orvacabtagene autoleucel (JCARH125)

P1/2, N=169, Completed, Juno Therapeutics, a Subsidiary of Celgene | Active, not recruiting --> Completed

Pts received a single BMS-986354 infusion 2–7 days after lymphodepleting chemotherapy (3 days fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2])...Median onset was day 4 (range, 2–8), median duration was 4 days (range, 1–8), and common treatments included tocilizumab (n = 38), steroids (n = 25), and anakinra (n = 9)... BMS-986354, a NEX-T investigational BCMA-targeted CAR T-cell product, is a less differentiated, more potent cellular drug product than orva-cel and can be manufactured with a more rapid processing time. At low doses, BMS-986354 demonstrated a favorable safety profile and promising efficacy, including deep and durable responses in pts with heavily pretreated RRMM. The study continues to enroll patients in the dose-expansion phase.

Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor...Patients treated received a median of 8 (range of 4 – 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel...Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050

Other Constructs of Interest Orva-cel (orvacabtagene autoleucel) is an anti-BCMA CAR T product with a construct containing a fully human scFv, an optimized spacer, a 4-1BB co-stimulatory domain, and a CD3z activation domain...Bb21217 has an identical construct to ide-cel except for coculturing with the phosphoinositide 3 kinase inhibitor (PI3K) bb007 during ex vivo culture to enrich for T cells displaying a memory-like phenotype...The ORR was 94%.17 P-BCMA-101 is a novel construct using an anti-BCMA Centyrin™ fused to a 4-1BB costimulatory domain and CD3z signaling domain...Both ide-cel and cilta-cel are being evaluated in various patient populations, including early-relapse and newly diagnosed high-risk patients...The first results of an allogeneic BCMA-directed CAR-T was with ALLO-715. The initial results from the UNIVERSAL phase 1 study in RRMM are encouraging, with responses reported and more attenuated toxicity.26 Others, including CTX120, BCMAUCART, UCART CS1, and PBCAR269A, are in development and in early-phase studies...Despite these impressive results, however, patients with MM continue to relapse. Moving these therapies earlier in the course of the disease, continued refinement of next-generation products, and rational combination strategies that may defer or prevent relapse should continue to improve on these results with the goal of finally reaching that elusive cure.

Conclusions : The orva-cel manufacturing process results in drug products characterized by highly pure T cells, with high frequencies of early memory and polyfunctional CAR+ T cells. Orva-cel drug products showed robust antigen-specific degranulation, production of multiple cytokines, sustained in vitro and in vivo proliferation, and in vivo persistence.

Peak postinfusion levels of several inflammatory factors were associated with CRS (eg, IL-6 and IL-8) and NE (eg, tumor necrosis factor-α) grades (P < 0.05). Correlative analysis is ongoing, and updated results will be presented.