P1387: treatment with a leukemia-derived dendritic cell vaccine induces innate and adaptive immune response correlating with clinical response in aml patients in cr1 with measurable residual disease

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Priming the immune system to eradicate or control residual disease could be an effective strategy in AML maintenance therapy. In this phase 2 study (ADVANCE-II, Clintrials.gov: NCT03697707) AML patients in first complete remission (CR1), with measurable residual disease (MRD), ineligible for transplant, were treated with an allogenic leukemia-derived dendritic cell vaccine (vididencel). Aims: Analysis of circulating immune cells was performed to investigate the immune system activation induced upon treatment with vididencel, which could have an impact on clinical outcome. Methods: Twenty evaluable AML-patients received four biweekly intradermal injections of vididencel followed by two booster doses at week 14 and 18. MRD was assessed at baseline, week 14, 20 and 32. Peripheral blood was drawn on day 1, 3, 42, 44, week 11, 18, 20 and 32 and peripheral blood mononuclear cells (PBMCs) cryopreserved. Functional T-cell responses, against WT1, PRAME and RHAMM, were assessed using using IFNy ELISPOT. Multiparametric flow cytometry (40 marker panel; Cytek 5 laser Aurora) was performed, followed by high dimensional reduction using FlowSom. Results: Seven out of 20 patients showed a MRD response with five patients showing MRD conversion (to MRD negative), and 2 with a reduction of at least 1Log10 in MRD level. Seven patients remained in CR with MRD positive status and only 6 patients relapsed within 32 weeks after start of treatment. At data cut-off (November 2022, median FU 19.4 months) 14 patients were alive and in follow up, with the median RFS not yet reached and median OS of 30,9 months. Functional T-cell analysis showed vaccine induced responses (VIRs) to antigens present in vididencel in 17 out of 20 patients, with highest number of VIRs in MRD responders, providing a positive correlation of VIRs with clinical response. Analysis of immune cell populations with flow cytometry using high dimensionality reduction methods showed changes in specific populations during vaccination. Changes in both the innate and adaptive immune cell compartments are observed; B-cells and monocytes (cDC1) increase, while CD8+Lag3+ decreased. B-cell levels increased in all responder categories, while cDC1 increased in patients in CR with stable MRD responses, while relapse patients were unable to mount an increase. CD8+Lag3+ decreased during vaccination, especially in those patients with higher baseline values (relapsed patients) (Figure 1). CD4+ T-cell subsets did not change significantly during vaccination, but differences were observed at baseline across the response groups with more tumor-reactive subsets were identified in patients remaining in CR, whereas more suppressive subsets were identified in relapsed patients. Summary/Conclusion: In conclusion, immunotherapy with vididencel is able to induce immune responses in AML patients in CR1 after chemotherapy induction/consolidation, with the number of responses correlating positively with clinical responses. Additionally, the vaccine induces a broader immune activation, in both the innate and adaptive immune system, and reduces the number of inhibiting CD8Lag3+ T-cells. This leads to reduction of residual disease in a proportion of patients and promising relapse-free and overall survival.Keywords: Minimal residual disease (MRD), Dendritic cell vaccine, Cancer immunotherapy, AML