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CAR T cell therapies in multiple myeloma
try. As CAR-T can eliminate cells expressing less than 100 target antigens/cell, CD19 has become a relevant CAR tar- get antigen. In preclinical models, BCMA-CD19 bispecific CAR-T eliminated myeloma cell lines more potently than BCMA- or CD19-directed CAR-T alone.30 Due to an off- target expression limited to B cells, toxicity concerns of (co-)targeting CD19 are limited and clinical evaluation of bispecific CAR-T is ongoing (clinicaltrials gov. Identifier: NCT03455972, NCT03549442).
SLAMF7
The elotuzumab target antigen signaling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7, aliases: CD319, CS-1, CRACC) is an immunomodulatory transmembrane receptor, initially identified on the surface of natural killer (NK) cells.31 It is expressed on a variety of other innate immune cells,32 but also T cells, B cells and plasma cells.31-33 Importantly, SLAMF7 is expressed on aberrant plasma cells and its precursor34 and confers hom- ing of the myeloma cells to the BM niche. While redirect- ing T cells against a self-antigen may appear difficult, pre- clinical experiments demonstrated that it is feasible to generate clinically relevant doses of SLAMF7-directed CAR-T, with or without additional inactivation of the endogenous SLAMF7 gene.33-35 In preclinical models, potent anti-myeloma activity was demonstrated, resulting in rapid, comprehensive and sustained cell depletion.33 SLAMF7-directed CAR-T eliminated SLAMF7 positive lymphocytes in vitro, while SLAMF7 negative lympho- cytes were spared and retained their functions.33 Clinical evaluation of SLAMF7 CAR-T with functional safety switches is currently ongoing (clinicaltrials gov. Identifier: NCT03958656, EudraCT Nr.2019-001264-30).
CD38
Successfully targeting CD38 (cyclic ADP ribose hydro- lase, ADPRC1) with daratumumab and isatuximab has led to the development of anti-CD38 CAR-T. CD38 is a trans- membrane glycoprotein that functions as an ectoenzyme, adhesion molecule and regulator of migration and signal- ing. It is expressed on malignant plasma cells,36 but low expression can be found on lymphoid and myeloid cells, hematopoietic precursors,37 thymocytes, cerebellar Purkinje cells and other tissues. CD38 is an activation marker of T cells at intermediate or late activation stages. As CD38-directed CAR-T demonstrated great antigen- specific efficacy in preclinical myeloma models,38 affinity modification of the CAR was developed as an approach to mitigate on-target, off-tumor toxicity towards other CD38 positive hematopoietic cells. Affinity reduction of the antigen binding domain by a factor of 1,000 enabled selec- tive elimination of myeloma cells with high CD38 expres- sion while sparing normal cells with less pronounced CD38 expression. However, it has been reported that lev- els of CD38 expression on myeloma cells can decline over the disease course.39 In this regard, agents that induce selective modulation of CD38 expression levels, such as all-trans retinoic acid (ATRA) or histone deacetylase (HDAC) inhibitors,40 represent a promising group for com- bination therapy with CD38-directed CAR-T. In order to address the issue of antigen reduction by increasing the potency of the cell product, a novel construct termed “dimeric antigen receptor” (DAR) was developed. In fact, the DAR T cells that incorporate a fragment antigen-bind-
ing (Fab) moiety instead of the single chain variable frag- ment (scFv), demonstrated superior preclinical activity. However, their clinical relevance, and the risk of on-target, off-tumor effects, remains to be determined.
CD44v6
CD44 glycoproteins are encoded by a highly conserved gene,41 but are nevertheless characterized by considerable protein heterogeneity due to post-transcriptional modifi- cations or splicing variants. While CD44 plays a role in physiological processes and is expressed on healthy tis- sues,42 the isoform variant 6 is relatively restricted to malignant cells43,44 including plasma cells. In healthy tis- sues, CD44v6 expression is limited to skin keratinocytes. It is absent on hematopoietic precursor cells, but low level expression can be found on activated T cells and mono- cytes. While the development of an anti-CD44v6 immunoconjugate was discontinued due to severe skin toxicities,45 preclinical investigation of CD44v6-directed CAR-T showed promising efficacy with no impact on ker- atinocytes that represent potentially immune-privileged sites.46 The clinical relevance of the observed monocyte depletion remains unclear. However, as monocyte-derived cytokines play a relevant role for the pathogenesis of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), a benefi- cial effect is possible and clinical evaluation is ongoing (clinicaltrials gov. Identifier: NCT04097301).
GPRC5D
The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), is expressed ubiquitously in malig- nant bone marrow plasma cells (500 to 1,000 times higher expression than on normal cells), hair follicles, and in the lung. CAR-T targeting GPRC5D have demonstrated promising preclinical activity, and a phase I clinical trial is ongoing (clinicaltrials gov. Identifier: NCT04555551).
CD229
CD229, a SLAM family receptor ("SALM3"), is generally expressed on myeloma cells and "precursor" myeloma cells. Its high expression suggests a potential as a target for CAR-T studies have shown that this newly designed CD229 CAR-T has high activity against MM cells, mem- ory B cells and MM stem cells in vitro and in vivo.47
Clinical studies
B-cell maturation antigen-specific chimeric antigen receptor T cells
The National Cancer Institute group performed the first study with BCMA-specific CAR-T with a CD28 costimu- latory domain (murine scFv) in heavily pretreated patients.20 At the highest CAR-T dose (9x106 cells/kg), 13 of 16 patients (81%) achieved at least partial response (PR) with a median event-free survival of 31 weeks. Other studies confirmed high activity of BCMA CAR-T in this patient subset.48-50 Advanced clinical findings have been reported with ide-cel50,51 and cilta-cel.48 Both therapies received Food and Drug Administration breakthrough designation. In this section, we will discuss these two CAR-T products. CAR-T constructs and main clinical characteristics are summarized in Table 2.
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