First-in-Human Trial of BCMA-CD19 Compound CAR (cCAR) in Desensitization of Donor-Specific Anti-HLA Antibodies (DSAs) in Haploidentical Stem Cell Transplant Recipients

Background: DSAs are recipient antibodies targeted against donor class I/II human leukocyte antigens (HLAs). The existence of DSAs before HLA haploidentical hematopoietic stem cell transplantation (haplo-HCT) is known to cause primary graft failure. Currently there is no established method of DSA desensitization. cCAR targets the “root cause” of DSA production, B cells and plasma/long-lived plasma cells, and thus may achieve desensitization through a dual reset of humoral and B cell immune system. Aims:We present the safety and efficacy of cCAR, which targets antibody- producing “root cause”, B cells and plasma/long-lived plasma cells in our first-in-human clinical trial. Methods:cCAR is comprised of a complete BCMA CAR fused to a complete CD19 CAR, separated by a self-cleaving P2A peptide. CAR T cells were manufactured in a cGMP facility. Beginning May 2019 through October 2020, 4 haplo-HCT candidates with high titer of DSA (MFI>5000） were enrolled in this study. All patients received conditioning with fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d). CAR T cells were given by dose escalation at 2～4.5×106/kg with a single dose. The primary endpoint is to evaluate toxicity of cCAR and the second endpoint is to observe the reduction of DSA after cCAR therapy and engraftment post-haplo-HCT. Results:The median patient age was 35 years (range, 21～48). All were female; 2 with acute myeloid leukemia (AML), 1 with acute lymphocytic leukemia (ALL) and 1 aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH). All donors were from haploidentical family members. Cytokine release syndrome (CRS) occurred in 3 patients, all grade 1, and resolved within 3～8 days after supportive care or administration of low dose steroids. No neurotoxicity occurred. One patient suffered grade Ⅳ cytopenia which resolved in 2 weeks. No other toxicity occurred. All patients demonstrated B cell and plasma cell depletion at 4 weeks post-cCAR infusion. The average median fluorescence intensity (MFI) value was 82187 (range, 7820～249840) and 2995 (range, 0～4343) before and after cCAR therapy, respectively. All patients received a haplo-HCT within 49～135 days and achieved successful engraftment with full chimerism. The median time for neutrophil and platelet engraftment was12 and 13 days, respectively. Conclusion:Our first-in-human clinical trial of cCAR demonstrated profound efficacy in reducing DSA levels in haplo-HCT candidates. Remarkable depletion of antibody-producing “roots cause”, B cells and plasma/long-lived plasma cells was observed in all patients. Our results suggest cCAR has the potential to benefit patients receiving solid organ transplants or those with other antibody-mediated diseases.