Identifying an Innovative Strategy to Enhance Efficacy of the Chimeric Antigen Receptor T-Cell-Based Immunotherapy Against Lung Cancer
Abstract
Lung cancer is the leading cause of cancer related death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80%–85% of lung cancers. The chimeric antigen receptor (CAR)-T cell therapy offers curative potential for lung cancer patients. In the CAR-T therapy, autologous T cells isolated from cancer patients are engineered with the chimeric receptors that recognize surface antigens of cancer cells. The engineered T cells are then infused back to cancer patients to allow the CAR-T cells to track down, bind, and kill cancer cells. The CAR-T cell-based therapy has been successful in patients with B-cell leukemia/lymphoma and is being developed against solid tumors including lung cancer, but with limited success so far. The mechanisms underlying the insufficient solid cancer responses to the CAR-T therapy include (1) inadequate selections of CAR-T targeted tumor antigens; (2) antigen escape of tumor cells; (3) immuno- suppressive tumor microenvironment (TME); (4) inadequate ability of CAR-T cell trafficking, tumor infiltration, expansion, and persistence; and (5) CAR-T cell exhaustion. This proposal offers an innovative solution for last two major problems. CD44 is a cell surface receptor for hyaluronan; is up-regulated in many cancer types; and promotes cancer progression including that of lung cancer. CD44 is also referred as lymphocyte homing receptor and is a prominent marker that distinguishes memory and effector T cells from their naïve counterparts. CD44 is known to play important roles in enhancing T cell receptor-signaling and T cell migration, proliferation, and survival. Lymphocytes mainly express hematopoietic form of CD44 (CD44H). The CD44-related cancer studies have been exclusively focused on cancer cells, and little is done to investigate the contributions of CD44+ T/memory T cells to cancer progression and response to immunotherapy. This proposal plans to identify an innovative strategy for the treatment of lung cancer by establishing that the CD44 armored CAR-T cells represents an innovative strategy to enhance efficacy of the CAR-T cell-based therapy against lung cancer (an Area of Emphasis). The proposal is based on our novel finding that an immune checkpoint inhibitor (ICI) displayed reduced efficacy against lung cancer in CD44-null mice comparing to wild type (wt) mice and the established but unexplored CD44 functions in T cells. We hypothesize that CD44 expressed by T cells plays critical roles in enhancing efficacy of the immune checkpoint inhibitors against lung cancer via promoting T cell infiltration into and expansion/survival in lung cancer and by inhibiting T cell exhaustion and that constitutive CD44H expression in CAR-T cells, such as the ROR1-targeting CAR-T cells, enhances efficacy of the CAR-T cell-based therapy by promoting intra-lung cancer infiltration, expansion, and survival of the CAR-T cells. Two Specific Aims are proposed. Aim 1 is to establish that CD44 expressed by T cells plays critical roles in enhancing efficacy of the immune checkpoint inhibitors against lung cancer by promoting T cell infiltration into and expansion/survival in lung cancer and by inhibiting T cell exhaustion. Aim 2 is to establish that constitutive expression of CD44H in the ROR1-targeting CAR-T cells enhances efficacy of the CAR T cell therapy against lung cancer by promoting CAR-T cell expansion, migration, and survival. Successful accomplishment of this proposal will establish (1) CD44 expressed by T cells as a novel determinant of efficacy of the immune checkpoint inhibitors and the CAR-T cell-based immunotherapy and (2) that CD44 plays critical roles in promoting T/CAR-T cell infiltration into and expansion/survival in lung cancer and in inhibiting T/CAR-T cell exhaustion, as well as (3) that constitutive expression of CD44H in the ROR1-targeting CAR-T cells enhances efficacy of the CAR-T cell therapy (short-term impact). Positive results will lead to rapid clinic translat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310013
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army