Active Immunotherapy with Vididencel As Maintenance Treatment in MRD+ AML Patients in CR1 Results in Strong Anti-Tumor Immune Responses and Durable Long-Term Survival in Patients with an Immune Competent Immune Profile

Background. Maintaining remissions in AML patients after intensive induction therapy continues to be a challenge, specifically in patients with measurable residual disease (MRD⁺). Immunotherapy could be an effective way to induce durable disease control for patients in complete remission. This Phase 2 trial used vididencel, an allogenic leukemia-derived dendritic cell vaccine, to induce an effective anti-leukemic response aiming for durable disease control. (ADVANCE-II, Clintrials.gov: NCT03697707). This abstract presents the 3-year follow-up of patients with data collected up to 5^th July 2024.

Methods. A total of 20 evaluable AML patients, in first complete remission (CR1/CRi), MRD⁺ and ineligible for HSCT at inclusion, received 4 biweekly doses of vididencel, followed by 2 booster doses at week 14 and 18. Assessment of MRD was performed at baseline and at week 14, 20 and 32. Follow-up for relapse-free (RFS) and overall survival (OS) continued until 5 years after first dose of vididencel. Peripheral blood samples were taken at baseline, week 6, 11, 14, 18, 20 and 32 to assess immune responses induced by vididencel. Vaccine-induced responses to WT1, PRAME and RHAMM were measured by IFNY ELISPOT, and sustained responses to the same antigen at 2 independent timepoints were annotated. Flow cytometric analysis of peripheral blood was performed using a 40 color Cytek panel, for immune phenotyping of T, B, NK and DC’s, including markers for activation and exhaustion. Standard Boolean gating was performed. Statistical analysis of immune cell subsets and survival parameters was performed in JMP17.

Results. On July 5^th 2024, the median follow-up for all patients was 37.4 Mo (range 6.6-60.1). Thirteen patients are still alive with 11 still in CR1. Three patients were transplanted on study before relapse occurred. Without censoring for HSCT, the median RFS and OS have not yet been reached. Estimated 1-and 3-year RFS is 75% (range 55-87%) and 57% (range 34-74%), respectively. Estimated 1-and 3-year OS is 88% (range 69-95%) and 69% (range 46-84%), respectively.

Patients with a MRD response (7 out of 20), defined as conversion to MRD negative (n=5) or a 10-fold reduction in MRD level (n=2), showed superior survival with 5 of 7 patients in CR1 and 6 still alive today. Both patients with 10-fold reduction in MRD remained in CR1 after vididencel treatment. Vaccine-induced T-cell responses were observed in 17 out of 20 patients, with 9 patients showing sustained VIRs. These patients had a significantly better OS than patients without a sustained VIR (KM; p=0.038, log rank).

Immune cell subsets measured at baseline with flow cytometry were correlated with long-term survival data, revealing that high levels of B-cells or low levels of CD8⁺LAG3⁺ central memory (CM) T cells strongly correlated with improved survival. A total of 8 patients were identified with having both high B-cell and low CD8+LAG3+ CM levels, which showed significantly improved OS (KM; p=0.0097, log rank).

Conclusion/discussion. Active immunotherapy with vididencel after achieving CR revealed reduction or clearance of MRD and lead to long term disease control in a subset of patients. Optimum results were obtained in patients in which sustained T-cell responses towards tumor-associated antigens were induced and in those with an immune competent immune profile (high in B-cells and low in immune suppressive CD8+LAG3+ CM T-cells), supporting the presumed mechanism of action of vididencel as active immunotherapy. Currently, vididencel is being assessed in combination with oral azacitidine as AML maintenance therapy after intensive induction therapy, aiming to further improve RFS and OS.