due to uncoupling of the balance between bone formation and resorption, with an

increase in the number and activity of osteoclasts and a decrease in the number of

osteoblasts leading to enhanced osteoporosis and the development of lytic lesions

(Coleman 1997; Walker et al. 2014). All these factors account for the key symptoms

of MM including bone pain, pathological fractures, weight loss, spinal cord com-

pression, hypercalcemia, kidney problems, frequent infections, and death (Coleman

1997; Croucher and Apperley 1998).

Treatment advancements for the past two decades have led to the development of

many new drugs for MM including immunomodulatory agents (e.g., thalidomide

and pomalidomide), proteasome inhibitors (e.g., bortezomib), histone deacetylase

inhibitors, and monoclonal antibodies (e.g., daratumumab and elotuzumab). The

incorporation of several agents alone or in combination into the MM treatment has

resulted in improved survival and has dramatically changed the outcome of MM

patients. However, despite these advanced therapies, MM still remains an incurable

malignancy. Most of the MM patients eventually relapse and develop refractory

disease. Since MM constitutes 1% of all malignancies and 10% of all hematological

malignancies (Rajkumar et al. 2014; Vincent Rajkumar 2014), therefore, there is a

need to develop alternative effective treatment strategies that can combat chemo-

therapeutic resistance in MM.

Immunotherapy has emerged as a promising new strategy to eliminate cancer

cells. This strategy engages the host immune cells to produce its effects and relies on

target antigen specificity. The immunosuppression of T cells in MM emphasizes the

need for establishing treatments aimed at enhancing T cell anti-MM activity. Chi-

meric antigen receptor T cell therapy is a subtype of autologous adoptive cell

immunotherapy in which T cells are taken from the patient, modified ex vivo,

expanded, and then reinfused back to the patient. For this, the host T cells are

engineered to express a new chimeric antigen receptor (CAR) (Fig. 25.1). Hence,

this immunotherapy is referred to as chimeric antigen receptor T cell (CAR-T)

therapy.

25.2

What Are Chimeric Antigen Receptors?

CARs are the engineered receptors that bind to a desired antigen and redirect the

engineered effector cells to a specific target cell (myeloma cells in case of MM).

Basically, CAR is a fusion construct with an extracellular antigen recognition

domain, a spacer, a transmembrane domain, and a CD3ζ intracellular domain for

signaling to stimulate T cell activation upon antigen binding (Fig. 25.2) (Jensen and

Riddell 2015; Van Der Stegen et al. 2015). The extracellular antigen recognition

domain of CAR is composed of variable region of the heavy (VH) and light (VL)

chains of an immunoglobulin moiety. In contrast to the natural T cell receptors,

CARs bind unprocessed antigens expressed by the target cells. This is noteworthy in

view of the fact that similar to most cancers, MM is associated with downregulation

of major histocompatibility complex and antigen presentation. Notably, an intracel-

lular costimulatory signaling domain is also included in CAR T cells to mimic the

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E. S. Sinha