PVX-410 is a multi-peptide therapeutic cancer vaccine being developed for patients with SMM. The goal of treatment with PVX-410 is to induce an immune response against multiple myeloma (MM) cells by “educating” the patient’s cytotoxic T lymphocytes (CTLs) to target specific tumor associated antigens. By targeting multiple antigens simultaneously, multiple peptides are employed to target the tumor cell heterogeneity observed in MM, as in all cancers, and decrease the likelihood of tumor cells developing resistance to CTLs. The vaccine is composed of a unique combination of four peptides which specifically target the highly over-expressed tumor antigens XBP1, CD138 and CS1.
PVX-410 has the potential to be utilized as a stand-alone therapy and in combination with other immunotherapeutic drug-like checkpoint inhibitors. In 2013, PVX-410 was granted orphan drug designation from the U.S. Food and Drug Administration for the treatment of MM.
Development in SMM
The Phase 1 dose escalation study of PVX-410 enrolled a total of 22 patients with smoldering multiple myeloma at moderate or high risk of progression to multiple myeloma. Twelve patients were enrolled in the dose escalation stage of the study and received PVX-410 plus adjuvant and 10 patients received PVX-410 plus adjuvant and lenalidomide. Lenalidomide (Revlimid®, Celgene, Corp.) is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Given the clinical experience in high risk SMM and the known immunomodulatory properties, OncoPep investigated whether the co-administration of lenalidomide could enhance the T cell-mediated immune response induced by PVX-410.
All tested doses of PVX-410 were found to be well tolerated, both as a stand-alone therapy and in combination with lenalidomide. A flow cytometry based assay (FACS) was used to detect antigen specific T cell responses to the vaccine. An immune response to PVX-410 was observed, as determined by the level of increase in the percentage of tetramer and interferon gamma positive cells after vaccination with PVX-410 alone. This response was enhanced by the addition of lenalidomide. Final results from the study were presented in a poster presentation at the American Society of Hematology in December 2016. Based on these promising findings, OncoPep is planning to initiate a Phase 2 clinical trial of PVX-410 to determine the optimal dosing regimen in the moderate and high-risk SMM patient population.
Additional clinical trials are being developed to evaluate the combination of PVX-410 plus checkpoint antibodies to the PD-1/PD-L1 ligand. Blocking immune checkpoint receptors on activated T cells should enhance the vaccine-stimulated immune response. The premise of the checkpoint antibody strategy is to use a vaccine, such as PVX-410, that will stimulate an immune response to critical antigens on MM cells while simultaneously removing the PD-1/PD-L1 mediated inhibition of the patient’s immune response. PVX-410 is currently being evaluated in an investigator initiated study in combination with an immunomodulator plus the PD1/PDL1 checkpoint inhibitor, durvalumab (Celgene, Inc.) in SMM and TNBC. A second investigator study is planned to evaluate PVX-410 in combination with the PD-1/PD-L1 checkpoint inhibitor, nivolumab (Bristol Myers Squibb) in SMM.
Development in TNBC
Building on the scientific rationale for combining a vaccine approach with PD-1/PD-L1 mediated inhibition of the patient’s immune response for the treatment of solid tumors, PVX-410 is being studied in triple negative breast cancer (TNBC) in combination with checkpoint antibodies. A Phase 1b investigator sponsored study is underway to investigate PVX-410 in combination with the PD-L1 inhibitor, durvalumab (AstraZeneca, Inc.) as an adjuvant treatment for patients with (Stage II/III) TNBC who have completed a standard treatment regimen. A second investigator sponsored Phase 1b study opened in Q4 2017 to evaluate PVX-410 in combination with the PD-1 inhibitor, pembrolizumab (Merck, Inc.) for patients with metastatic TNBC.