Chimeric antigen receptor T (CAR-T) cells: Novel cell therapy for hematological malignancies

Abstract

Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR-T), which includes the engineering of T cells to recognize tumor-specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR-T-cell-based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non-Hodgkin's lymphoma (NHL). However, CAR-T-cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR-T-cell-based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR-T-cell therapy.

Keywords: T-cell therapy; chimeric antigen receptor T cells; hematological malignancies; immune therapy; tumor immunology.

FIGURE 1

The antitumor mechanism of chimeric antigen receptors (CARs) T‐cell therapy. (A) The T‐cell receptor (TCR) recognizes intracellular and extracellular tumor‐associated antigens (TAAs) depending on presentation of MHC; but often expression of MHC downregulated by tumor cells in order to escape from killer T cells. (B) However, CAR‐T cells are able to recognize the specific TAAs in a MHC‐independent manner. Next, T cells were activated by phosphorylation of immunoreceptor tyrosine‐based activation motif (ITAM) followed by enhanced cytotoxicity, T‐cell proliferation, as well as secretion of cytokines (such as IL‐2, IL‐4, IFN‐γ, IL‐12, and TNF). Interleukin‐12 (IL‐12) recruit and reinforce functions of macrophages and NK cells. The activated CAR‐T and T cells creates cytotoxicity through production and secretion of granzyme and perforin, as well as through induction of the death receptor pathway (such as Fas/Fas‐L).

FIGURE 2

The process of CAR‐T‐cell therapy. Peripheral blood samples are taken from the patient. T cells are isolated and genetically engineered to present chimeric antigen receptors (CARs) and recognize a specific tumor associated antigen (TAAs). The obtained CAR‐T cells are expanded, and infused to the patient.

FIGURE 3

The history of CAR‐T cells progress and milestones in previous years. CAR‐T, chimeric antigen receptor‐T; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B‐cell lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; LBCL, diffuse large B‐cell lymphoma.

FIGURE 4

Different generations of CAR‐T cells. (A) The first generation contains only CD3ζ as an intracellular domain. (B) The second generation also consists of CD28 or 4‐1BB motifs. (C) The third generation contains both CD28 and 4‐1BB motifs. (D) The fourth generation contains IL‐12 or IL‐18 encoding genes that are tethered to the intracellular domain. (E) The fifth generation contains IL‐2 receptor and STAT3 transcription factor binding site to induce cytokine storm.

FIGURE 5

Limitations in use of CAR‐T‐cell therapy. (A) Immunosuppressive tumor microenvironment or engineering CARs cells to overcome to immunosuppressive factors. (B) CAR‐T trafficking and infiltration of tumors or engineering CARs that increase penetration from physical barriers. (C) On‐target/off‐tumor effects or binding to target antigen on cancer cells that also expressed on normal cells. (D) Antigen escape or design of a CARs that able to target multiple antigens. (E) CAR‐T‐cell‐associated toxicities or alteration of CARs structure to ameliorate toxicity.