Posted April 26, 2016
Smita K. Nair, Ph.D., and Matthias Gromeier, Ph.D., Duke University

In the March 29, 2015 episode of 60 Minutes titled "Killing Cancer," researchers and clinicians at Duke University presented exciting results on the use of a modified poliovirus as an oncolytic immunotherapy. With support of a Department of Defense (DoD) Breast Cancer Research Program (BCRP) 2003 Concept Award (BC033115), Dr. Matthias Gromeier, a molecular biologist at Duke University, established that this approach is suitable, in principle, for breast cancer as well. The oncolytic therapy functions by targeting the poliovirus receptor, CD155, which is aberrantly expressed in most cancer cells. Due to CD155 overexpression in brain cancers, as described in the 60 Minutes episode, the first clinical trial using the oncolytic poliovirus (PVSRIPO) as an immunotherapy was done in patients suffering from an aggressive brain tumor called glioblastoma. Of the 22 patients that participated in the Phase 1 clinical trial, at least three showed remarkable results and are considered cancer-free, a diagnosis rarely seen in patients with recurrent glioblastoma.

Considering these groundbreaking results in glioblastoma, the PVSRIPO oncolytic immunotherapy could have an even greater impact since it is expected to have utility in a diverse range of tumors expressing CD155, including breast cancer. To move this promising vaccine into breast cancer clinical trials, however, rigorous preclinical studies demonstrating efficacy must be performed to obtain approval by the Food and Drug Administration (FDA) as an Investigational New Drug (IND) for breast cancer. Dr. Smita Nair, an immunologist interested in translational research in the Department of Surgery at Duke University and a colleague of Dr. Gromeier, submitted an application for a 2015 DoD BCRP Breakthrough Award Funding Level 3 that was recommended for funding. The goal of this pending award is to achieve FDA approval in order to conduct Phase I trials of PVSRIPO oncolytic immunotherapy in triple-negative breast cancer patients. PVSRIPO, which causes inflammation, is proposed to stimulate innate and adaptive immunity. Immune cell activation and infiltration into tumors can activate adaptive immune resistance by the upregulation of the programmed death molecule 1 ligand (PD-L1). Therefore, Dr. Nair has proposed to combine PD-L1 inhibitors with PVSRIPO in order to eliminate adaptive resistance and potentiate a durable antitumor immune response. The research team will investigate PVSRIPO-mediated tumor cell killing, inflammation, and PD-L1 upregulation in human breast cancer cell lines and xenograft mouse models, as well as in primary triple-negative breast cancer tumor tissue. Furthermore, they plan to establish PVSRIPO efficacy in an immunocompetent breast cancer mouse model and investigate whether blocking PD-L1 augments therapeutic response. If PVSRIPO proves to be bioactive and effective in the preclinical experiments, the team will pursue a pilot clinical study of intratumoral injection in women with locally recurrent triple negative breast cancer. If successful, this treatment combination will contribute to a pathway toward eradicating the mortality associated with metastatic breast cancer.

Links:

Abstracts for Dr. Gromeier

Public and Technical Abstracts: Targeting Breast Cancer CNS Metastasis with Oncolytic Polioviruses

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