Use of Anti-CAIX/CD70 Bispecific CAR T-Cell Factories to Change the Tumor Microenvironment, Mitigate On-Target Off-Tumor Toxicities, and Achieve RCC Cures
Abstract
Background: A modified T cell receptor called Chimeric Antigen Receptor (CAR) T cell therapy (CART) is a new form of cellular immune therapy to treat cancer. It has proven to be a powerful, clinically translatable immunotherapy for hematologic malignancies. This new therapy is made by extracting immune system T cells from an individual patient, altering their DNA to sharpen their ability to spot and kill cancer cells, and infusing them back into the same patient. On August 30, 2017, the first CART cell therapy was approved for treatment of certain children and young adults with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapses. Subsequently, FDA approved the second CART cell therapy on October 18, 2017, for patients with large-B-cell lymphomas who had received at least two prior treatment regimens. However, this promising treatment has not been translatable to solid tumors. There are several reasons why CART cell immunotherapy has not been successful for solid tumors. These include inefficient homing of CART cells to tumor locations, low persistence of CART cells in vivo, and the strong ability of tumors to suppress our 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 CART therapy to have adverse side effects that are sometimes severe. The goal of our translational proposal is to engineer improvements in CART cells so that they can be safely delivered to patients with clear cell renal cell carcinoma (ccRCC) with the goal of achieving cancer cures. Objectives: In solid tumors, a normal process by which our immune system limits damage after an infection or injury, called checkpoint blockade, is highjacked by the cancer cells. Recently, new drugs called monoclonal antibodies that are based on proteins that our immune system produces have been developed to invigorate our immune systems to fight cancer. We have generated remarkable preclinical data demonstrating that we can engineer CART 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 that this was possible by engineering CART cells to produce a human antibody drug called anti-PDL1. We call this new therapy CART cell factories and the goal of our proposal is to make safer CART cell factories to treat RCC. 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 will use our tools to make CART cells recognize two proteins on the RCC surface instead of just one protein. We believe that this engineering advance will make the CART factories safer and decrease the likelihood that they will inadvertently bind to and injure healthy non-cancer cells in the body. Short-Term Impact of Proposed Research: We will perform discovery research to identify antibodies to a second RCC target protein called CD70; we already have antibodies to the first target called CAIX. We have other technology that allows us to tether two antibodies together and our plan is to engineer CART cells to recognize both CAIX and CD70. Once we accomplish this we will test the therapy in tissue culture and in humanized mice; the latter refers to a weakened strain of mice that can be made to carry a primitive human immune system. We will test these humanized mice carrying human RCC tumors for the ability of the CART factories to kill the tumor cells and restore anti-cancer immunity without causing adverse side effects. Long-Term Impact of Proposed Research on Service Members, Their Families, Veterans, and the American Public: Our long-term goal is to move this innovative therapy into the clinic. Our studies will allow us to understand how to use CART cell factories to reverse the suppression of the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810568
Entities
People
- Wayne A Marasco
Organizations
- Dana–Farber Cancer Institute
- United States Army