Stober and Nichols, who previously spoke with ScienceBoard in 2020, provided an update on the platform's key mechanisms of action. The modified poliovirus vaccine is known to elicit direct tumor cell killing. The executives explained that PVSRIPO selectively kills solid tumor cells through the poliovirus receptor, CD155, which is expressed in many solid tumor cells, including melanoma and breast cancer. The viral infection causes apoptosis and cell lysis.

Matt Stober, president and CEO of Istari Oncology.

Furthermore, while CD155 is present on antigen-presenting cells (dendritic cells and macrophages), PVSRIPO has been shown to enter these cells with no adverse impacts. This T-cell priming via antigen-presenting cell activation also enhances the activation of interferon alpha, beta, and lambda, as well as CXCL10. Stober noted that recall of the polio vaccine-specific T cells amplify immune responses; therefore, PVSRIPO can induce potent antitumor T-cell memory, as demonstrated by increases in T-cell function (interferon gamma and tumor necrosis factor alpha).

Importantly, Istari has invested in proof of concept for the combination of PVSRIPO with immune checkpoint blockade therapy (alpha programmed cell death 1 (PD-1)/PD ligand-1 (PD-L1)) in preclinical models of melanoma and glioma. The company is eager to demonstrate synergies for the treatment of solid tumors.

Pushing the envelope with PVSRIPO clinical trials

Istari is currently focused on the clinical investigation of PVSRIPO for the treatment of various cancers through its Luminos family of clinical programs. The Luminos 101 study is investigating the treatment as a monotherapy and in combination with pembrolizumab, an anticancer antibody therapeutic that is sold under the brand name Keytruda. The company expects follow-up data from the phase II monotherapy study and phase I combination study in the first half of 2022. PVSRIPO was granted breakthrough therapy designation and orphan status by the U.S. Food and Drug Administration (FDA) in 2016 for recurrent glioblastoma.

More recently in 2021, the FDA granted Istari an orphan drug designation and fast track designation to PVSRIPO for the treatment of advanced melanoma. The company's Luminos 102 phase I study is investigating PVSRIPO as a monotherapy for the treatment of alpha PD-1 refractory melanoma. Based on strong safety and efficacy results of the phase I study, Istari initiated a phase II combination study with a monotherapy arm and a combination arm with PVSRIPO and immune checkpoint blockade therapy.

Dr. Garrett Nichols, chief medical officer of Istari Oncology.

Lastly, Stober and Nichols shared that Istari is rapidly advancing the Luminos 103 basket trial for the treatment of patients with solid tumors, including cancers involving the bladder, head and neck, with plans to expand to other cancer types. In this design, PVSRIPO will be investigated as a monotherapy in a phase I study involving six to 18 patients to evaluate safety and tolerability. A phase II study will investigate the therapy in combination with checkpoint inhibitors once the monotherapy dosing regimen has been established and considered safe.

Both leaders were enthusiastic about the potential to investigate PVSRIPO for the treatment of new solid tumor indications with high unmet needs.

To execute these complex studies, Istari has recruited a network of key opinion leaders and experts from leading clinical institutions. Stober explained that these leaders have assisted Istari in designing clinical trials and protocols based on past lessons learned and iterations of other cancer clinical trials.

Stober said that Istari has experienced strong support from the FDA. He went on to say the company has had access to preinvestigational new drug meetings for various tumor indications, which has informed Istari about how to rapidly evaluate PVSRIPO in different tumor types and move toward approval.

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