Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Biological therapies, adult, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human, Vaccines
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 2.26×106/kg (range 6.4×105/kg to 4.46×106/kg) on day 0 and four doses of DC vaccination with a median dose of 5.44×106 (range 2.97×106/dose to 2.68×107/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.
Disclosures: No relevant conflicts of interest to declare.
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