City of Hope
Department of Experimental Therapeutics
Location - Tech L211
Hosted by Chad Mirkin
"Clinical and Developmental Strategies for Immunotherapy of Solid Tumors using Checkpoint Inhibition"
Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for over twenty-five years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO) with an RNA(i) inhibitory expressing plasmid, and an enzyme PEGPH20 (Halozyme Therapeutics) which depletes extracellular matrix hyaluronan, we observed extended survival of mice with frequent total regression of orthotopic PDAC tumors. This was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleen into tumors, which was not observed using a scrambled RNAi control sequence (shScr-ST). Collectively, our data demonstrate that entry of shIDO-ST and PMN into otherwise impermeable fibrotic (desmoplastic) tumors is facilitated by PEGPH20-mediated HA removal. The stimulus for developing shIDO-ST as an experimental alternative to a traditional tumor vaccine came from our first-in-human, Phase I trial of a Modified Vaccinia Ankara vector delivering wild type human p53 (p53MVA) in patients with refractory GI cancers (PDAC and colon). p53 is an attractive target for immunotherapy of a wide range of malignancies, and data from in vitro studies, murine models and clinical trials support the rationale of targeting this protein. p53MVA was well tolerated and elevated the p53-specific CD8+ T cell response. Furthermore, higher anti-p53 immune responses were detected in patients with lower frequencies of PD1+ T cells and enhanced responses were achievable with antibody blockade of PD1 in vitro. These findings support the continued development of p53MVA, particularly in combination with immune checkpoint inhibition delivered by antibodies or RNAi targeting immunosuppressive molecules.
Dr. Diamond was appointed in 2014 to lead the Department of Experimental Therapeutics. Since 1999, he has lead the Division of Translational Vaccine Research, a multidisciplinary laboratory comprised of 20 faculty, physicians, fellows, technicians, and graduate students. The focus is to develop vaccines to combat hematologic malignancies, solid tumors, and infectious pathogens such as the herpes virus, CMV. Annually the laboratory is supported by multiple grant mechanisms including funding from the NCI, NIAID, NHLBI, NICHD, and private foundations. He is the sponsor of three active INDs involving his vaccine inventions. A therapeutic CMV peptide vaccine developed in the TVR is undergoing Phase 2 human efficacy testing in stem cell transplant recipients in a multi-site study with the University of Minnesota. At the same time, a second generation CMV vaccine based on the attenuated pox virus MVA is well underway in Phase 1 human safety testing (22/24 recipients received the vaccine). A vaccine developed in the TVR also based on the MVA platform, expressing unmutated germline p53 has completed Phase 1 human testing in City of Hope gastrointestinal cancer patients. Currently, it is undergoing pilot Phase 2 evaluation in platinum-resistant ovarian cancer patients at COH. His portfolio has expanded to include salmonella delivery of cancer vaccines and RNA silencing plasmids to develop an oncotherapeutic to control the progression of pancreatic ductal adenocarcinoma. Finally, in collaboration with Peter Barry Ph.D., director of the Center for Comparative Medicine at UC Davis and the California National Primate Research Center, they have developed a prophylactic human CMV vaccine that promises to control gestational infection that causes a wide range of birth defects. Annually, he serves as chair for the Division of AIDS Phase 1 and 2 clinical trial applications, vaccine and infectious disease applications of the NIAID, and NCI special emphasis panels as needed. He is considered a leading expert in vaccines for infectious disease, including HIV, CMV, HCV, influenza, and emerging pandemic pathogens. He has reviewed the US DOD HIV program on multiple occasions. He is the author of 115 peer-reviewed publications, received 17 US patents, and additional patents pending.