Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T Cells

Abstract

can then selectively target and kill cells expressing the tumor antigen (Fig. 1). Prior attempts at similar T-cell-mediated immunotherapy led to disappointing results, with little to no responses elicited. Earlier models of T cell immunotherapy transduced T cells that contained only extracellular antigen receptors to recognize tumor cells. Such constructs were unable to mount sufficient immune responses to overcome tumor cells, despite their recognition of the cells (1, 2). The current CAR T cell therapies in development differ from past efforts by including intracellular costimulatory domains, such as CD28 or 4-1BB, and CD3ζ signaling domains for optimization of the T cell response. Such domains amplify the ability of the CAR T cells to mount an immune response against tumors, and recent data suggest that these newer, second-generation constructs are leading to responses to treatment for many patients (3-5). Clinical trials have investigated CAR T cells in several tumor types, using CAR T cells with different extracellular and intracellular domains. The approved therapy, tisagenlecleucel (Kymriah), often previously referred to as CTL019 or "CART-19," targets CD19, which is highly expressed in B cell neoplasms such as acute lymphoblastic leukemia (ALL; the approved indication), and has demonstrated activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). B cell maturation antigen (BCMA), has also been identified as a potential tumor target, expressed broadly on myeloma cells and normal plasma cells (6). CAR T cell therapies have demonstrated significant improvements in overall response and survival in several tumor types among relapsed and refractory patients with historically poor outcomes.

A novel bispecific antibody targeting CD3 and prolactin receptor (PRLR) against PRLR-expression breast cancer

“…Immunotherapy for the treatment of cancer get more attention recently. The BsAbs which could redirect the T cells to tumor cells and kill them showed to be a highly promising strategy both in pre-clinical and clinical sets [11][12][13][14][19][20][21]. And here in our study, we generated a bispecific antibody targeting the PRLR and CD3 exhibiting a favorable activity both in vitro and in vivo.…”

“…However, the PRLR antibody is showed to be lack of efficacy in clinical trials despite of its favorable pre-clinical data [9]. Tumor immunotherapies including immune checkpoints [10,11], CAR-T [12], oncolytic virus [13] and bispecific antibodies [14] are proved to be effective anti-tumor treatments. The PD-1/PD-L1 checkpoint blockade has significant progress in melanoma, lung cancer, and lymphoma [15,16], and a number of clinical trials in breast cancer and glioma are also being efficiently carried out worldwide [17,18].…”

Cancer immunotherapy: Adoptive cell therapies, cytokine-related toxicities, and the kidneys

“…34,42,44 Current published data suggest that CAR T cells persist in the body for months to years after infusion; true long-term persistence is still unknown. 46 Initial work investigating the clinical efficacy of CAR T-cell therapy has focused on B-cell malignancies due to the abundance of CD19 expression on B cells, CD19 is expressed on both benign and malignant B cells with limited non-B lymphocyte expression. 31,46 Brentjens et al 47 reported 75% overall response in patients with refractory chronic lymphocytic leukemia and acute lymphoblastic leukemia who received CD19-specific CAR T cells.…”

“…46 Initial work investigating the clinical efficacy of CAR T-cell therapy has focused on B-cell malignancies due to the abundance of CD19 expression on B cells, CD19 is expressed on both benign and malignant B cells with limited non-B lymphocyte expression. 31,46 Brentjens et al 47 reported 75% overall response in patients with refractory chronic lymphocytic leukemia and acute lymphoblastic leukemia who received CD19-specific CAR T cells. Subsequent trials reported significant overall response rates ranging from 50% to 90%.…”

“…7,55 Multiple barriers to therapy have been identified, including the expression of CAR targets on normal tissues leading to cross-reactivity with significant morbidity and mortality, inefficient T-cell trafficking into the tumor, solid tumors are also more likely to have very Table 2. Examples of chimeric antigen receptor targets in hematological and solid malignancies (adapted from Fesnak et al, 31 Curran et al, 43 and Littman and Hexner 46 hostile microenvironments with inhibitory cytokines and T regulatory cells. 7,44,55,58 Attempts to circumvent these barriers include the development of regional delivery methods to deliver specific CAR T cells directly into tumors; this is currently being studied in glioblastoma and ovarian cancers.…”