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CAR T cell therapies in multiple myeloma
CAR-T. Patients were highly pretreated with a median of six prior therapy lines and 84% had triple-class refractory disease (refractory to one protease inhibitor [PI], one IMiD, and a CD38 antibody). At least PR was achieved by 73% including ≥CR in 33%. MRD-negative CR was achieved in 26%. Median time to response was 1 month. Fifty-four patients, who received 450x106 CAR-T, had superior response (≥PR: 82%; ≥CR: 39%; MRD-negative CR: 28%) when compared to lower doses. Revised Multiple Myeloma International Staging System (R-ISS) stage 3 disease at enrollment had inferior response, com- pared to R-ISS stage 1 or 2. As in the phase I trial, baseline BCMA expression did not affect response to ide-cel. With median follow-up of 13.3 months, overall median PFS was 8.8 months. Median PFS increased with higher CAR-T dose with a median PFS of 12.1 months for patients who received 450x106 CAR-T. Patients, who achieved at least CR, also experienced better PFS (≥CR: median PFS of 20.2 months; very good partial response [VGPR]: median PFS of 11.3 months; PR: median PFS of 5.4 months; no- response: 1.8 months). Median OS was 19.4 months. Durable CAR-T persistence was observed up to 1 year: CAR-T were detected at 1, 3, 6, 9, and 12 months in 99%, 75%, 59%, 37%, and 46% respectively. CAR-T expansion was increased at higher doses. In an ongoing phase III study, ide-cel is compared with standard-of-care regimens in patients with 2-4 prior regimens, including IMiD, PI, and CD38 antibody (KarMMa-3). Ide-cel is also evaluated in the multi-cohort KarMMa-2 study, in patients with early relapse after first-line therapy or patients with sub- optimal response after autografting (<VGPR).
Cilta-cel (JNJ-4528)
The CARTITUDE-1 study evaluates cilta-cel (target dose: 0.75x106 CAR+ T /kg) in patients exposed to PI, IMiD and CD38 antibody. Preliminary results were pre- sented at the 2020 ASH conference. Sixteen of 113 patients, who underwent apheresis, were not dosed because of consent withdrawal (n=5), progressive disease (n=2) or death (n=9). The remaining 97 patients had received a median of six prior lines of therapy. Ninety- seven percent of patients achieved at least PR with strin- gent CR in 67%. Fourty-eight of the 57 patients evaluable for MRD, 93% were MRD-negative at the level of 10-5. Response was independent of baseline BCMA expression. Median time to first response was 1 month. At a median follow-up of 12.4 months, 12-month PFS was 77%. Peak CAR-T expansion was observed around day 10-14, and CAR-T were observed in 36% of patients at 3 months of follow-up.52 Interestingly, response to cilta-cel was inde- pendent of CAR-T expansion and persistence.52 In the Chinese LEGEND-2 trial, different conditioning regimens were used, as well as variable CAR-T infusion methods (split vs. single infusion). The Xi’an site, which used cyclophosphamide lymphodepletion therapy and three CAR-T cell infusions (dose: 0.07-2.1x106/kg; median dose: 0.50x106/kg), enrolled 57 out of 74 patients.53 These patients had received a median of three prior lines of ther- apy (prior PI and IMiD: 60%). Overall response rate (ORR) was 88% with CR in 74% (median time to response: 1 month). MRD-negative CR was achieved in 68%. At a median follow-up of 25 months, median PFS was 19.9 months for all patients, while it was 28.2 months for those in CR. Median OS was 36.1 months (not reached for patients in CR). Cilta-cel is also being evaluated in a phase
III study (CARTITUDE-4), which compares CAR-T versus pomalidomide, bortezomib and dexamethasone or dara- tumumab, pomalidomide and dexamethasone in relapsed and lenalidomide-refractory MM. In addition, the ongoing CARTITUDE-2 study is evaluating cilta-cel in different patient populations, including those with early relapse after frontline therapy, prior exposure to a BCMA-target- ing drug, and those with <CR post-auto-SCT.
Other B-cell maturation antigen-specific chimeric antigen receptor T cells
In order to further improve the activity and/or persist- ence of CAR-T, several studies are evaluating novel BCMA-targeting CAR-T. Studies include CAR constructs containing a fully human BCMA-specific binding domain to reduce development of humoral and/or cellular immune responses against CAR-T, which may impair CAR-T persistence.49,54-56 One of these products with a fully human antigen-binding domain is orva-cel (orvacab- tagene autoleucel), which is currently evaluated in the phase I/II EVOLVE study. This study shows promising efficacy of orva-cel in heavily pretreated MM (median of six prior lines of therapy; 94% triple-class refractory). At least PR was achieved in 92% of 62 patients treated at higher dose levels (300-600x106 CAR-T), with CR in 36%. Follow-up is ongoing. Treatment was associated with a low incidence of grade ≥3 cytokine release syndrome (3%) and grade ≥3 neurotoxicity (3%). Following CAR-T, there was robust expansion and durable persistence (69% of patients had detectable CAR-T at 6 months). Moreover, preclinical studies have shown that enrichment for BCMA-targeting CAR-T displaying a memory-like pheno- type leads to improved persistence in mouse models,57 which may result in more durable disease control. Bb21217 uses the same CAR molecule as ide-cel, but bb21217 is cultured in the presence of a PI3 kinase inhibitor, which leads to enrichment for CAR-T with a memory-like phenotype. Preliminary results showed effi- cacy in 69 heavily pretreated patients (64% triple-class refractory) with an ORR of 68% (CR of 29%; median response duration: 17.0 months). Interestingly, a high memory-like T-cell count in the drug product was associ- ated with superior CAR-T expansion and less progression at 6 months. The manufacturing process for orva-cel is also designed to produce CAR-T enriched for central memory T-cell phenotype.56 Other trials are evaluating combinations of CAR-T with other drugs to improve activity and durability of response. Based on preclinical data showing that the T-cell stimulatory effects of IMiD enhance the efficacy of CAR-T,58-60 several ongoing clinical studies are evaluating the combination of lenalidomide and CAR-T. The combination of BCMA CAR-T with γ- secretase inhibitors is also investigated, because in vitro studies show that γ-secretase inhibitors block BCMA cleavage and increase BCMA cell surface expression lev- els.54,61 These results are confirmed in an ongoing clinical study, which shows that gamma secretase inhibition enhances BCMA surface expression on MM cells and reduces soluble BCMA levels.54
CD19-specific CAR-T
Recent studies showed that MM cells express ultra-low levels of CD19,30 moreover MM cells with disease-propa- gating properties also express CD19. This formed the rationale for the evaluation of CD19-specific CAR-T in
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