Further Optimizing 2nd Generation Dual-targeted Fine-tuned Immune-Restoring (DFIR) CAR T Cells to Achieve Cures of Advanced 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. 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 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 that can cause the CAR-T therapy to have adverse and sometimes severe side-effects. Two proteins, CAIX and CD70, are overexpressed on ccRCC cancer cells and can be used as therapeutic targets. We designed our first-generation Dual-targeted, Fine-tuned, Immune Restoring (DFIR) CAR-T cells to 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. We have also engineered these DFIR CAR-T cells to secrete antibody drugs called checkpoint blockade inhibitors (CBIs) and have shown that secretion of anti-PDL1 CBI greatly improves CAR-T cell killing. There is an urgent need to develop novel therapies for ccRCC with the goal of achieving cures. While we plan to advance our first-generation DFIR CAR-T cell therapy into the clinic, we also recognize that improvements in this therapy can be made. The goal of our Idea Development Award studies is to further enhance the safety profiling of second-generation anti-CD70/CAIX DFIR CAR-T cells by fine-tuning the affinity/avidity of both anti-CD70 and anti-CAIX antibodies so that the CAR moiety only recognizes high-density TAAs on tumor cells but not the low expression of CAIX on normal tissues. We will also use scRNAseq data from ccRCC patients with advanced disease to study their tumor microenvironment (TME) and use this data to select CBI targets that are public and shared by all patients. Our existing panel or newly discovered CBIs will be used as secreted payloads. 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 is 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 DF 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-T cells to secrete monoclonal antibodies at the tumor site to rest
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110482
Entities
People
- Wayne A Marasco
Organizations
- Dana–Farber Cancer Institute
- United States Army