Randomized Phase 2 Clinical Trial of Pembrolizumab Combined with Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 in Recurrent Ovarian Cancer Patients
Abstract
As a physician, I have no curative options to offer my patients who come to me with advanced ovarian cancer (OC). These women endure multiple rounds of chemo or targeted therapy that drives cancer cell resistance and make them extremely sick with a host of side effects that may linger for the rest of their lives. In addition, these women often have a poor quality of life (QoL), resulting in less time spent with family and friends and increasingly less time doing things that bring meaning to their lives. We know cancer will recur in most women, leading to a poor prognosis and increased, shorter intervals where cancer progresses until death. As a physician who designs clinical trials, I know we need to find better, longer-lasting (durable) treatment options to offer our patients that are less toxic, with fewer side effects that don t linger, giving them a good QoL with the people they love. Our group completed a successful clinical trial that accomplished some of these objectives. This proposal builds on what we learned from biospecimens gathered from our exceptional responders who had limited toxicity, a good QoL, and a durable progression-free and overall survival, ~4 and 2 times that of non-responders, respectively. One way to avoid toxic chemotherapy is to better assist the patient s immune system (immunotherapy) in fighting cancer. Immunotherapy has worked in some cancers like melanoma, but not others. We are still trying to figure out what cells and signals generate an effective immune response with immunotherapy and why some patients respond and others do not. While immunotherapy is less toxic than chemotherapy, it is not yet approved for OC patients because it doesn t work well by itself, but is more effective when combined with other drugs. If we can determine how to better turn on a patient s immune system to better respond to immunotherapy, we can treat OC patients with better, less toxic therapies. In OC, we know the presence of a particular type of immune cell, a cytotoxic T cell, means better survival. T-cells stimulated with a cancer protein target can expand and travel to the tumor through blood vessels; these T-cells also need to move into the site of the tumor or tumor microenvironment (TME) to stimulate the immune response for immunotherapy. In addition, there is a battle between the signals (cytokines) that recruit the good or cytotoxic immune T cells to kill cancer cells and the bad immune cells (T-regs), which turn off the immune response. We also don t know the role of the humoral B cell immune response in OC. In our clinical trial in 40 women with recurrent OC, we strategically chose the immunotherapy drug, Pembrolizumab (Keytruda) to activate T cells, Avastin, a targeted blood vessel drug to enhance good T cells into the TME, and an oral drug, Cytoxan, to deplete the bad immunosuppressive T-reg immune cells in a triple combination. We showed 47.5% of patients had a reduction in tumor volume by 50%, an increase in median PFS of 10 mo. vs. 2.9 mo. (with triple vs. single immunotherapy), minimal toxicity, and significantly improved QoL. A remarkable, durable clinical response of >12 mo. was achieved in ~30% of patients. Translational data from responder patient samples showed 1) more T and B cells present in baseline tumor biopsies, increased B cell proliferation, B cell receptor activation, and B cell signaling pathways in tumors, and CD40, a protein on antigen-presenting and B cells, highly expressed. These results suggest that B cells may play a significant role in generating durable responses in OC. Our new study aims to use a novel antibody against CD40 (CDX-1140) to prime T cells in immunologically cold OC tumors by dendritic and B cells combined with Avastin and Pembrolizumab. We will conduct a novel two-arm randomized phase 2 trial in recurrent OC patients to 1.) determine the effectiveness and toxicity of pembrolizumab, bevacizumab, and CDX1140, and 2) determine if
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311063
Entities
People
- Emese Zsiros
Organizations
- United States Army