title: Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells.
abstract: OBJECTIVE
  Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.
  
  
  METHODS
  In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant.
  
  
  RESULTS
  T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%).
  
  
  CONCLUSIONS
  A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
authors: Authors' Affiliations: University of Maryland Marlene and Stewart Greenebaum Cancer Center; Center for Vaccine Development and Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Oncovir Inc., Washington, District of Columbia; Department of Pathology, University of Pennsylvania; and Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Aaron P
authors: AP
authors: Rapoport
authors: Nicole A
authors: NA
authors: Aqui
authors: Edward A
authors: EA
authors: Stadtmauer
authors: Dan T
authors: DT
authors: Vogl
authors: Yin Yan
authors: YY
authors: Xu
authors: Michael
authors: M
authors: Kalos
authors: Ling
authors: L
authors: Cai
authors: Hong-Bin
authors: HB
authors: Fang
authors: Brendan M
authors: BM
authors: Weiss
authors: Ashraf
authors: A
authors: Badros
authors: Saul
authors: S
authors: Yanovich
authors: Gorgun
authors: G
authors: Akpek
authors: Patricia
authors: P
authors: Tsao
authors: Alan
authors: A
authors: Cross
authors: Dean
authors: D
authors: Mann
authors: Sunita
authors: S
authors: Philip
authors: Naseem
authors: N
authors: Kerr
authors: Andrea
authors: A
authors: Brennan
authors: Zhaohui
authors: Z
authors: Zheng
authors: Kathleen
authors: K
authors: Ruehle
authors: Todd
authors: T
authors: Milliron
authors: Scott E
authors: SE
authors: Strome
authors: Andres M
authors: AM
authors: Salazar
authors: Bruce L
authors: BL
authors: Levine
authors: Carl H
authors: CH
authors: June
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C