Redirecting Engineered T Cells Using a Small Molecule Drug: A Novel Approach for the Treatment of Metastatic Prostate Cancer
Abstract
Cancer immunotherapy, which harnesses the patient s own immune system to fight cancer rather than use cytotoxic agents, is considered to be a major breakthrough in cancer therapy. Among several other approaches, chimeric antigen receptor (CAR)-engineered T-cell therapy has garnered great attention recently based on its remarkable capability of eliminating high tumor burden in B-cell leukemia patients. More importantly, this therapy has shown great therapeutic responses against chemotherapy-resistant, refractory tumors because CAR-T cells utilize multiple killing mechanisms and thus are less likely affected by drug-resistance methods exploited by cancer cells. Therefore, CAR-T therapy is a highly attractive therapeutic option for the treatment of high-risk metastatic prostate cancer patients for whom conventional anti-cancer therapies as well as hormone therapies are largely proven to be ineffective. Despite the promising anti-tumor activity, there are significant safety concerns associated with this rapidly emerging cell-based therapy. For example, the surface receptor in the CAR-T cells that are designed for targeting B leukemia cells cannot discriminate between normal, healthy, and malignant B cells, and thus entire B-cell populations are eliminated in these patients long after tumor clearance. Undoubtedly, this safety risk becomes a greater issue if the CAR-T cells were designed to target a tumor antigen that is less restricted and is also expressed on normal tissues. In the case of prostate cancer, prostate specific membrane antigen (PSMA) is one of the most promising target antigens for targeted therapy because it is highly overexpressed in many prostate cancer cells. However, very low levels of PSMA expression in other tissues have been reported, suggesting that a long-lived, highly sensitive PSMA-targeting CART cells may potentially result in serious adverse effects. In an attempt to overcome this safety issue of current CAR-T therapy, herein we propose a novel CAR-T platform in which the activity and specificity of CAR-T cells are strictly controlled by a small "switch" molecule. For the purpose of applying this concept as a treatment option for prostate cancer, we have developed a small molecule switch that can potently and selectively redirect CAR-T cells to PSMA-positive prostate cancer cells (in the absence of switch, the CAR-T cell has no activity). In this proposal, we intend to further evaluate the efficacy and safety of our approach using various cell-based assays as well as prostate cancer models in mice. Our goal is to demonstrate that our approach can be used to finely tune the activity of the CAR-T cells (and thus only kills the cancer cells that highly express PSMA) and terminate the response of CAR-T cells by simply halting switch dosing. If successful, our approach will provide a novel way to safely apply the potent CAR-T cells for the treatment of refractory prostate cancer patients with minimized safety concerns associated with current CAR-T therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510424
Entities
People
- Chan Hyuk Kim
Organizations
- United States Army