Engineering Chimeric Antibody Signaling and Secreting (CASS) B Cells to Achieve ccRCC Cures
Abstract
Scientific Objective and Rationale: Clear cell renal cell carcinoma (ccRCC) is the major type of RCC, which is among the 10 most common cancers in both men and women. Despite many advances in the field, curative therapies for advanced ccRCC are rare. There is an urgent need to develop therapies against ccRCC that result in CURES. In this grant, we plan on completing pilot studies that will advance a new kind of therapy that we call Chimeric Antibody Signaling and Secreting (CASS) B cells. Monoclonal antibody (Ab) drugs are promising agents to treat ccRCC. These Abs exert their antitumor effects by binding to and directly killing cancer cells or acting as immune checkpoint blockade inhibitors (CBIs) to restore anti-cancer immunity or disrupting tumor vasculature to starve the tumor of its blood supply. These Abs are delivered intravenousely and as a result have systemic toxicities and require repeated administration. However, the idea of engineering human CASS B cells to seek out cancer cells and secrete these Abs at the tumor site in vivo is novel and untested but could provide a powerful new way to treat primary and metastatic ccRCC. It would also provide a lifelong antitumor immune surveillance system to prevent cancer reoccurrence. The main role of B cells in our immune system is to recognize foreign invaders, from microbes to cancer cells, and eliminate them by production of antibodies that bind and clear the threat. They accomplish this by expressing a membrane-bound Ab (B Cell Receptor, BCRs) that binds the tumor antigen, causing the B cell to switch and become an Ab-secreting cell. We propose to engineer CASS B cells to recognize the tumor-associated antigen, carbonic anhydrase IX (CAIX), that is overexpressed on the surface of ccRCC cells. These CASS B cells will be further engineered so that once they arrive at the tumor site, they will be activated to secrete an anti-PDL1 Ab that functions as a CBI and reverses exhaustion of the immune cells that have arrived at the tumor site. CASS B cell therapy should help to restore antitumor immunity. This work represents a significant advancement in the field of antitumor immunotherapy. We will test this new therapy in Aim 1 by first building CASS B cells through engineering an artificial B cell receptor, which is an Ab expressed on the surface of B cells so that they will recognize CAIX. Next, we will further engineer the cells to secrete an anti-PDL1 Ab under the control of a switch that does not get activated until the CASS B cells come in contact with the tumor cells. We will first run tissue culture experiments to show that our engineering has been successful; we have some back-up strategies if refinements are needed. In Aim 2, we will test this therapy in a humanized mouse model with a humanized immune system that also bears ccRCC tumors. The CASS B cells can be injected intravenously to see if they can find the tumor and whether this therapy can cure tumors by reversing immune system exhaustion and restoring antitumor immunity. This project is in line with the goal of the FY20 KCRP Concept Award to support highly innovative, untested, potentially groundbreaking novel concepts in kidney cancer. We are confident that this research program will generate sufficient preliminary data to enable our team to further refine this novel translational approach to treat kidney cancer. We plan to submit additional grant applications to support future research in this area.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110166
Entities
People
- Wayne A Marasco
Organizations
- Dana–Farber Cancer Institute
- United States Army