Combining CAR T Cells with Blockade of Tumor-Induced Immunosuppression to Target Metastatic Prostate Cancer
Abstract
Metastatic castration-resistant prostate cancer presents a formidable challenge for developing effective anticancer therapies. While the cancer may initially respond to therapy, once it has metastasized from the prostate, the tumors find ways to resist both the patient s normal immune defenses and the chemotherapy/radiation treatments. Immunotherapy is a powerful new approach that directs and stimulates the patient s own immune system to combat cancer and is potentially more effective and less toxic than conventional chemotherapy and radiation therapies. In recent years, immunotherapy has shown long-lasting remissions in blood cancers, as well as in some solid cancers. We propose an adoptive immunotherapy for metastatic prostate cancer, in which a patient s immune T cells are (1) removed from the blood, (2) genetically reprogrammed with chimeric antigen receptors (CARs) that can directly bind to PSCA protein on prostate cancer cells, and (3) reintroduced into the patient s bloodstream where they multiply, seek out, and destroy tumor cells that show PSCA on their surface. CAR T cell immunotherapy is showing particularly impressive outcomes for leukemia and other blood cancers and is now under active investigation in solid cancers. Recent laboratory studies have demonstrated promise for CAR therapy in solid tumors such as prostate cancer, targeting tumor markers including PSMA and PSCA, which is highly expressed in nearly 100% of metastatic prostate cancers. Another advantage of CAR T cell therapy over conventional therapy is the potential for these immune cells to take up permanent residence in the patient s bloodstream, where they are on continual surveillance and killing of cancer cells. A serious problem, which has been highlighted in a patient with metastatic colon cancer treated at the National Cancer Institute with CAR T cells targeting HER2, is that the therapeutic T cells may have recognized and attacked low levels of HER2 in lung tissue, ultimately resulting in the patient s death. While PSCA is overexpressed in tumor cells, it is expressed at low levels in several normal tissues, including the esophagus, colon, and kidney. Our investigations have confronted this problem of CAR T cell destruction of normal tissue by redesigning our PSCA-CARs to have a more selective recognition/binding to PSCA such that they are only able to "see" PSCA when it is presented at high density on the cell surface of a tumor cell. Normal cells, like the colon, that display only a small amount of PSCA expression would be essentially invisible to these therapeutic cells. We have already created one such variant of our PSCA-CAR by modifying the components of the CAR molecule and aim to assess this selective targeting of PSCA-expressing prostate cancer cells in clinically relevant tumor models. We will use a mouse prostate cancer model with human PSCA as a therapeutic target to evaluate this potential off-tumor toxicity in a preclinical setting. A second major challenge our proposal addresses applies to the general field of immunotherapy for solid tumors. Solid cancers have developed strategies to evade the patient s immune defenses by sending out chemical signals that shut down immune cells and recruit cells to the tumor that can suppress an immune response. Suppression of the immune response can also decrease the effectiveness of immunotherapies like PSCA-CAR T cells. We therefore propose to unleash the patient s immune system by treating with drugs that block the colony-stimulating factor-1 receptor (CSF1R) signaling pathway. CSF1R is important to the development of prostate cancer and is involved in promoting the suppression of the immune system. We anticipate that combining CSF1R blockade with PSCA-CAR T cells will release the brakes on CAR T cells and greatly magnify the killing and the length of time these cells live in the patient s bloodstream. We ultimately propose a novel combination therapy including P
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710208
Entities
People
- Saul J Priceman
Organizations
- Beckman Research Institute of City of Hope
- United States Army