CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma

Abstract

Chimeric antigen receptor (CAR) T-cells have shown remarkable results in patients with B-cell leukemia and lymphoma. However, while CAR T-cells have shown complete responses in a majority of patients with acute lymphoblastic leukemia (ALL), lymphomas are more difficult to treat. Different CAR designs and conditioning protocols seem to affect the persistence of patient responses. However, factors that determine if patients receiving the same CARs will respond or not remain obscure. In Sweden, a phase I/IIa trial using third-generation CAR T-cells is ongoing in which we intend to compare tumor biology and immunology, in each patient, to treatment response. CAR T-cell therapy is a powerful tool to add to the treatment options for this patient group but we need to perform the necessary basic research on the multifactorial mechanisms of action to give patients the best possible option of survival. Such studies are also crucial to expand the success of CAR T-cells beyond CD19+ B-cell malignancy. This review will focus on possible barriers of treating lymphoma to define factors that need to be investigated to develop the next generation of CAR T-cell therapy.

Figure 1.

(A) T-cells interact with antigen-presenting cells such as dendritic cells (DCs) to become activated. The first signal of activation is transmitted via the T-cell receptor (TcR) that binds to major histocompatibility complex (MHC) molecules presenting antigen peptides to the T-cell. The second signal is delivered in terms of multiple interactions with co-stimulatory molecules such as CD80, 41BBL, and CD70 presented to the T-cell by mature DCs. A chimeric antigen receptor (CAR) receptor consists of an antigen-binding region such as a single chain fragment (scFv) from a tumor-targeting antibody and an intracellular signaling region. The signaling region of the first-generation (1G) CAR mimicked TcR signaling via fusing the antigen-binding region to the CD3-ζ chain. The second-generation (2G) CAR mimicked both TcR and costimulatory signaling by adding, for example, CD28 or 41BB domains to the intracellular region, while the third-generation (3G) CAR has two costimulatory domains fused with the TcR CD3-ζ chain. (B) The CAR gene is inserted to T-cells and expressed to produce protein CAR, which is transported to the plasma membrane. A CD19-targeting CAR interacts with CD19+ malignant B-cells to receive activation signaling leading to FasL and perforin/granzyme B-mediated cytotoxicity.