Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Introduction: We are conducting a clinical trial in which patients with acute myeloid leukemia (AML) who are undergoing allogeneic transplant undergo post-transplant vaccination with DC/AML fusion cells. Allogeneic transplantation is uniquely curative for a subset of patients with AML, however, post-transplant relapse and graft versus host disease remain significant concerns. We have developed a promising leukemia vaccine in which patient derived AML cells are fused with donor-derived dendritic cells (DCs), presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population. We hypothesize that DC/AML vaccination post-transplant would elicit the durable expansion of leukemia specific T cells within the donor T cell repertoire to effectively protect against disease relapse.

Methods: Patients undergo collection and cryopreservation of leukemia cells at the time of diagnosis with AML. Patients who undergo an allogeneic transplant in complete remission from a matched related or unrelated donor (cohort A) or a haplo-identical donor (Cohort B) are assessed for eligibility to undergo leukapheresis for dendritic cell generation between day 25-45 post-transplant. In order to proceed with leukapheresis, patients must demonstrate donor hematopoietic recovery in the absence of ongoing grade 2 or higher GVHD. Patients initiate vaccination between day 70-100 post-transplant. 2 vaccines are given at 3 week intervals, in conjunction with GMCSF 100 mcg daily at the vaccine site for 4 days. A booster vaccine may be given 30-60 days following the taper of immune suppression, in the absence of GVHD.

Results: To date, 12 participants have undergone vaccine generation. The median age is 62 years (range 23-74). 10 participants were enrolled to cohort A: 7 were transplanted with a matched unrelated donor and 3 were transplanted with a matched sibling donor. 2 participants were enrolled to cohort B following transplant from a haplo-identical donor. The mean yield of leukemia cells was 314 x10⁶ (range 95-to 818-x10⁶)and mean viability was 96%. For DC generation, patients underwent leukapharesis and adherent mononuclear cells were cultured with GM-CSF, IL-4 and TNFa. The mean yield of DCs was 131 x10⁶ and viability 77%. Fusion vaccine was successfully generated in 11/12 patients, with mean fusion efficiency of 51% with viability of 76%. One patient had insufficient DC for vaccine generation. Mean Fusion Vaccine Dose was 4.7 x 10⁶ fusion cells. 3 patients did not meet eligibility to initiate vaccination due to ongoing toxicity following transplant (2 patients) and GVHD (1 patient). 8 participants have initiated vaccine administration and are evaluable for toxicity and response. The most common side effects have been grade 1 vaccine site reactions (n=9 grade 1, n=1 grade 2). 4 patients developed GVHD that was determined to be possibly related to vaccination, at a median time of 16.5 days after vaccination (range 5-21 days). 2 of these patients developed grade 2 acute GVHD of the skin, one patient developed grade 2 gastrointestinal GVHD that subsequently evolved into moderate, chronic GVHD affecting the skin, GI tract, eyes and mouth, and one patient developed mild transaminitis attributed to liver GVHD. An additional 3 patients developed GVHD with a median time of 99 days post vaccination (range 91-123 days), assessed as being unlikely related to vaccine. 7 of the 8 patients remain in a CR at a median time of 15.5 months post-transplant (range 4.8-22.4 months). One patient relapsed 14.8 months post haplo-identical transplant. Immunologic response following vaccination is being assessed, with respect to the presence of leukemia-reactive T cells, T cells targeting previously identified leukemia- associated antigens, T cell clonality, T regulatory cells, and PD-1 expressing T cells. In the absence of treatment associated toxicity, a second cohort is planned, in which vaccine will be given in conjunction with decitabine.

Conclusions: Vaccine generation using donor derived DC isolated following engraftment is feasible. Mild to moderate graft versus host disease has been observed in a subset of patients, and 7/8 vaccinated patients remain relapse free. Correlative science studies to assess immune response to vaccination, identify neoantigen targets, and characterize the immune milieu, will be reported.