population of tumor cells that are responsible for self-renewal and drug resistance

(Johnsen et al. 2016). Besides MM, CD19 has been demonstrated to be present in

many B cell malignancies including acute lymphocytic leukemia and chronic lym-

phocytic leukemia. This makes CD19 a potential target for CAR-T therapy in B cell

malignancies including MM. Interestingly, CAR T cells targeting CD19 when used

in conjunction with melphalan and autologous stem cell transplantation have shown

therapeutic activity in relapsed/refractory MM (RRMM) (Garfall et al. 2015). These

dual-target CAR T cells are in clinical trials for RRMM. Due to high response rates

in patients, two CD19-engineered CAR T cell products, axicabtagene ciloleucel

(Yescarta, Kite) and tisagenlecleucel (Kymriah, Novartis), have already been

approved by the FDA for therapy of advanced B cell malignancies.

CD19- and BCMA-targeted CAR-T combination trial has shown significant

results in RRMM. The CAR used in this study contains an anti-BCMA and anti-

CD19 single chain antigen recognition fragment, cytoplasmic portion of the OX40

and CD28 costimulatory moiety, and a CD3ζ domain for signaling (Lingzhi et al.

2017).

25.4.3 SLAMF7

SLAMF7 (also known as CD319 or CS1) is an antigen abundantly expressed on the

surface of activated B cells, monocytes, normal and neoplastic plasma cells, NK

cells, some CD8⁺ T cells, and dendritic cells. Since it is absent on non-hematologic

organs and hematopoietic stem cells, SLAMF7 is under intense investigation as a

target for CAR-T therapy in MM. Elotuzumab, a monoclonal antibody against

SLAMF7, has gained FDA approval for the treatment of MM. SLAMF7-specific

CARs have proven to be highly cytotoxic for MM tumor cells (MM cell lines and

primary MM cells) when tested in vitro, ex vivo, and in MM xenograft mouse

models (Gogishvili et al. 2017). Notably, SLAMF7-targeted CAR T cells are in

clinical phase I trials.

25.4.4 CD138

CD138, also known as syndecan 1, plays a significant role in the development and

proliferation of plasma cells. It is a surface molecule which is highly expressed on

most malignant and normal plasma cells but is absent from T cells, B cells, and other

hematopoietic cells. These facts make CD138 a specific and ideal target in MM

treatment. Despite the attractiveness of CD138 as a target for MM, the shedding of

CD138 from malignant cells and its expression in mature epithelial cells are two

potential drawbacks. In a preclinical study with CD138-specific CAR T cells, no

off-tumor toxicities were reported neither in vitro nor in animal model (Sun et al.

2019).

25

Chimeric Antigen Receptor T Cell Therapy: A Cutting-Edge Therapy for. . .

479