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Autoantigen CAR T Cell Therapy Well-Tolerated in Mucosal-Dominant Pemphigus Vulgaris

Investigators found a dose-dependent increase in CAART cell persistence.

DSG3 autoantigen-expressing chimeric antigen receptor (CAR) T-cells (DSG3-CAART) were found to be well-tolerated with dose-dependent persistence in participants with mucosal-dominant pemphigus vulgaris (mPV).

Data from an ongoing Phase 1 open-label trial (NCT04422912) were presented at the American Society of Gene & Cell Therapy 25th Annual Meeting, May 16-19, 2022, in Washington DC, by David J. Chang, MD, MPH, FACR, chief medical officer, Cabaletta Bio.

"Based on the long-lasting remission of B cell cancers with chimeric antigen receptor T (CART) cells, we developed chimeric autoantibody receptor T cells to target B cell-mediated autoimmune diseases, using the same construct but switching the targeting domain to the autoantigen. For mPV patients, autologous T cells have been genetically modified to express DSG3-CAART and target only the anti-DSG3 B cells,” Chang and colleagues wrote.

Investigators at Cabaletta Bio are assessing the maximum tolerated dose of DSG3-CAART in adult participants with inadequately managed active, anti-DSG3 Ab positive, biopsy confirmed mPV. The study is primarily assessing safety via the incidence of treatment-related adverse events (AEs) and dose-limiting toxicities (DLTs) such as cytokine release syndrome (CRS) and neurotoxicity within 3 months of infusion. The trial is also assessing CAART persistence by qPCR, anti-DSG3 Ab levels by enzyme-linked immunoassay (ELISA), and disease activity by Pemphigus Disease Area Index (PDAI) as secondary endpoints.

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Twelve participants have received fractionated infusions of DSG3-CAAR T-cells in 4 cohorts of 2e7, 1e8, 5e8, and 2.5e9-cell doses without lymphodepletion, with 4 participants discontinuing or tapering immunosuppressives. Of the 12, 9 have completed 3-month follow-up post-infusion. These patients were 67% female with an average age of 53 years (range, 32-70) and an average disease duration of 4.3 years (range, 0.4-15.4). They had an average PDAI score of 12 (range, 2-20) and an average 100 U/mL anti-DSG3 antibodies (range, 51-169). Participants’ prior medications included prednisone (n = 9), rituximab (n = 6) and mycophenolate (n = 6).

Investigators found that DSG3-CAART infusion did not result in any DLTs, serious AEs, or clinically relevant AEs during the 3 months of follow-up, with no cases or CRS or neurotoxicity. A dose-dependent increase in DSG3-CAART cell persistence was observed in cohort 3 through day 29. Anti-DSG3 antibody levels increased in 3 participants, were stable in 5 participants, and decreased in 1 participant through month 3. Increased antibody levels and disease activity were observed in participants that stopped or tapered immunosuppressive therapies or received lower doses. Chang and colleagues found that disease activity cleared in some participants during pre-infusion (n =1), month 1 (n = 2), month 2 (n = 5), and month 3 (n = 3) compared to all participants having disease activity at baseline.

“Dose-dependent increase in persistence indicates that DSG3-CAART cells were not eliminated by soluble anti-DSG3 Ab; peak persistence in cohort 3 was 10-1000x lower than observed with CART therapy in B cell cancers, likely due to differences in target frequency and lymphodepletion. The favorable DSG3-CAART safety profile and absence of DLTs allow the study to evaluate higher doses and a manufacturing enhancement, intended to increase in vivo presence of DSG3-CAART, to reach deep and durable remission for mPV patients without generalized immunosuppression,” Chang and colleagues concluded.

To read more coverage of ASGCT 2022, click here.

Chang DJ, Basu S, Porter D, et al. A phase 1 trial of targeted DSG3-CAART cell therapy in mucosal-dominant pemphigus vulgaris (mPV) patients: Early cohort data. Presented at ASGCT 25th Annual Meeting, May 16-19, 2022; Washington DC. Abstract 793.