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B. Bruno et al.
murine anti-BCMA CAR-T was investigated in 22 patients.63 The study had a median follow-up of 6 months and reported a high ORR of 95%, with CR of 57%, and relatively low CRS of grades ≥3 (4%).63 Preliminary results of two other CD19/BCMA studies showed similar ORR but lower CR (22% and 16%).83,84 One study investigated dual-target CAR-T co-expressing two full-length recep- tors, namely CD38 and BCMA.85 Median follow-up was 9 months and the ORR was 88%. PFS was 75% and higher CRS of grades ≥3 were noted compared with tandem CAR (25%). OR-gate tandem CAR consist of a single CAR structure targeting two antigens with two distinct antigen recognition domains (scFv) linked consecutively with a single signal transducing intracellular domain.82-86 A recent study using CS1/BCMA tandem CAR-T showed superior CAR expression and function in comparison with T cells co-expressing individual CS1 and BCMA CAR. When compared to the OR-gate (tandem) CAR, dual-target CAR require a much larger genetic payload, leading to poorer transduction efficiency and reduced proliferation. A recent Chinese study using BCMA-CD19 dual FasT CAR-T showed an overall response rate of 93.8% with median duration of follow up of 7.3 months at cutoff. Importantly, most patients showed high-risk features.87 A much more compact genetic footprint may greatly support viral inte- gration, thus product manufacturing, suggesting an advan- tage for single-chain tandem CAR in relation to dual-tar- geting. With respect to CARpools, this strategy could avoid poor transduction efficiency. Among these three approaches, mechanistically, CAR pool may be the least effective.80
Targeting the tumor microenvironment
The BM milieu is heavily involved in MM pathogenesis and resistance to treatment. Conflicting data exist on whether monoclonal antibodies against CD38 are effec- tive in the BM microenvironment,88 whereas immunomodulatory agents may be able to overcome these inhibitory effects.89 Accordingly, combining these drugs with CAR-T therapy may provide synergistic effects.59 Conversely, tissue microenvironment itself is
modulated by secretory programs and stable cell-cycle arrest, defined as cellular senescence, which is a tumor- suppressive mechanism. Accumulating aberrant senescent cells create an inflammatory milieu resulting in tissue damage and fibrosis. In order to eliminate these senescent cells, “senolytic” CAR-T have been proposed.90 One study discovered the cell-surface protein urokinase-type plas- minogen activator receptor (uPAR) being broadly induced during senescence,88 and further dissected that anti-uPAR CAR-T efficiently ablated senescent cells in vitro and in vivo, restoring tissue homeostasis in mice with liver fibro- sis.90 In MM, it has been shown that u-PAR contributes to the functioning of cancer-associated fibroblasts during MM progression,91 and that higher expression of u-PAR was associated with disease progression, worse survival and early extramedullary spread of MM cells. Although it has to be noted that a caveat of senolytic CAR-T are the potential off-target toxicities,92 these results may encour- age the incorporation of cellular strategies specifically addressing the MM microenvironment.
Availability and management
Allogeneic chimeric antigen receptor T cells
Allogeneic CAR-T may decrease cost and enable broad- er availability.93 Notwithstanding, allogeneic CAR-T bare the risk for graft-versus-host disease (GvHD). For this rea- son, TALEN- and CRISPR-based gene editing has been introduced to produce allogeneic CAR-T with off-the- shelf availability.68,93,94 One recent study on allogeneic anti- BCMA CAR-T used gene editing, namely TALEN, to con- fer resistance to lymphodepletion and to reduce GvHD risk.95 By further incorporating a CD20 mimotope-based switch-off within the CAR, rituximab could be given to eliminate the CAR-T in case of adverse events. Another preclinical approach using similar safety features but anti- CS1 CAR-T (UCARTCS1),35 specifically degranulated and proliferated in response to MM cells, supporting further evaluation and testing of this universal therapy. Current investigational studies also include (i) the non-viral piggyBac system, aimed at transposing stem cell memory T cells together with (ii) the Cas-CLOVERTM gene editing
Figure 2. Overview of current multi-targeted chimeric antigen receptor T-cell approaches. Multi-targeting may be a mean to improve efficacy of CAR-T. Three major methods could be exploited: OR-gate (tandem) CAR-T: consist of the expression of two different CAR on the same T cell; dual-target CAR-T: consist of encoding two different target specific single-chain variable fragment antibodies on same CAR protein using a single vector; CARpool: involves production of two separate single tar- get CAR-T products infused together or sequentially.
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haematologica | 2021; 106(8)