Co-Stimulatory Receptor Signaling in CAR-T Cells

Abstract

T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor T (CAR-T) cell therapy represents a prominent synthetic biology approach to re-direct the specificity of a patient’s autologous T cells toward a desired tumor antigen. CAR-T therapy is currently FDA approved for the treatment of hematological malignancies, including subsets of B cell lymphoma, acute lymphoblastic leukemia (ALL) and multiple myeloma. Mechanistically, CAR-mediated recognition of a tumor antigen results in propagation of T cell activation signals, including a co-stimulatory signal, resulting in CAR-T cell activation, proliferation, evasion of apoptosis, and acquisition of effector functions. The importance of including a co-stimulatory domain in CARs was recognized following limited success of early iteration CAR-T cell designs lacking co-stimulation. Today, all CAR-T cells in clinical use contain either a CD28 or 4-1BB co-stimulatory domain. Preclinical investigations are exploring utility of including additional co-stimulatory molecules such as ICOS, OX40 and CD27 or various combinations of multiple co-stimulatory domains. Clinical and preclinical evidence implicates the co-stimulatory signal in several aspects of CAR-T cell therapy including response kinetics, persistence and durability, and toxicity profiles each of which impact the safety and anti-tumor efficacy of this immunotherapy. Herein we provide an overview of CAR-T cell co-stimulation by the prototypical receptors and discuss current and emerging strategies to modulate co-stimulatory signals to enhance CAR-T cell function.

CD4+T and CD8+T Cells in Uterus Exhibit Both Selective Dysfunction and Residency Signatures

“…Intriguingly, most uterine γδ T cells expressed activation marker CD25, about 70% [ 10 ] but not CD4 + T and CD8 + T cells. CD4 + T and CD8 + T cells in uterus expressed much lower levels of costimulatory receptors CD27 which is involved in the regulation of T cell activation, especially in T cell memory [ 26 , 27 ]. These may indicate uterine γδ T cells and αβ T cells play different roles in intrauterine immune microenvironment with the latter favoring maternal–fetal tolerance.…”

Exploring the efficacy and safety of anti-BCMA chimeric antigen receptor T-cell therapy for multiple myeloma: Systematic review and meta-analysis

“…This approach stimulates cytokine production, sustaining the anti-tumor immune response, and fostering improved overall patient survival. [ 37 ] Honikel and Olejniczak [ 36 ] showed that illuminating the significance of CD28 allows an understanding of its role as a potent costimulatory signal for T-cell activation and function. The interactions between CAR design and T-cell biology outline the therapy’s multifaceted effectiveness in combating MM.…”

Endogenous CD28 drives CAR T cell responses in multiple myeloma

“…Co-stimulation has long been known to be critical for anti-tumor effects of CAR T cells 83,84 , with different CAR-encoded co-stimulatory domains having distinct effects on CAR T cell properties 17 . Clinically available CARs contain either a CD28 or a 4-1BB co-stimulatory domain.…”