Abstract LB-116: Strong MAGE-A3-specific humoral and cellular immune responses in multiple myeloma patients receiving MAGE-A3 protein immunotherapy and peripheral blood lymphocyte reconstitution

Abstract

Abstract MAGE-A3 is an immunogenic tumor-associated antigen expressed in multiple myeloma (MM) patients and conferring poor prognosis, making it a rational target for immunotherapy. Recombinant MAGE-A3 protein was administered in AS15 immunostimulant (containing MPL, QS-21, and CpG 7909) to 13 MM patients pre- and post-autologous stem cell transplant (ASCT) coupled with infusion of vaccine-primed autologous peripheral blood lymphocytes (PBL) early post-ASCT (NCT01380145). All patients had MAGE-A+ myeloma cells at baseline and had an acceptable safety profile during immunotherapy. Robust antibody responses against MAGE-A3 (assessed by ELISA) were induced in all 13 subjects, with high antibody titers (1:10^4-10^6) that persisted to at least 1-year post-ASCT. Subclass analysis demonstrated a prevalence of IgG1 and IgG3. Epitope mapping identified 7 distinct epitopes clustering in hydrophilic regions of MAGE-A3. Peripheral blood T cell responses were evaluated in 8 subjects by IFNγ-ELISpot after in vitro re-stimulation with MAGE-A3 overlapping peptide pools. All patients quickly developed strong MAGE-A3-specific CD4 responses post-vaccination and ASCT, persisting 1-year post-ASCT. Intracellular cytokine staining confirmed polyfunctional, Th1-biased CD4 T cell responses. One patient developed CD8 responses against MAGE-A3 that recognized naturally processed antigen. To date, 6 patients relapsed and 1 died of progressive MM, with no notable difference in cytogenetics or antibody titers compared to non-progressors. MAGE-A expression was assessed by immunohistochemistry in relapse bone marrow biopsies, and interestingly, 4/6 were negative. MAGE-A3 protein-based immunotherapy and PBL reconstitution is generally well tolerated, feasible, and induces antibody and Th1-biased CD4 T cell responses, but only rare CD8 responses, in the setting of ASCT for MM. Cellular immune assessments are ongoing. The magnitudes of antibody and CD4 responses appear greater than those seen historically with older immunostimulant formulations of MAGE-A3 in other cancers, despite significant immune compromise after ASCT, suggesting a benefit from the new AS15 immunostimulant formulation, or from immunization and autologous PBL transfer in the peri-ASCT setting, or both. The frequent loss of MAGE-A3 expression in relapsing patients implies antigen-specific immune selective pressure, and suggests that combination strategies aimed at limiting immune escape should be investigated. Funding Sources: GlaxoSmithKline Biologicals SA, Ludwig Institute for Cancer Research, Cancer Research Institute. Citation Format: Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Rafik Fellague-Chebra, Olivier Gruselle, Adam Cohen, Nikoletta Lendvai, Hearn J. Cho. Strong MAGE-A3-specific humoral and cellular immune responses in multiple myeloma patients receiving MAGE-A3 protein immunotherapy and peripheral blood lymphocyte reconstitution. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-116. doi:10.1158/1538-7445.AM2015-LB-116