrE0505 and DREAM3R trials, as well as a cohort of resectable MPM treated with neoadjuvant ICB. The underlying premise of the proposed research is that unravelling the clonal dynamics and mechanisms through which MPM adapts to evade anti-tumour immune responses will be critical for the future development of tailored immune-targeted strategies for this lethal malignancy.

NCARD Research Team

Anna Nowak, Joost Lesterhuis, Alistair Cook, Jonathan Chee, Melvin Chin

Students: Joel Kidman