In three evaluable patients with pemphigus vulgaris (PV) treated with rese-cel at 1 x 10^6 cells/kg without preconditioning, Cabaletta Bio reported complete peripheral B cell depletion in two patients and substantial depletion in the third. Early Pemphigus Disease Area Index (PDAI) activity scores improved from 24 to 10 at four months, 83 to 3 at three months, and 22 to 2 at one month. CAR T expansion kinetics matched those seen in preconditioned cohorts across other RESET trials. Safety was manageable with no ICANS, one case of grade 1 CRS, and one early disease flare requiring steroids that subsequently tapered below baseline by month three. All three patients discontinued immunomodulators post-infusion and were off or tapering steroids at the data cut.
The news event is Cabaletta’s first clinical signal that CD19 CAR T therapy may be feasible in PV without cyclophosphamide/fludarabine lymphodepletion, presented as a late-breaking update at ESGCT. The company will expand enrollment in RESET-PV at the current dose, consider dose escalation, and move to incorporate chemo-free regimens into selected cohorts across its broader autoimmune program. Separately, the adult Phase 1/2 cohorts in myositis, lupus, scleroderma, and myasthenia gravis within the RESET platform are now fully enrolled.
Strategically, removing preconditioning is an attempt to compress toxicity, logistics, and cost from autoimmune CAR T while preserving potency. If validated, this would attack a key adoption barrier: the chemo component that drives cytopenias, infections, and inpatient utilization, and that narrows eligibility in an elective, non-oncology setting. The translational readout matters as much as the clinical scores: expansion comparable to preconditioned cohorts and the expected BAFF surge support deep B cell clearance without lymphodepletion, countering the dogma that chemo is required for engraftment and early persistence. The tension is durability and control. Without lymphodepletion, persistence may wane sooner, and the immediate withdrawal of background immunomodulators can provoke early flares, as seen in one patient. Protocolized tapering, infection prophylaxis, and immunoglobulin management become central operating levers if the regimen moves to outpatient.
For sites, a chemo-free CAR T pathway could rebalance resource requirements—less marrow suppression and potentially shorter admissions—while maintaining the need for CAR T infrastructure, 24/7 monitoring, CRS/ICANS response capabilities, and dermatology expertise for PDAI assessments. Sponsors and CROs gain design flexibility: fewer exclusion criteria tied to marrow reserve and an easier consent conversation may lift enrollment velocity in small, refractory populations. Regulators will focus on durability, steroid-sparing, and rescue-medication independence, with PDAI activity scores aligning to precedent in PV. Vendors and manufacturers should read this as momentum toward higher-volume autoimmune use cases with tighter vein-to-vein expectations and a premium on consistent cell product quality, absent the crutch of lymphodepletion.
What matters next is not the month-one and month-three drops in PDAI but whether responses hold as B cells reconstitute, immunoglobulin levels normalize, and steroid independence persists beyond six to 12 months. Dose exploration without preconditioning will test whether higher cell numbers can extend persistence without tipping safety. Parallel cohorts with and without lymphodepletion would clarify the trade-off between simplicity and durability and could shape the registrational approach. Watch for standardized steroid-taper protocols, infection signal tracking, outpatient site activation, and whether Cabaletta can replicate chemo-free expansion in systemic indications already fully enrolled. If the chemo-free thesis sustains, the center of gravity in autoimmune CAR T may shift from oncology-grade conditioning to operationally lighter, site-friendly regimens—provided durability and reproducibility are proven at scale.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
