PURPOSE A combination of anti–B-cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induced high response rates in patients with relapsed or refractory (R/R) multiple myeloma (MM), but long-term outcomes have not been assessed yet. PATIENTS AND METHODS In this single-arm, phase II trial, patients with R/R MM received a combination of anti-BCMA CAR T cells and anti-CD19 CAR T cells at a dose of 1 × 106 cells/kg, after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS Of 69 enrolled patients, 62 received the combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.3 months. The overall response rate was 92% (57/62), and complete response or better was observed in 37 patients (60%). Minimal residual disease–negativity was confirmed in 77% (43/56) of the patients with available minimal residual disease detection. The estimated median duration of response was 20.3 months (95% CI, 9.1 to 31.5). The median progression-free survival was 18.3 months (95% CI, 9.9 to 26.7), and the median overall survival was not reached. Patients with extramedullary disease had significantly inferior survival. Fifty-nine patients (95%) had cytokine release syndrome, with 10% grade 3 or higher. Neurotoxic events occurred in seven patients (11%), including 3% grade 3 or higher. Late adverse effects were rare, except for B-cell aplasia, hypogammaglobulinemia, and infections. CONCLUSION The combination of anti-BCMA and anti-CD19 CAR T cells induced durable response in patients with R/R MM, with a median progression-free survival of 18.3 months and a manageable long-term safety profile.

Systematic and dynamic humoral immune reconstitution is little known for relapse/refractory (R/R) multiple myeloma (MM) patients who received anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy. We investigated the kinetics of B cell, normal plasma cell and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR-T cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (23-270). B cell count reached nadir on a median of day 7 and returned to baseline level on a median of day 97. BCMA positive cells in bone marrow turned undetectable on a median time of day 28 (13-159) in 94.87% (37/39) patients. Normal plasma cells in bone marrow were first re-detectable on a median of day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on a median of day 60. Recovery of serum IgG, IgM and IgA was observed in 53.33% (8/15) patients (non- IgG MM), 73.08% (19/26) patients (non- IgM MM) and 23.81% (5/21) patients (non- IgA MM) at 1-year, respectively. Median times to IgG, IgM and IgA recovery were on day 386, 254 and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients developed a total of 44 infection events. No infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and a longer hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR-T cell therapy, especially for IgA.

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) patients with central nervous system leukemia (CNSL) due to concerns for poor response and treatment-related neurotoxicity. Our study included 48 relapsed/refractory B-ALL (R/R B-ALL) patients with CNSL to evaluate the efficacy and safety of CD19-specific CAR T-cell-based therapy. The infusion resulted in overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival (EFS) was 8.7 months (95% CI, 3.7-18.8), and the median overall survival (OS) was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse (CIR) in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (p=0.040). The treatment was generally well tolerated with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3-4 neurotoxic events (NEs), which developed in 11 patients (22.9%), were associated with a higher pre-infusion disease burden in CNS and were effectively controlled under intensive management. Our results suggested that CD19-specific CAR T-cell-based therapy could induce similar high response rate in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for those previously excluded CNSL patients with manageable neurotoxicity. Clinical trials were registered at www.clinicaltrials.gov as # NCT02782351 and www.chictr.org.cn as # ChiCTR-OPN-16008526.

Objectives. This study aims to investigate the effect of betulinic acid (BA) on myocardial ischemia reperfusion/injury in an open-chest anesthetized rat model. Methods. The model was induced by 30 minutes left anterior descending occlusion followed by 2 hours reperfusion. There are six groups in our present study: sham operation group, ischemia/reperfusion group, low-dosage BA group, medium-dosage BA group, high-dosage BA group, and fosinopril sodium group. Rats in the latter four groups were administrated with BA (50, 100, and 200 mg/kg, i.g.) or fosinopril sodium (10 mg/kg, i.g.) once a day for 7 days before operation, respectively. Rats in the former two groups were given the same volume of vehicle (0.5% CMC-Na, i.g.). During the operation, cardiac function was continuously monitored. Serum LDH and CK were measured with colorimetric assays. The expression of Bcl-2 and Bax and the apoptosis of cardiomyocytes were investigated with western blot and TUNEL assay, respectively. Results. Pretreatment with BA improved cardiac function and attenuated LDH and CK activities compared with IR group. Further investigation demonstrated that the expression of Bcl-2 and Bax and TUNEL assay was in line with the above results. Conclusion. BA may reduce the release of LDH and CK, prevent cardiomyocytes apoptosis, and eventually alleviate the extent of the myocardial ischemia/reperfusion injury.

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