546P - Combination therapy with anti-PD-1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation

Background

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although combination therapy of ipilimumab plus nivolumab has proven to bring about a better outcome in patients with MPM, long-term survival remains unsatisfactory. To further improve the prognosis, developing a novel treatment strategy to maximize the antitumor effect of ICI is a pressing issue. We examined whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-PD-1 antibody (Ab).

Methods

We established subcutaneous mice mesothelioma allograft model. Mice were treated either with vehicle, anti-PD-1 Ab, nintedanib or anti-PD-1 Ab plus nintedanib. Tumor size was routinely measured with a caliper. Mice were euthanized before they became moribund, and allografts were collected for histological analyses. Angiogenesis and infiltrating immune cells were assessed by immunohistochemistry (IHC). We further performed ex vivo study using bone marrow-derived macrophages (BMDMs) to elucidate the antitumor mechanism of the combination therapy of anti-PD-1 Ab plus nintedanib.

Results

Nintedanib significantly suppressed the growth of mesothelioma allografts. Combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy. IHC analyses revealed that nintedanib not only inhibited angiogenesis but also decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, ex vivo study using BMDMs showed that nintedanib could polarize TAMs from M2 to M1 phenotype. Thus, nintedanib could suppress protumor activity of TAMs both numerically and functionally. On the other hand, nintedanib upregulated the expression of PD-1 and PD-L1 in BMDMs and mesothelioma cells, respectively, and impaired the phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal.

Conclusions

Combination therapy of anti-PD-1 Ab plus nintedanib exerts synergistic antitumor activity and can become a novel therapeutic option for patients with MPM.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Minami: Financial Interests, Institutional, Research Grant: Nippon Boehringer Ingelheim. All other authors have declared no conflicts of interest.