Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Translational Research, Clinical Research, Diseases, Immunology, Biological Processes, Myeloid Malignancies
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.
Disclosures: Stone: Epizyme Inc: Consultancy, Other: consulting fees; DAVA Oncology: Consultancy, Other: consulting fees; Actinium Pharmaceuticals, Inc.,: Consultancy, Other: consulting fees; AbbVie: Consultancy, Other: consulting fees; Celularity: Consultancy, Other: consulting fees; CTI BioPharma: Consultancy, Other: consulting fees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Syntrix Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Amgen: Consultancy, Other: consulting fees; Aptevo Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; AROG Pharmaceuticals: Consultancy, Other: consulting fees; AvenCell: Consultancy, Other: consulting fees; BerGenBio: Consultancy, Other: consulting fees; Bristol Myers Squibb: Consultancy, Other: consulting fees; Boston Scientific: Consultancy, Other: consulting fees; Janssen: Consultancy, Other: consulting fees; GSK: Consultancy, Other: consulting fees; Syros Pharmaceuticals: Consultancy, Other: consulting fees; Ligand Pharmaceuticals: Consultancy, Other: consulting fees; Novartis: Consultancy, Other: consulting fees; Rigel Therapeutics, Inc.: Consultancy, Other: consulting fees; Hemavant Sciences: Consultancy, Other: consulting fees; LAVA Therapeutics: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Kura Oncology: Consultancy, Other: consulting fees. Wucherpfennig: Fate Therapeutics: Research Funding; Novartis: Research Funding; Immunitas Therapeutics: Other: Co-founder; Nextechinvest: Membership on an entity's Board of Directors or advisory committees; D2M Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Solu Therapeutics: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma: Membership on an entity's Board of Directors or advisory committees; TScan therapeutics: Current equity holder in publicly-traded company. Fathi: Abbvie: Consultancy, Research Funding; Astellas: Consultancy; Agios: Ended employment in the past 24 months; Pfizer: Consultancy; Rigel: Consultancy; Remix: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Autolus: Consultancy; ImmunoGen: Consultancy; Mablytics: Consultancy; Genentech: Honoraria; Ispen: Consultancy; Novartis: Consultancy; Kite: Consultancy; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; Ipsen: Consultancy; EnClear: Consultancy; BMS/Celgene: Consultancy; PureTech: Consultancy; Takeda: Consultancy; Forma: Consultancy; Servier: Consultancy, Research Funding; MorphoSys: Consultancy; AstraZeneca: Honoraria; Gilead: Consultancy; Menarini Group: Consultancy; Orum: Consultancy. Neuberg: Madrigal Pharmaceutical: Current equity holder in publicly-traded company. Liegel: Beth Israel Deaconess Medical Center: Current Employment; Seagen: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Garcia: Newave: Research Funding; Servier: Consultancy; Taiho: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding. DeAngelo: Incyte: Consultancy; Jazz: Consultancy; Kite: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Meyers Squibb: Honoraria; Abvie: Research Funding; Glycomimetics: Research Funding; Daiichi-Sankyo: Other: DSMB; Fibrogen: Other: DSMB; MT Sinai MPN Consortium: Other: DSMB; Gilead: Consultancy; Curis: Consultancy; Blueprint: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy, Honoraria. Stroopinsky: Takeda: Current Employment. Vlachos: Harvard Stem Cell Institute: Research Funding; NIDDK: Research Funding; Guidepoint Global: Consultancy; NCI: Research Funding; NHLBI: Research Funding; Mosaic: Consultancy. Abdelhakim: Iovance Biotherapeutics: Research Funding. McGuirk: Legend biotech: Consultancy; Sana technologies: Consultancy; Caribou bio: Consultancy; BMS: Consultancy; CRISPR therapeutics: Consultancy; NEKTAR therapeutics: Consultancy; Autolus: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Novartis: Consultancy; Kite: Consultancy. Avigan: Kite, a Gilead Company: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Other: Advisory Role, Research Funding; Kowa Pharmaceutical: Consultancy, Other: Advisory Board; Takeda: Consultancy, Other: Advisory Role; Chugai Pharma: Consultancy, Other: Advisory Role; Paraxel: Current Employment; Sanofi: Consultancy, Other: Advisory Board; Kite/Gilead: Consultancy, Other: Advisory Role, Research Funding; Janssen: Consultancy, Other: Advisory Board; Bristol Myers Squibb: Consultancy, Other: Advisory Board; Karyopharm Therapeutics: Consultancy, Other: Advisory Role; Partners Therapeutics: Consultancy, Other: Advisory Board; Aviv Med Tech: Consultancy, Other: Advisory Board; Legend Biotech: Consultancy, Other: Advisory Role; Juno Therapeutics: Consultancy, Other: Advisory Role. Rosenblatt: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopham therapeutics: Other: DSMB; Parexel/Calyx: Consultancy, Other: blinded adjudicator for clinical trial data; Clario (BioClinica): Consultancy, Other: blinded adjudicator for clinical trial data; Sanofi: Research Funding; Bristol myers squibb: Research Funding; Attivare therapeutics: Consultancy; KITE: Membership on an entity's Board of Directors or advisory committees; USPTO: Patents & Royalties: US patent no. 11, 026,921, .