Photoregulated Immunotherapy
Abstract
This study addresses at least two Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) topic areas (immunotherapy and lymphoma) and FY18 PRCRP military relevance focus areas (militarily relevant risk factors associated with cancer and gaps in cancer treatment). Hematologic malignancies such as non-Hodgkin B-cell Lymphoma (NHL) is reported to affect the Veteran, surviving spouses, dependent children and dependent parents of Veterans who were exposed to herbicides during military Service. Immunotherapy constitutes a new pillar of treatment and has shown highly promising therapeutic outcomes in such cancer patients. As of 2018, over 150 active clinical trials using engineered immune cells for cancer therapy have been carried out in the United States. Among these, chimeric antigen receptor (CAR) T-cell therapy has demonstrated curative potential for elimination of tumors and has been recently approved by the Food and Drug Administration (Yescarta™ and Kymriah™) to treat NHL and leukemia. The T cells used in this approach are collected from a patient or a donor, and are then engineered ex vivo to express tumor-specific recombinant receptors composed of key signaling modules from both the T cell receptor (TCR) and co-stimulatory receptors. CAR-T cells can mount effective anti-tumor immunity. The membrane receptor of these CAR-T cells can be specific to a cell surface antigen on the target cancer cells, and is fused to a T cell activating protein in the cytoplasm. Following reintroduction into patients, the CAR-T cells are able to recognize their cognate target antigen on cancer cells and become activated to attack cancer cells expressing the antigen. While these advances in CAR-T therapy are promising, significant safety challenges have been encountered, including cytokine release syndrome (CRS) and "on-target, off-tumor" toxicity, which could result in a potentially fatal "cytokine storm." As CAR-T cells are activated, they exponentially proliferate and eventually reach precarious levels where a cytokine response exceeds a patient s tolerability level. The speedy elimination of a large number of tumor cells in a short period of time can also result in tumor lysis syndrome. These conditions can lead to undesirable clinical complications, including hypertension, neurological changes, and multi-organ failure, events that have resulted in patient fatalities in several CAR-T cell trials. The use of conventional CAR-T cell also leads to "on-target, off-tumor" destruction of normal tissues. Upon antigen engagement, CAR-T cells execute multiple key therapeutic functions, including the production of anti-tumor cytokines, the expansion of the infused T cell population (up to 1000-fold within a week) and the killing of targeted tumor cells. However, because tumor antigens are also expressed at low levels in normal tissues such as the heart and pulmonary vasculature, the aggressively amplified CAR-T cells can cross-react with these normal tissues, causing severe consequences, including the death of the patients. This proposal aims to establish a tool to explore in vivo the relationship between CAR-T activation and cytokine storm mitigate these side effects and safety concerns associated with CART cells through the development of nano-optogenetic methodologies, which allow for the precise control of CAR-T cell activation at tumor sites, thereby delivering personalized doses of therapeutics.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910379
Entities
People
- Gang Han
Organizations
- United States Army
- University of Massachusetts Medical School