Bladder Cancer Cell-Intrinsic PD-L1 Signals Affecting Virulence and Treatment Resistance
Abstract
Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP). TOPIC AREAS ADDRESSED: (1) Bladder cancer and (2) immunotherapy. SCIENTIFIC OBJECTIVES: We will define specific signals within the bladder cancer (BC) cells from the PD-L1 molecule on bladder cancer cells. These signals appear to mediate important bladder cancer virulence and treatment resistance mechanisms. These data will be used at the completion of studies proposed here to support a much larger research grant for detailed studies of promising leads developed here. RATIONALE: Ultimate applicability of the research. Immunotherapy with antibodies blocking specific immune checkpoint molecules (such as PD-L1) have greatly improved treatment of advanced stage BC, but still only a minority of patients respond, and mechanisms for treatment response versus failures, and biomarkers to identify patients likely to respond or not are poorly defined. Our goal is to define specific mechanisms for immunotherapy utility versus failure, so that the information can be used to improve bladder cancer immunotherapies. These data likely can also help improve other treatment modalities such as small molecule targeted therapies that have only limited to no significant clinical utility in bladder cancer as single agents. As mechanisms mediating treatment resistance or success are defined, the molecules involved could be treatment response biomarkers to improve patient selection. Improving patient selection means identifying drugs likely to work in a given patient, to steer the patient toward it, and to identify drugs unlikely to work, to steer the patient in a different direction. Finally, these mechanisms likely also are involved in treatment resistance in other cancers, as our studies in melanoma and ovarian cancer suggest, and could improve treatments or biomarkers for them as well. What types of patients will our research help, and how will it help them? Our studies are focused on BC and patients to be treated with BC immunotherapy. We study treatments for patients with localized disease in the bladder as well as bladder cancer that has metastasized (spread) to the lungs. However, we anticipate that findings from these studies will also help improve treatments: (1) for bladder cancer that has spread to other organs aside from lungs, (2) for other treatment approaches in addition to immunotherapies, including cytotoxic chemotherapy and targeted small molecules, and (3) should apply to other cancers aside from bladder cancers. What are the potential clinical applications, benefits, and risks? Our studies show how to improve immunotherapy with two Food and Drug Administration (FDA)-approved approaches: antibodies blocking PD-L1 or PD-1 molecules, and an experimental approach showing great promise in human bladder cancer trials: IL-2 engineered to improve the activity of tumor killer cells normally in the host, but which are not optimally activated. These approaches diverge radically from the current, incompletely effective treatment paradigm by focusing on resistance molecule signals inside the cancer cell, as opposed to signals on the surface, the focus of the current paradigm. We showed that signals inside the cancer cells are highly virulent and need to be addressed for optimal treatment efficacy, a consideration not presently accounted for in current treatment approaches with these FDA-approved agents. What is the projected time it may take to achieve a clinically relevant outcome? Treatments studied – anti- PD-L1 and anti-PD-1 antibodies – are already FDA-approved and can be used in clinical trials relatively quickly. It appears that the resistance pathways we study can also be targeted by other FDA-approved drugs such as chloroquine or rapamycin. Thus, as we confirm efficacy pre-clinically, these approaches could easily go into a human trial in combination with anti-PD-L1 or anti-PD-1 within 18 months. The engineered cytokines that we study as BC drugs a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010757
Entities
People
- Tyler J Curiel
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio