Combining a WT1 cancer vaccine (galinpepimut-S) with checkpoint inhibition (nivolumab) in patients with WT1-expressing diffuse pleural mesothelioma (DPM): A phase I study.

8083 Background: Diffuse pleural mesothelioma (DPM) is an aggressive malignancy with poor outcomes and only two FDA-approved therapeutic regimens. The Wilms’ tumor suppressor protein (WT1) is often presented on the surface of DPM and is an ideal therapeutic target. A phase I study confirmed the safety and immunogenicity of galinpepimut-S (GS), a tetravalent, non-HLA restricted, heteroclitic WT1-specific peptide vaccine, in patients with WT1-expressing cancers, and our prior randomized Phase II study of adjuvant GS in patients with DPM suggested an improvement in median overall survival. Vaccine-dependent upregulation of T cell suppressive programmed death-ligand 1 (PD-L1) has been observed in the tumor microenvironment of other malignancies. To further enhance the immunogenicity of GS by reversing the effect of T cell suppression by PD1/PD-L1, we combined GS with checkpoint inhibition using nivolumab, an anti-PD1 monoclonal antibody. This open-label, non-randomized phase I study, examined the tolerability and immunogenicity of GS in combination with nivolumab in patients with previously treated DPM. Methods: We enrolled patients with WT1-positive metastatic or recurrent and measurable DPM treated with at least one course of pemetrexed-based chemotherapy. Patients received 2 doses of GS followed by 4 dose of GS with intravenous nivolumab every 2 weeks, and up to six additional cycles until disease progression, as measured by mRECIST 1.1 on CT imaging, or unacceptable toxicity. Primary endpoint was tolerability of the combination with < 3 patients with severe toxicity. Peripheral blood mononuclear cells (PBMC) were collected every 2 weeks for immune correlative testing. Toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Eliciting of antigen-specific T cells responses was evaluated via WT1 vaccine peptide pool expansion culture of PBMC samples for 10 days in the presence of IL-2 and IL-15 followed by short-term (6 hour) peptide pool restimulation and flow cytometry evaluating CD4/CD8 T cell intracellular cytokine production. Results: Ten patients were treated; 70% experienced treatment-related adverse events which were mostly mild; 2 experienced a grade ≥3 adverse event. Four (50%) of 8 patients had T-cell responses to WT1 peptides. There were no partial responses, but three patients had prolonged stable disease with up to 17% decrease in tumor volume. Median overall survival was 13.5 months from the most recent prior line of therapy. Conclusions: Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses in a subset of patients as indicated by immunophenotyping and disease control rate of 30% at 8 weeks but initial response and survival benefit were limited which may be due to the small sample size. Clinical trial information: NCT04040231 .