A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Abstract

Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment.

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

“…T cells genetically modified to express a chimeric antigen receptor (CAR) to specifically target a tumor cell surface antigen can successfully treat B cell malignancies, but have had less activity against acute myeloid leukemia (AML). 1–3 The ideal CAR target antigen should be highly expressed on cancer cells and their clonal progenitors, but absent on normal cells and stem cells. Although no antigenic target fully meets these criteria for AML, a transmembrane glycoprotein (C-type lectin like molecule 1 (CLL-1); C-type lectin domain family 12 (CLEC12A); CD371), has emerged as a promising candidate.…”

Cell interactions in the bone marrow microenvironment affecting myeloid malignancies

“…Despite the known immune responsiveness of AML, it has been difficult to gain traction against the disease with immune therapies. There are a number of factors contributing to that, 71 including the suppressive Tregs and MDSCs, a population that impairs T-effector cells through metabolic and cytokine modifications. 45,46 Leukemia cell heterogeneity is 1 of those factors.…”

Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery

“…CAR T cell benefits can last for many years, with memory CAR T cells observed in various patients at long-term follow up and can be directed to a variety of cell surface targets [41][42][43][44]. However, CAR T cell therapies have not generally been successful for the majority of solid tumors due to the lack of unique TAAs, and inhibition by the immunosuppressive TME [21,45,46], with severe toxicities in some cases [47], and relapse in some patients due to either CAR T cell exhaustion [48,49] or downregulation of the cognate antigen by tumor cells [50].…”