One major development in cancer research is our advancing knowledge about how to teach the immune system to recognize and eliminate tumors. Therapies designed around this principle are expected to be effective even when tumors become resistant to chemotherapy. In this project, we stimulate immune recognition of platinum-resistant ovarian cancer by infecting tumor cells with a virus. The virus studied in this work is an adenovirus, which is similar to the virus that causes the common cold. However, the virus used in this study (CRAd-S-pk7) was engineered so that it only multiplies in cancer cells, not healthy cells. The virus will amplify within the cancer cell, until it bursts and releases viral progeny that can infect and kill neighboring tumor cells. It is a virus that is part of a broad class of therapeutics called oncolytic viruses. The addition of pk7 was made so that the virus will infect ovarian cancer cells more efficiently, but healthy liver cells less efficiently, than the common cold virus. The "S" refers to another safety feature that was added so that the virus will only multiply in ovarian cancer cells, based on their unique expression of survivin. 80% of platinum-resistant ovarian tumors have elevated levels of survivin, whereas healthy adult tissue within the peritoneal cavity does not.
Our team administers CRAd-S-pk7 not as a 'naked' virus, but rather within neural stem cells (NSCs). NSCs have a natural ability to "home" to tumors, and can carry the oncolytic virus to each disseminated metastasis in the peritoneal cavity. The NSCs also protect CRAd-S-pk7 from rapid elimination by the body’s immune system. The NSCs we use are well-characterized, minimally-immunogenic and have already shown safety in four previous clinical trials for glioma patients. These NSCs demonstrate impressive selectivity and penetration of peritoneal ovarian cancer metastases after intraperitoneal administration.
This CIRM award was used to identify a therapeutic dose range and regimen for CRAd-S-pk7 NSCs that is capable of achieving significant long-term survival improvements in preclinical models of ovarian cancer. We also completed pilot toxicology studies to confirm that our therapeutic dose range did not harm liver function. We demonstrated that this treatment stimulates immune cell infiltration into the tumor, and produced evidence that this treatment can elicit an anti-tumor immune response. We drafted a clinical protocol synopsis, and recieved feedback from the FDA on our Pre-IND package which detailed 1) our results to date, and 2) our plans to test this treatment in patients with Stage III platinum-resistant ovarian cancer.
Our long-term goal is to demonstrate safety of CRAd-S-pk7 NSCs within the peritoneal cavity, and eventually, to improve survival outcomes for patients suffering from stage III ovarian cancer.
