Background: The recent clinical success of immune checkpoint inhibitors in melanoma revealed the therapeutic potential of an anti-tumor T cell response. Previous studies using peptide vaccines to elicit anti tumor T cell response have been limited in efficacy. We have discovered that an oncolytic poliovirus leads to persistent IFN dominant activation of antigen presenting cells. Based upon these findings, we propose to use a recombinant poliovirus (PVS-RIPO) expressing tumor antigens to activate antigen presenting cells and elicit an anti tumor T cell response.
PVS-RIPO is the live attenuated vaccine (SABIN) type 1 containing a foreign human rhinovirus IRES. Preliminary studies in our lab showed that PVS-RIPO is a potent human dendritic cell and CD8 T cell activator. In addition, PVS-RIPO has recently achieved breakthrough status following a very promising phase I clinical trial targeting recurrent glioblastoma (GBM). The efficacy of PVS-RIPO against GBM is thought to be mediated mainly by an anti-tumor CD8 T cells response. The potent activation of dendritic cells as well as the promising results of the phase I clinical trial makes PVS-RIPO a prime candidate for use as a therapeutic tumor vaccine.
The PVS-RIPO vector technology can be adapted to multiple tumor mutations, we are planning to target 2 glioma mutations at this stage: IDH1R132H and EGFRviii mutations. IDH1R132H is a point mutation in the enzyme isocitrate dehydrogenase 1, the mutation is present at high frequency (>70%) in low grade glioma. EGFRviii is a deletion in exon 2-7 of the EGFR gene, it is present in 67% of patients with GBM.
Adjuvancy of PVS-RIPO
We first tested the immune adjuvancy of PVS-RIPO in an in vitro human system. PVS-RIPO was found to sub lethally infect and activate dendritic cells leading to pro inflammatory cytokine production. In addition, dendritic cell incubated with tumor cell lysate, PVS-RIPO and autologous T cells produced an anti tumor CD8 T cell response.
Designing stable PVS-RIPO Vectors
Previous attempts to use poliovirus as a vaccine vector were unsuccessful because of its notorious genetic instability. Our lab has developed a novel strategy to generate stable poliovirus vectors: we use the relative genetic plasticity of the IRES (the dispensable stem-loop Domain VI) to encode tumor antigens. We have successfully made stable PVS-RIPO vectors expressing EGFRviii and IDH1R132H antigens.
Mouse models to study efficiency of vaccine in vivo
Because PVS-RIPO has a rhinovirus IRES, it is incompetent in mouse cells and first had to be adapted for mouse competency. Through murine cell passaging, we have successfully generated a mouse adapted PVS-RIPO virus (mPVS-RIPO) with 5 point mutations in the IRES. We also generated 3 different transgenic (expressing the human poliovirus receptor, CD155) mouse tumor models: 1. Chemically induced model: CT2A-CD155 (C57BL/6-CD155), 2. Genetic model: Neuro Stem Cell-P53fl/fl-mPDGFB-CD155 (C57BL/6-CD155) and 3. Spontaneous tumor model: SMA560-CD155 (VM/DK-CD155).
Conclusion: Here we have put together all the required tools to test the antitumor efficacy of a PVS-RIPO vector vaccine in vivo. Given that PVS-RIPO has some replication competence in muscle cells and also in tumor cells, we are planning to administer the mPVS-RIPO vector intramuscularly as well as intratumorally in mice and monitor its anti tumor efficacy.
Citation Format: M Mubeen Mosaheb, Elena Dobrikova, Michael C. Brown, Christopher Pirozzi, Vidyalakshmi Chandramohan, Eda Holl, Smita Nair, Matthias Gromeier. Using oncolytic polio expressing tumor as a cancer vaccine [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A032.
- ©2016 American Association for Cancer Research.