Contributions
Abstract: EP403
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
The allogeneic, leukemia-derived dendritic cell vaccine, DCP-001, is a relapse vaccine capable of generating cellular and humoral immune responses in acute myeloid leukemia patients (AML). In an ongoing phase II study (Clintrials.gov: NCT03697707), DCP-001 is observed to induce immune response specifically against tumour associated antigens relevant for AML. Preclinical efficacy studies have previously shown DCP-001 vaccination to significantly repress subcutaneous tumour growth in a humanised immunocompetent mouse model of AML. The reproducibility of the preclinical model provides a platform for optimizing vaccination strategies and evaluating DCP-001 efficacy in combination with established AML treatment agents.
Aims
To determine, in a preclinical setting, whether DCP-001 vaccination was compatible with the approved AML drug therapy comprised of 5-Azacitidine (5-AZA) and Venetoclax (VEN).
Methods
25 female NSGS mice were inoculated with 1 x 105 human CD34+ cells. A 12-week maturation period was permitted for engraftment and human immune cell development during which blood was sampled to track chimerism by FACS (hCD45, mCD45, hCD3 and hCD19) and complete blood count (CBC) analysis. Subsequently, the leukemia cell line DCOneLUC was engrafted subcutaneously (5 x 106 cells/mouse) and animals were randomized by weight and chimerism and assigned to the following groups: untreated control (n = 6), vaccination (DCP-001, QWx2., n = 7), treatment (AZA 1mg/kg and VEN 50 mg/kg, QDx5, n = 6) and combination (DCP-001, QWx2 + AZA 1mg/kg and VEN 50 mg/kg, QDx5, n = 6). Disease progression and therapy response were monitored by calliper-based measurement of tumour volumes and optical imaging of the bioluminescent cell line, DCOneLUC.
Results
Tumour volumes indicated that all therapy groups were capable of slowing DCOneLUC tumour growth as compared with control group. Importantly, mean tumour volume (± SEM) 6 weeks after therapy initiation was significantly reduced in the combination group (181.8 ± 29 mm3) as compared to control (522 ± 97.5 mm3), but also vaccination (326.9 ± 54.6 mm3) or drug treatment alone (293.8.8 ± 29 mm3). Bioluminescence imaging and quantification corroborated tumour volume data indicating combination therapy to be the most efficient. AZA-VEN treatment was associated with transient but reversible weight loss and also a reduction in chimerism as determined by the fraction of peripheral blood cells expressing hCD45 at endpoint.
Conclusion
Preclinical modelling of AML in a humanized mouse model reproduced evidence that DCP-001 vaccination is capable of slowing AML cell line derived tumour growth. Furthermore, vaccination efficacy was significantly enhanced when combined with AZA-VEN drug treatment. Off target effects of drug treatment reduced circulating human immune cells, suggesting optimization of treatment and vaccination scheduling may further enhance the anti-leukemic effect of the combination therapy. These preclinical results support use of DCP-001 as add-on to treatment with AZA-VEN in clinical trials in AML patients.
Keyword(s): AML, Azacitidine, Mouse model, Vaccination
Abstract: EP403
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
The allogeneic, leukemia-derived dendritic cell vaccine, DCP-001, is a relapse vaccine capable of generating cellular and humoral immune responses in acute myeloid leukemia patients (AML). In an ongoing phase II study (Clintrials.gov: NCT03697707), DCP-001 is observed to induce immune response specifically against tumour associated antigens relevant for AML. Preclinical efficacy studies have previously shown DCP-001 vaccination to significantly repress subcutaneous tumour growth in a humanised immunocompetent mouse model of AML. The reproducibility of the preclinical model provides a platform for optimizing vaccination strategies and evaluating DCP-001 efficacy in combination with established AML treatment agents.
Aims
To determine, in a preclinical setting, whether DCP-001 vaccination was compatible with the approved AML drug therapy comprised of 5-Azacitidine (5-AZA) and Venetoclax (VEN).
Methods
25 female NSGS mice were inoculated with 1 x 105 human CD34+ cells. A 12-week maturation period was permitted for engraftment and human immune cell development during which blood was sampled to track chimerism by FACS (hCD45, mCD45, hCD3 and hCD19) and complete blood count (CBC) analysis. Subsequently, the leukemia cell line DCOneLUC was engrafted subcutaneously (5 x 106 cells/mouse) and animals were randomized by weight and chimerism and assigned to the following groups: untreated control (n = 6), vaccination (DCP-001, QWx2., n = 7), treatment (AZA 1mg/kg and VEN 50 mg/kg, QDx5, n = 6) and combination (DCP-001, QWx2 + AZA 1mg/kg and VEN 50 mg/kg, QDx5, n = 6). Disease progression and therapy response were monitored by calliper-based measurement of tumour volumes and optical imaging of the bioluminescent cell line, DCOneLUC.
Results
Tumour volumes indicated that all therapy groups were capable of slowing DCOneLUC tumour growth as compared with control group. Importantly, mean tumour volume (± SEM) 6 weeks after therapy initiation was significantly reduced in the combination group (181.8 ± 29 mm3) as compared to control (522 ± 97.5 mm3), but also vaccination (326.9 ± 54.6 mm3) or drug treatment alone (293.8.8 ± 29 mm3). Bioluminescence imaging and quantification corroborated tumour volume data indicating combination therapy to be the most efficient. AZA-VEN treatment was associated with transient but reversible weight loss and also a reduction in chimerism as determined by the fraction of peripheral blood cells expressing hCD45 at endpoint.
Conclusion
Preclinical modelling of AML in a humanized mouse model reproduced evidence that DCP-001 vaccination is capable of slowing AML cell line derived tumour growth. Furthermore, vaccination efficacy was significantly enhanced when combined with AZA-VEN drug treatment. Off target effects of drug treatment reduced circulating human immune cells, suggesting optimization of treatment and vaccination scheduling may further enhance the anti-leukemic effect of the combination therapy. These preclinical results support use of DCP-001 as add-on to treatment with AZA-VEN in clinical trials in AML patients.
Keyword(s): AML, Azacitidine, Mouse model, Vaccination