CD44 Enhances Efficacy of the Chimeric Antigen Receptor T-Cell Therapy Against Prostate Cancer
Abstract
Even though there are high initial response rates of prostate cancer (PCa) patients to the androgen-deprivation therapy (ADT), castration-resistant prostate cancer (CRPC) often occurs with poor prognosis and limited treatment options. The chimeric antigen receptor (CAR)-T cell therapy offers curative potential for CRPC 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 the 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 PCa, but still with limited success. 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) the inadequate ability of CAR-T cell trafficking, tumor infiltration, expansion, and persistence; and (5) CAR-T cell exhaustion. This proposal plans to offer 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 PCa. CD44 is also referred as a lymphocyte homing receptor and is a prominent marker that distinguishes memory and effector T cells from their naïve counterparts. 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. Lymphocytes mainly express the standard or hematopoietic form of CD44 (CD44s/CD44H). Studies have shown that CD44 plays important roles in enhancing T cell receptor (TCR)-signaling and T cell migration, proliferation, and survival. This proposal aims to develop treatments that improve outcomes for men with lethal PCa (a FY22 PCRP Overarching Challenge) by establishing that the CD44 armored CAR-T cells represent an innovative strategy to enhance efficacy of the CAR-T cell-based therapy against advanced PCa. The proposal is based on our novel findings: (1) anti-PD1 antibody (an immune checkpoint inhibitor, ICI) displayed reduced efficacy against PCa in CD44-knockout mice comparing to wild type (wt) mice; (2) loss of CD44 led to reduction of the numbers of intra-PCa CD3+/CD8+ T cells and the numbers of the anti-PD-1 antibody-induced increase of intra-PCa CD3+/CD8+ T cells; and (3) constitutive CD44H expression inhibits exhaustion and death of the CD19-targeting CAR-T cells. We hypothesize innovatively that CD44 expressed by T cells plays a critical role in enhancing the efficacy of the ICIs against PCa via promoting T cell infiltration into and expansion/survival in PCa and by inhibiting T cell exhaustion and that reduced or lost CD44 expression in T cells leads to the PCa resistance to the ICIs. We further hypothesize that constitutive CD44H expression in CAR-T cells, such as the prostate-specific membrane antigen (PSMA)-targeting CAR-T cells enhances the efficacy of the CAR-T cell-based therapy by promoting intra-PCa 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 a critical role in enhancing the efficacy of the immune checkpoint inhibitors (ICIs) against PCa by promoting T cell infiltration into and expansion/survival in PCa and by inhibiting T cell exhaustion. In this aim, CD44-null mice on C57BL/6 or FVB background will be intravenously implanted with pan-T/CD4+/CD8+ T cells that are CD44-null, wt, or constitutively express v5-tagged CD44H (CD44H-v5) and then orthotopically implanted with TrampC2 or Myc-CaP mouse PCa cells, which will be followed by treatment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310021
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army