Novel Immunotherapy Combinations Against Castration-Resistant Prostate Cancer
Abstract
The latest clinical study reported that an anti-PD-1 antibody, Keytruda, have antitumor activity in patients with metastatic castration-resistant prostate cancer (CRPC) refractory to docetaxel. However, many patients did not respond at all, and approximately only 10% (17/163) of cancer patients responded to immunotherapy in this clinical trial (NCT02787005). Given that tumors with poor T cell trafficking are thought to be less susceptible to single-agent checkpoint blockade cancer immunotherapy, the treatment for CRPC may require combinatorial regimens in order to induce a clinically meaningful response. We have recently identified the oncogenic role of Gal-1 in ovarian cancer (OCa) and prostate cancer (PCa) and discovered a novel small molecule inhibitor of Gal-1, named LLS30, that significantly inhibits the growth of OCa and PCa xenografts in athymic mice (Clinical Cancer Research, 2018, DOI: 10.1158/1078-0432.CCR-18-0157; Molecular Cancer Therapeutics, 2017, DOI: 10.1158/1535-7163.MCT-16-0690). Our preliminary results showed that Gal-1 can induce T cell apoptosis. Most importantly, LLS30 was able to significantly prevent T cell apoptosis induced by Gal-1. LLS30 was not toxic to mice when administered systemically at dose levels ranging from 10 to 50 mg/kg. LLS30 exhibited a favorable pharmacokinetic behavior. Here, we propose to determine whether the efficacy of immunotherapy with an immune checkpoint inhibitor can be enhanced via combining immunotherapy with LLS30. There is a scientific rationale for the combination of LLS30 and anti-PD-1 antibody. This novel drug combination strategy may lead to better therapeutic efficacy in CRPC patients. In addition, LLS30 is smaller and more potent than Gal-1 inhibitor OTX008, which is in phase I clinical trials. LLS30 potentially could be developed into a promising antitumor agent that targets Galectin-1 as a first-in class therapeutic agent. In addition, Gal-1 can be further developed into a prognostic and predictive biomarker of response to checkpoint blockade immunotherapy in CRPC. Since we are planning to arrange pre-Investigational New Drug consultation with the U.S. Food and Drug Administration for LLS30, successful completion of this project can lead to a clinical trial.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910532
Entities
People
- Tsung Shih
Organizations
- United States Army
- University of California, Davis