Vididencel, a Leukemia-Derived Dendritic Cell Vaccine, Acts Synergistically with Azacitidine/Venetoclax Treatment in a Preclinical AML Model

Vididencel is an active immunotherapy comprising irradiated leukemic-derived dendritic cells from the DCOne cell line, which are administered via intradermal injection. In clinical studies, vididencel treatment has been shown to be safe and feasible in treatment of patients with acute myeloid leukemia (AML), with side effects limited to local injection site reactions. Use of vididencel monotherapy in AML patients after intensive induction therapy has shown induction of strong T cell responses and durable disease control. This makes vididencel an excellent drug to add to previous standard-of-care, such as azacitidine and venetoclax.

To investigate the synergistic anti-tumor potential of vididencel in combination with azacitidine (AZA) and/or venetoclax (VEN), in vitro and in vivo experiments were performed using clinically relevant concentrations. Firstly, the effect of either AZA, VEN or combination of both on the efficacy of vididencel was established. For this, research grade vididencel further referred to as DCOne derived mature dendritic cells (DCOne mDC) were either pretreated with AZA, VEN or combination of both and viability, recovery and phenotype of the cells was measured. Subsequently, the potential of these cells to stimulate T cell proliferation and differentiation was studied, in a mixed lymphocyte reaction. For this, CFSE-labelled PBMCs were co-cultured with different amounts of DCOne mDC for 6 days and dilution of CFSE was analyzed as a measure of T cell proliferation using flow cytometer. Moreover, the effect of AZA, VEN and their combination on the endocytosis of DCOne mDC-derived antigenic material by host antigen presenting cells (APC) was studied by co-culture of CFSE-labelled DCOne mDC with violet proliferation dye 450 (VPD450) labelled PBMC. Endocytosis was evaluated as the percentage of the CFSE/VPD450-positive population in the PBMCs by flow cytometry. Secondly, to mimic the clinical setting where patients are pre-exposed to AZA or VEN, peripheral blood mononuclear cells (PBMC) from heathy donors were pre-treated with AZA, VEN or a combination thereof were used to study the ability of DCOne mDCs to interact with immune cells and stimulate T cell proliferation and differentiation into effector cells. Lastly, efficacy of DCOne mDC in combination with AZA and VEN was tested in a humanized mouse model. Female NSGS mice were inoculated with 1x10⁵ human CD34⁺ cells. A 12-week maturation period was permitted for engraftment and human immune cell development. Subsequently, the leukemia cell line DCOne^LUC was engrafted sub-cutaneously and animals were randomized by weight and chimerism and assigned to the following groups: untreated control, DCOne mDC (QWx2), AZA/VEN (AZA 1 mg/kg and VEN 50 mg/kg, QDx5) and combination (DCOne mDC + AZA/VEN). Tumor progression and therapy response were monitored measuring tumor volumes.

No significant difference in the viability, recovery or phenotype of DCOne mDC was observed between cells cultured alone or with AZA and/or VEN. We did not observe any detrimental impact of either AZA or VEN on DCOne mDC's potential to stimulate proliferation and differentiation of healthy donor-derived allogeneic PBMC. The ability of PBMC to endocytose DCOne mDC-derived cellular content remains unaffected in the presence of AZA. However, the endocytosis of DCOne mDC was significantly increased by monocytes and plasmacytoid dendritic cells during 3-hour exposure to VEN suggesting positive effect on cross-presentation and cross-priming of T cells in vivo. The in vivo experiments showed that tumor growth reduction was greatest with the combination of DCOne mDC and AZA/VEN, with significantly smaller mean tumor volume (± SEM) 6 weeks after therapy initiation in the combination group (181.8 ± 29 mm³) as compared to control (522 ± 97.5 mm³, unpaired-t-test, p <0.05). DCOne mDC monotherapy (326.9 ± 54.6 mm³) or AZA/VEN alone (293.8 ± 29 mm³) also lead to tumor growth reduction, but less than the combination of the two treatment regimens.

In conclusion, results from these in vitro and in vivo experiments show that vididencel can be combined with AZA and/or VEN and that combination treatment leads to synergism, with superior tumor growth reduction. This provides support for the use of vididencel in combination with both azacitidine and venetoclax in clinical trials.

Zuo:Mendus AB: Current Employment. Leitch:KinN Therapeutics AS: Ended employment in the past 24 months. Kaspers:Mendus AB: Current Employment. Popa:KinN Therapeutics AS: Current Employment. Karlsson-Parra:Mendus AB: Current Employment, Current equity holder in publicly-traded company. Manting:Mendus AB: Current Employment, Current equity holder in publicly-traded company; Synerkine Pharma BV: Membership on an entity's Board of Directors or advisory committees; Transcode Therapeutics Inc.: Other: Independent Director . Rovers:Mendus AB: Current Employment, Current equity holder in publicly-traded company. Gjertsen:Kinn Therapeutics AS: Current equity holder in private company; AOP Orphan Pharmaceuticals GmbH: Consultancy; Astellas Pharma: Consultancy; AstraZeneca: Consultancy; Delbert Pharma: Consultancy; Incyte: Consultancy; JAZZ Pharmaceuticals: Consultancy; MSD: Consultancy; Novartis: Consultancy; Otsuka Pharma: Consultancy; Sanofi: Consultancy; Alden Cancer Therapy AS: Current equity holder in private company; Bjorgvin Therapeutic Group AS: Current equity holder in private company. Singh:Mendus AB: Current Employment.