Unleashing the Full Potential of Checkpoint Inhibitor Antibodies with T-Cell-Stimulating Oncolytic Adenoviruses for Treatment of Ovarian Cancer
Abstract
Ovarian cancer stands out as one of the deadliest cancers in women with a yearly rising trend in new cases and deaths. In 2021, more than 20,000 American women are estimated to be affected by it, and expected 13,000 deaths will result from the disease. Over the next 5 years, an estimated 2,600 members of military families will be diagnosed with ovarian cancer, which will cost TRICARE approximately $971.2 million. Currently, the standard treatment includes surgery, chemotherapy, and/or other systemic therapies. While initial cancer shrinkage and, even cancer disappearance, is often achieved, it will eventually return more aggressive but resistant/refractory to platinum chemotherapy and often not effectively treatable with any of the aforementioned therapies. With the life expectancy of those patients remaining short, it is critical to develop new treatment options for ovarian cancer patients. Immunotherapies - which induce and/or enhance the patient’s own immune system response against cancer – may offer the key for this therapeutic gap. The past decades produced reliable evidence that the approach can lead to cancer shrinkage, cancer disappearance and, importantly, long lasting cancer-free periods or cures. In advanced ovarian cancer, immunotherapy has led to promising anticancer responses, however the approach only works in a few patients. Current treatments focus on surgery and platinum-based chemotherapy, which are not curative for most patients. A particular problem in OvCa is platinum-resistant patients, who progress sooner than six months after platinum- based chemotherapy. Platinum-resistance ultimately occurs in the majority of recurrent OvCa patients, and no therapy is considered standard for these patients because of poor response rates. Ongoing trials investigate new treatment approaches, such as immune checkpoint inhibitors (ICI), which show much promise in many indications, but the overall response rates in OvCa remain low: a bit over 10%. The unmet medical need requires development of more effective treatments. Adenoviruses are a well-known family of viruses, which can be repurposed for cancer therapy. They can be easily genetically modified to selectively target, infect and destroy cancer cells. Oncolytic adenoviruses, as they are called, are inherently capable of stimulating the immune system and can be further engineered with the addition of genes that enhance anticancer immune responses. In particular, oncolytic adenoviruses engineered with immune stimulatory genes have been shown promising for the treatment of patients with ovarian cancer and beneficial in combination with a wide range of other immunotherapies in animal models. TILT Biotherapeutics (TILT) proposes to develop a double punch therapeutic optimized for ovarian cancer, in this application. For this purpose, they will make use of a genetically-engineered common cold oncolytic adenovirus TILT-123 that (1) selectively kills cancer cells without harming healthy ones and (2) stimulates the immune system to kill cancer cells. The latter is achieved by the release of IL-2 variant, a growth factor that is known to increase the anticancer immune cells without stimulating regulator immune cells. In order to do so, TILT will utilize their novel technology, TILT-123 in combination with pembrolizumab to make them effective enough to treat ovarian cancer that is resistant/refractory to platinum chemotherapy. The proposed project is an open-label, phase 1, dose-escalation study evaluating the safety of TILT-123 when given in combination with pembrolizumab to subjects with platinum refractory/resistant ovarian cancer (NCT05271318). A total of 15-24 female subjects will be recruited into a maximum of three cohorts. The study will consist of screening, a treatment period (up to 2 years), and a safety follow-up period. TILT-123 dose will increase between each cohort. Finally, a cohort expansion at maximum tolerated dose will be a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310988
Entities
People
- Akseli Hemminki
Organizations
- United States Army