Induction of a Systemic Immune Response during Use of an Allogenic Leukemia-Derived Dendritic Cell Vaccine in MRD+ AML Patients Correlates with Clinical Response and MRD Conversion

Background. Priming the immune system to eradicate or control residual disease could be an effective strategy in AML maintenance therapy. In this phase II study (ADVANCE-II, Clintrials.gov: NCT03697707) AML patients in first complete remission (CR1), with measurable residual disease (MRD), ineligible for HSCT, were treated with an intradermal allogenic leukemia-derived dendritic cell vaccine (DCP-001).

Methods. A total of 20 evaluable AML-patients received 4 biweekly doses at 25e6 or 50e6 cells per vaccination followed by 2 booster doses of 10e6 cells at week 14 and 18. MRD as a clinical outcome parameter, was assessed at baseline, week 14, 20 and 32. Peripheral blood samples were drawn on day 1, 3, 42, 44, week 11, 18, 20 and 32 and PBMCs cryopreserved. Immune monitoring was performed on these PBMCs by IFNy ELISPOT to tumor associated antigens (WT1, RHAMM and PRAME) and multiparametric flow cytometry. Immunohistochemistry was performed on skin biopsies taken from the site of injection on day 3, 44 and week 18..

Results. All 20 patients have received 4 initial vaccinations, 17 patients received all booster vaccinations and 1 patient received only one booster. Vaccination with DCP-001 resulted in substantial MRD responses with five patients showing MRD conversion, and 2 with a reduction of at least 1Log10 in MRD levels. Immune monitoring was performed on all samples, until week 32 or end of study.

Evaluation of skin biopsies, taken 2 days after the 1^st, 4^th or 6^th vaccination, showed in all patients moderate to high levels of infiltrating CD4, CD8 T-cells and CD68 positive cells.

Vaccine induced T-cell responses to WT1, PRAME and/or RHAMM assessed in PBMC revealed in 17/20 at least 1 vaccine induced response (VIR) to any of these antigens, with the highest total number of VIR in MRD responders, followed by those with stable MRD (Figure 1). Durable VIR were counted if at least 2 VIR to the same antigen at 2 timepoints after baseline were observed. The highest number of durable VIR were detected in MRD responders, indicative of a broad and durable T-cell response.

Further analysis for immune cell composition in blood by flow cytometry showed that patients with stable MRD levels or those with a MRD response had a higher number of circulating Dendritic Cells (pDC, cDC1 and cDC2) at baseline compared to patients who relapsed. In patients with stable MRD the total number of circulating DC increased after vaccination compared to baseline, where these remained at comparable level in the MRD responders. CD8 T-cell memory profiles were evaluated and indicated a difference in baseline levels of CD8 CD45RO+ (memory T cells) (Figure 2), with far higher number of especially CD8 Central memory T-cells in patients who relapsed.

Conclusion/discussion. Patients who showed a decrease in MRD or conversion to MRD negativity had the highest level of tumor-specific and sustained VIR accompanied by the highest level of baseline DC and lowest level of CD8 CM T-cells in the peripheral blood. Based on these data not just a single DC subset (cDC1, cDC2 or pDC) is important to exert an effect in a vaccination-based therapy for AML maintenance, but rather the full composition of DCs. This underscores the importance of cross-priming CD8 T-cells by either of these DCs. Interestingly, the vaccination induced a change in the DC compartment for patients who had a stable MRD response at week 32, with increasing DC frequencies after vaccination. Although the number in the peripheral blood is low, this might reflect the need of a certain number of DC, for an even better immune response. The number of DC as such might also require sufficient CD8 effector cells to either respond or to be primed after vaccination as reflected by low number of CD8 memory T-cells and high number of VIR in MRD responders.

The use of an allogenic dendritic cell-based vaccine induces a local and systemic immune response, in AML patients in CR1 but positive for MRD. Higher numbers of circulating autologous DC in combination with CD8 effector T-cells, instead of high CD8 CM T-cells might be a prerequisite for successful vaccination to prevent relapse or MRD conversion. Improvement in DC frequencies were observed in patients with stable MRD, which might suggest the potential for more booster vaccinations using this vaccine.

Van de Loosdrecht:Amgen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Alexion: Research Funding; Takeda: Honoraria. Cloos:Helsinn: Other: MRD assessments; Merus: Other: MRD assessments, Research Funding; Astellas: Speakers Bureau; Novartis: Consultancy, Other: MRD assessments, Research Funding; Janssen: Research Funding; Genentech: Research Funding; DC-One: Other: MRD assessments, Research Funding; Navigate: Patents & Royalties: Royalties for MRD analyses; Takeda: Research Funding. Platzbecker:Silence Therapeutics: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Geron: Honoraria; BMS/Celgene: Honoraria; Abbvie: Honoraria. Holderried:MSD: Speakers Bureau; Amgen: Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giagounidis:BMS: Honoraria. van der Burg:ISA Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PCI Biotech: Consultancy, Honoraria; IO Biotech: Consultancy, Honoraria; Mendus BV: Consultancy, Honoraria; Advaxis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Clovis Oncology: Consultancy, Honoraria; Carrick Therapeutics: Consultancy, Honoraria; Debiopharm: Consultancy, Honoraria; Eisai: Consultancy, Honoraria; Hoffman-la Roche: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; GSK: Consultancy, Honoraria; ImmunoGen: Consultancy, Honoraria; Millenium Pharmaceuticals: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Octimet Oncology: Consultancy, Honoraria; Oncoinvent: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Sotio: Consultancy, Honoraria. van Zeeburg:Mendus AB: Current Employment. Rovers:Mendus AB: Current Employment, Current equity holder in publicly-traded company.