Randomized Phase II Trial of Dendritic Cell/AML Fusion Cell Vaccination Compared to Standard of Care Therapy in AML CR1
Year: 2024
Type: conference-abstract
Abstract: Introduction: We have developed a personalized cancer vaccine in which patient derived AML cells are fused with autologous dendritic cells (DCs), presenting a broad array of antigens including shared and neoantigens. Here we report the results of the multicenter randomized phase II clinical trial (NCT03059485) of DC/AML fusion cell vaccination in AML patients who achieve a remission following chemotherapy or HMA/Venetoclax. Methods: Eligible patients were >55 years and were not candidates for allogeneic transplantation. The primary endpoint was to assess 2-year progression free survival. Leukemia cells were collected and cryopreserved at time of disease presentation. Patients underwent standard of care remission induction therapy, with either 7+3 or HMA/Ven, at the discretion of the treating physician. Patients in CR (CR/CRi) were randomized 2:1 to the vaccine (Arm A) or standard of care arm (Arm C). Arm B, vaccine with PD-1 blockade, was removed prior to any patient being treated. Patients in Arm C could receive maintenance therapy, while those in Arm A did not. Patients in Arm A underwent leukapheresis and DCs were generated by cytokine mediated differentiation. DC/AML fusions were created by co-culture of DCs and leukemia cells in the presence of polyethylene glycol. The trial was designed with a target accrual of 75 patients but closed to prematurely due to slow enrollment during COVID-19 and changes in standard of care leukemia therapy including maintenance HMA/Ven and IDH/FLT3 inhibitors. Herein, we report the results of 41 randomized patients. This trial is not powered to detect difference in clinical endpoints. Results: 41 patients with median age 68 years (range 55-86) were randomized, 27 to Arm A and 14 to Arm C. Two patients (one in each arm) withdrew consent and were not followed for response or survival. Additionally, In Arm A, 1 patient had disease progression, 1 proceeded to allogeneic transplantation, 1 had autoimmune hepatitis and were considered ineligible to proceed with vaccine generation. Fusion vaccine was successfully generated in 23 patients, with a mean fusion efficiency of 50.73%, and a viability of 75%. 2-year PFS in arm A was 31% by intention to treat and 36% in vaccinated patients (N=22) compared to 23% in arm C (N=13). 2-year OS was 73% in Arm A and 61% in Arm C. 2 grade-2 injection site reactions, 2 grade-2 and 1 grade-3 platelet count decrease were attributable to vaccine. Immune response was characterized by interferon gamma (IFN) secretion following ex-vivo exposure to autologous tumor lysate. A mean of 1.5-fold increase in the IFN+ CD4+ T cells and 1.85-fold in the IFN+ CD8+ T cells was observed following vaccination (pre-vaccine 1 compared to peak post-vaccination, n=19). Deep TCR repertoire sequencing of serial blood and bone marrow samples was performed from pre- and post-vaccination timepoints for four patients. These longitudinal data were used to identify T cell clonotypes that significantly increased following vaccination. Two major classes of treatment-expanded clonotypes were identified: pre-existing clonotypes that increased following vaccination and emergent clonotypes only detected following vaccination. Comparison of 3- and 6-month follow up blood samples demonstrated persistence of all emergent clones. Conclusion: In summary, DC/AML fusion vaccination in older patients in CR1 in the absence of maintenance therapy resulted in a 2-year PFS of 36% and OS of 73%. Immunologic response was characterized by emergence and persistence of specific T cell clonotypes. Ongoing studies include analyzing expanded T cell clones as a means for antigen discovery and evaluation of DC/AML vaccination following allogeneic transplant. Future directions include the potential to develop a novel combinatorial approach to maintenance therapy, by incorporating DC/AML fusion cell vaccination to HMA and targeted therapy based maintenance therapy for AML.
Source: Blood
Authors: Prateek Pophali, Giulia Cheloni, Richard M. Stone, Kai W Wucherpfennig, Aric C. Hall, Amir T. Fathi, Lina Bisharat, Emma K Logan, Yiwen Liu, Donna S. Neuberg, Malgorzata McMasters, Jessica Liegel, Jacqueline S. Garcia, Daniel J. DeAngelo, Michele Narcis, Dina Stroopinsky, Pavania Elavalakanar, Ioannis S Vlachos, Ilene A. Galinsky, Jason Pyrdol, Georges Chedid, Dimitra Karagkouni, Shivani Nanda, Kathrine S Rallis, Isabella Saldarriaga, Hazal Toros, Haitham Abdelhakim, Amelia Langston, Joseph P. McGuirk, Donald Kufe, David Avigan, Jacalyn Rosenblatt
Institutions: Beth Israel Deaconess Medical Center, Harvard University, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, University of Wisconsin–Madison, Massachusetts General Hospital, Mount Auburn Hospital, University of Kansas, The University of Kansas Cancer Center, Emory University, Winship Cancer Institute, University of Kansas Medical Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4405039306