University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Breast Oncology Program Seminar

February 13, 2019, 8:30 am – 10:00 am

Mount Zion
2340 Sutter Street
Lurie Seminar Room
San Francisco, CA 94143

Noriyuki Kasahara, MD, PhD, UCSF   >view speaker profile

"Retroviral Replicating Vector-mediated Gene Therapy / Immunotherapy: Current Clinical Trials and Translational Application to Breast Cancer"

Abstract: Retroviral replicating vectors (RRV) can deliver transgenes efficiently and selectively to tumors, as they only infect actively-dividing cells and are restricted in normal tissues by innate and adaptive immune mechanisms which are down-regulated in cancer. Toca 511 (vocimagene amiretrorepvec) is an RRV encoding an optimized yeast cytosine deaminase (CD) prodrug-activator enzyme, which converts an anti-fungal prodrug 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU).  Tumor-specific virus spread and persistent CD expression by Toca 511 enables repeated cycles of 5-FC prodrug conversion into active 5-FU exclusively within tumors, thereby avoiding adverse effects associated with systemic chemotherapy and leaving the immune system intact, leading to long-term survival benefit and development of durable anti-tumor immune responses.  In early-phase multi-center clinical trials for recurrent high-grade glioma (www.clinicaltrials.gov: NCT01156584, NCT01479794,  NCT01985256), all dose levels were safe and well-tolerated, and significant therapeutic benefit has been observed, including median overall survival surpassing historical benchmarks and complete responses without relapse for > 3-5 years.  Based on these results, a registrational Phase III study (NCT02414165) in patients with recurrent high-grade glioma is now on-going, and further preclinical validation in other disease models has led to initiation of another Phase Ib trial (NCT02576665) evaluating RRV-mediated gene therapy / immunotherapy in various systemic malignancies, including CNS-metastatic breast cancer.
 
The educational objectives of this presentation are to:
  1. Introduce the scientific rationale, previous clinical efforts, and current concepts related to the field of oncolytic virotherapy.
  2. Describe the unique advantages of employing retroviral replicating vectors (RRV) for prodrug-activator gene therapy, and explain the differences of this approach compared to conventional chemotherapy and other oncolytic virus-based therapies.
  3. Present peer-reviewed results of preclinical studies leading to clinical translation of RRV-mediated prodrug activator gene therapy, and introduce independent expert-reviewed interim results of current clinical trials.
By the end of this presentation, participants should be able to:
  • Discuss the principles of oncolytic virotherapy and current translational and clinical efforts to apply viruses for treatment of various malignancies, including breast cancer.
  • Identify the mechanism of action of RRV-mediated prodrug-activator gene therapy, and distinguish how this approach differs from conventional systemic chemotherapy and most oncolytic virotherapies.
  • Recognize the potential for viral therapies to evoke anti-tumor immune responses leading to long-term therapeutic benefit.

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