Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial
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Michael Schmitt1,*, Angela G. Hückelhoven1,*, Michael Hundemer1, Anita Schmitt1, Susanne Lipp1, Martina Emde1, Hans Salwender2, Mathias Hänel3, Katja Weisel4, Uta Bertsch1, Jan Dürig5, Anthony D. Ho1, Igor Wolfgang Blau6, Hartmut Goldschmidt1,7, Anja Seckinger1 and Dirk Hose1
1Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany
2Department of Internal Medicine II, Asklepios Klinik Altona, Hamburg, Germany
3Department of Internal Medicine III, Klinikum Chemnitz GmbH, Chemnitz, Germany
4Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany
5Department of Hematology, University Hospital Essen, Essen, Germany
6Medical Clinic III Hematology and Oncology, Charité University Medicine Berlin, Berlin, Germany
7Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany
*These authors contributed equally to this work
Dirk Hose, email: [email protected]
Keywords: tumor associated antigens, T cells, immunogenicity, multiple myeloma, RNA-sequencing
Received: May 20, 2016 Accepted: July 13, 2016 Published: August 11, 2016
Background: Raising T-cell response against antigens either expressed on normal and malignant plasma cells (e.g. HM1.24) or aberrantly on myeloma cells only (e.g. cancer testis antigens, CTA) by vaccination is a potential treatment approach for multiple myeloma.
Results: Expression by GEP is found for HM1.24 in all, HMMR in 318/458 (69.4%), MAGE-A3 in 209/458 (45.6%), NY-ESO-1/2 in 40/458 (8.7%), and WT-1 in 4/458 (0.8%) of samples with the pattern being confirmed by RNA-sequencing. T-cell-activation is found in 9/26 (34.6%) of patient samples, i.e. against HM1.24 (4/24), RHAMM-R3 (3/26), RHAMM1-8 (2/14), WT-1 (1/11), NY-ESO-1/2 (1/9), and MAGE-A3 (2/8). In 7/19 T-cell activation responses, myeloma cells lack respective antigen-expression. Expression of MAGE-A3, HMMR and NY-ESO-1/2 is associated with adverse survival.
Experimental design: We assessed expression of HM1.24 and the CTAs MAGE-A3, NY-ESO-1/2, WT-1 and HMMR in CD138-purified myeloma cell samples of previously untreated myeloma patients in the GMMG-MM5 multicenter-trial by gene expression profiling (GEP; n = 458) and RNA-sequencing (n = 152) as potential population regarding vaccination trials. We then validated the feasibility to generate T-cell responses (n = 72) against these antigens by IFN-γ EliSpot-assay (n = 26) related to antigen expression (n = 22). Lastly, we assessed survival impact of antigen expression in an independent cohort of 247 patients treated by high-dose therapy and autologous stem cell transplantation.
Conclusions: As T-cell responses can only be raised in a subfraction of patients despite antigen expression, and the number of responses increases with more antigens used, vaccination strategies should assess patients’ antigen expression and use a “cocktail” of peptide vaccines.
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