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

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Aaron P Rapoport, Nicole A Aqui, Edward A Stadtmauer, Dan T Vogl, Yin Yan Xu, Michael Kalos, Ling Cai, Hong-Bin Fang, Brendan M Weiss, Ashraf Badros, Saul Yanovich, Gorgun Akpek, Patricia Tsao, Alan Cross, Dean Mann, Sunita Philip, Naseem Kerr, Andrea Brennan, Zhaohui Zheng, Kathleen Ruehle, Todd Milliron, Scott E Strome, Andres M Salazar, Bruce L Levine, Carl H June
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 5 Pg. 1355-65 (Mar 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24520093 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• MAGEA3 protein, human
• Neoplasm Proteins
• Polylysine
• poly ICLC
• Carboxymethylcellulose Sodium
• Poly I-C

Topics

• Adult
• Aged
• Antigens, Neoplasm (immunology)
• Cancer Vaccines (immunology)
• Carboxymethylcellulose Sodium (analogs & derivatives)
• Female
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunization
• Immunotherapy, Adoptive (adverse effects)
• Male
• Middle Aged
• Multiple Myeloma (diagnosis, immunology, mortality, therapy)
• Neoplasm Proteins (immunology)
• Poly I-C (immunology)
• Polylysine (analogs & derivatives, immunology)
• T-Lymphocytes (immunology)
• Transplantation, Autologous
• Treatment Outcome