Ludwig Cancer Research and the Cancer Research Institute (CRI) announce the initiation of a clinical trial to evaluate the combination of ONCOS-102, an experimental anti-tumor virotherapy, with the checkpoint blockade antibody IMFINZI® (durvalumab) for advanced ovarian and colorectal cancers.
The Phase I/II trial, which has completed enrollment and the safety evaluation for the first patient cohort, could ultimately enroll as many as 78 adult patients in a multi-center program at leading academic centers including Memorial Sloan Kettering Cancer Center (MSK), the Roswell Park Cancer Institute, Sylvester Comprehensive Cancer Center at the University of Miami (UM/Sylvester) and the University of Virginia Health System (UVA). It is chaired by Ludwig and CRI investigator Dmitriy Zamarin of MSK. Kunle Odunsi of the Roswell Park Cancer Institute and Brian Slomovitz of UM/Sylvester are overseeing the trial at their respective institutions with locations to be added for the new cohorts. MedImmune, the global biologics research and development arm of AstraZeneca that developed durvalumab, and Targovax, the biopharmaceutical company that developed ONCOS-102, are also collaborators in the clinical trial.
"Patients diagnosed with advanced ovarian and colorectal cancers that have progressed on standard therapies have very few treatment options available to them," said Vanessa Lucey, director of the CRI Venture Fund and Clinical Accelerator. "Under a unique partnership model, this study leverages the capabilities of two prominent nonprofit groups, accelerates innovation with top academic centers, and includes two different bio-pharmaceutical companies. This is the type of coordination and collaboration we need to accelerate progress for patients."
"Although checkpoint blockade antibodies have been remarkably effective in treating a variety of cancers, many patients fail to respond to these immunotherapies," said Jonathan Skipper, Ludwig's executive vice president for technology development. "Eliciting therapeutic responses in such patients through combination therapies is a top priority of Ludwig's clinical research program, and a major objective of CRI's as well. We have good reason to believe that combining checkpoint blockade with oncolytic virotherapy is a highly promising strategy to that end. We very much look forward to seeing the results of this trial."
ONCOS-102 is a serotype 5 adenovirus--a relative of the cold virus--that has been engineered to selectively infect and kill cancer cells. The virus has also been modified to express a gene for an immune factor known as granulocyte-macrophage colony stimulating factor (GM-CSF), which boosts critical elements of the immune response. ONCOS-102 has been shown in a previous trial to be safe and to induce anti-cancer immune responses.
Durvalumab, which is already approved for clinical use in other cancers, is a human monoclonal antibody directed against PD-L1. PD-L1 ordinarily protects healthy cells from destruction by a runaway immune response. Tumor cells, however, can co-opt PD-L1 to evade attack by the immune system's killer T cells. Durvalumab blocks PD-L1 interaction with PD-1 and CD80, countering the tumor's immune-evading tactics and inducing an immune response.
There is emerging evidence that combining checkpoint blockade with virotherapy could have a therapeutic effect against cancers. Viral infection of cancer cells is hypothesized to draw activated killer T cells into tumors. Once in the tumor, the T cells are exposed to telltale antigens released by dying cancer cells, potentially awakening an immune response against the malignancy as well.
Preclinical research done on mice by Zamarin and others has shown that infecting a tumor with an oncolytic virus and following up with a checkpoint blockade therapy elicits a systemic immune response that targets not only the infected tumor but also other tumors in the body. It is hoped that the GM-CSF expressed by the virus as it multiplies in cancer cells will further boost this kind of anti-tumor response.
The current trial is enrolling patients whose colorectal or ovarian cancers have become resistant to all conventional treatment and whose tumors have spread into the peritoneum--the membrane around the abdominal cavity. ONCOS-102 is being delivered directly into the peritoneal membrane, while durvalumab will be given systemically.
The objectives of this open label trial are to test the safety and preliminary efficacy of the combination, optimize dosing, evaluate the feasibility of peritoneal delivery of ONCOS-102 and inform current and future translational research.