Dendritic Cell Vaccines Extend CD19 CAR-T Cell Persistence and Improve the Outcomes in Refractory/Relapsed Adult B-ALL

Abstract

Introduction: The long-term efficacy of anti-CD19 chimeric antigen receptor (CAR)-T cell in refractory or relapsed (r/r) adult B-cell acute lymphoblastic (B-ALL) patients is limited, and the recurrence rate is high. CAR-T cell depletion and limited CAR-T cell persistence are some of the most common reasons for relapse. Our previous in vitro studies confirmed that dendritic cell (DC) vaccines targeting tumor antigens could induce CAR-T cell rejuvenation and increase the killing function of CAR-T cells. So, we designed a clinical trial to study CD19 CAR-T cell combined with DC vaccination for adult r/r B-ALL to explore whether this therapy improves LFS. (clinicaltrials.gov, no: NCT03291444). Methods: Adult r/r B-ALL patients who expressed HLA-A1101, A2402, or A0201 and had high expression of EPS8 or WT1 were eligible. An EPS8 peptide-derived DC (EPS8-DCs) vaccine was used in EPS8-high patients, while a WT1 peptide-derived DC (WT1-DC) vaccine was used in EPS8-negative patients with WT1 positivity. Lymphodepleting chemotherapy comprising fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) was administered intravenously daily for 3 days before CD19 CAR-T cells infusion. After 4 weeks of CAR-T infusion, if bone marrow morphologic remission had been achieved, DC vaccination was administered intradermally every 2 weeks for 4 doses. Results: Eight adult patients with r/r B-ALL were enrolled and successfully received CAR-T cells and DC cells, of which 4 (50%) relapsed after allogeneic hematopoietic stem cell transplantation. They were successfully administered one dose of CD19 CAR-T with a median dose of 2.26×10 6/kg (range 6.4×10 5/kg to 4.46×10 6/kg) on day 0 and four doses of DC vaccination with a median dose of 5.44×10 6 (range 2.97×10 6/dose to 2.68×10 7/dose) every 2 weeks after 4 weeks of CAR-T infusion. All eight evaluable patients achieved complete response (CR) after receiving CD19 CAR-T. With a median follow-up of 608 days, the median LFS time was 489 days, and the median OS was not reached. Seven of the eight evaluable patients were still alive. Four (50%) were in continuous MRD-negative remission at the cutoff time, and two of them (pt 02 and pt 03) maintained MRD-negative CR for more than 4 years. The median peak of CAR-T cell expansion in the PB was detected on day 7 after infusion of CD19 CAR-T. The median persistence time of CAR-T was 336 days (range 84 to 1549 days). CAR-T cells were reamplified after infusion of the DC vaccine. For patients with an LFS of more than 2 years (pt 02, pt 03, and pt 05), CD19 CAR-T cells were still detectable for more than 1 year, with a maximum of 4.2 years in pt 03. The activity of the CTLs measured by IFN-γ ELIspot showed that IFN-γ-secreting CTLs were significantly increased after DC vaccination. These assays showed that antigen-specific cellular immune activity was enhanced after vaccination. No grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) occurred after infusion of 4sCAR19. No grade ≥3 events occurred during the infusion of the DC vaccine. Only 1 of 8 patients experienced local skin reactions after infusion of the DC vaccine. Conclusions: This study reports a novel combination therapy strategy (CAR-T cell combining with individualized DC vaccination) for adult r/r B-ALL. DC vaccination has higher safety, may prolong the persistence of CAR-T cells, and may prolong the survival time and quality of life. CAR-T cell therapy combining with DC vaccination is a potential therapy strategy for adult r/r ALL patients who are not eligible for transplantation or who relapse after transplantation.