Pre-IND Studies of First-Generation Dual-Targeted, Fine-Tuned, Immune-Restoring (DFIR) CAR-T Cell Therapy to Achieve Cures of Clear Cell Renal Cell Carcinoma (ccRCC)
Abstract
Background: Chimeric Antigen Receptor (CAR) T cell therapy (CAR-T) is a promising cellular immune therapy to treat cancer in which a patient s immune cells are engineered to express receptors that can attach to and kill cancer cells. This new therapy is made by extracting T cells from an individual patient, modifying their DNA to sharpen their ability to spot and kill cancer cells, and infusing them back into the same patient. CAR-T cell therapy has proven to be a powerful, clinically translatable immunotherapy for hematologic malignancies. However, the success of this treatment has not been readily translatable to solid tumors for reasons that include inefficient homing of CAR-T cells to tumor locations, low persistence of CAR-T cells in vivo, and the strong ability of tumors to suppress the patient s immune system. There are also safety concerns since protein targets that are expressed on the surface of solid tumors are often also expressed on normal tissues, which can cause the CAR-T therapy to have adverse and sometimes severe side effects. We found that two proteins, CAIX and CD70, are overexpressed on ccRCC cancer cells and can be used as therapeutic targets. We designed Dual-targeted, Fine-tuned, Immune Restoring (DFIR) CAR-T cells that have the property of killing both singly CAIX-positive, singly CD70-positive, and double CAIX/CD70-positive ccRCC tumor cells. The result of this approach is greater tumor killing efficacy and prevention of tumor escape by loss of expression of a single target. We have also engineered these DFIR CAR-T cells to secrete antibody drugs called checkpoint blockade inhibitors (CBIs). Two Food and Drug Administration (FDA)-approved CBIs, Nivolumab and Ipilimumab, have shown great promise when used in combination in the treatment of advanced ccRCC, although tumor cures with this type remain rare. There is an urgent need to develop innovative and improved therapies for ccRCC with the goal of achieving cures. In this Translational Research Partnership Award proposal, we will complete Investigational New Drug (IND)-enabling ex vivo and in vivo studies with the goal of moving our most advanced DFIR CAR-T cell therapy into the clinic. Our anti-CAIX/anti-CD70 DFIR CAR will also secrete anti-PD-1/CTLA4 bispecific antibody at the tumor site to change the tumor microenvironment and restore host antitumor immunity. Objectives: CAR-T cells are living drugs that have the potential to induce long-term durable remissions and cures of cancer. Immune checkpoints are the processes by which our immune system limits damage to healthy cells after an infection or injury. This protective pathway, a so-called immune brake, is highjacked by cancer cells to prevent their eradication by a patient s immune system. Interfering with this protective pathway using checkpoint blocking antibodies thus reinvigorates a patient s immune systems to fight cancer. We have generated remarkable preclinical data demonstrating that we can engineer CAR-T cells to produce these types of antibody drugs at the tumor site, which has shown a profound ability to restore anti-cancer immunity. We demonstrated this was possible by engineering CAR-T cells to produce an anti-PD-L1 monoclonal antibody. We call this new therapy immune restoring (IR) CAR-T cells and the goal of our proposal is to develop combination cellular immunotherapy for the cure of advanced ccRCC. DFIR CAR-T cells have been engineered to have greater accuracy to find cancer cells, efficacy to kill cancer cells, and safety to prevent killing of healthy cells. Areas of Emphasis: Immunotherapies Innovative Aspects of Proposal Research Project: We are biomedical engineers with years of experience in therapeutic human antibody drug development. We have used our tools to design DFIR CAR-T cells to recognize two proteins on the ccRCC cell surface to increase killing efficacy. To advance this therapy to clinic, we have further engineered the DFIR CAR
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110442
Entities
People
- Wayne A Marasco
Organizations
- Dana–Farber Cancer Institute
- United States Army