Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial.

Autor:	Schmitt M; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Hückelhoven AG; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Hundemer M; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Schmitt A; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Lipp S; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Emde M; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Salwender H; Department of Internal Medicine II, Asklepios Klinik Altona, Hamburg, Germany., Hänel M; Department of Internal Medicine III, Klinikum Chemnitz GmbH, Chemnitz, Germany., Weisel K; Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany., Bertsch U; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Dürig J; Department of Hematology, University Hospital Essen, Essen, Germany., Ho AD; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Blau IW; Medical Clinic III Hematology and Oncology, Charité University Medicine Berlin, Berlin, Germany., Goldschmidt H; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany.; Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany., Seckinger A; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Hose D; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Aug 11; Vol. 8 (49), pp. 84847-84862. Date of Electronic Publication: 2016 Aug 11 (Print Publication: 2017).
DOI:	10.18632/oncotarget.11215
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST The authors have no financial conflicts of interest.
Databáze:	MEDLINE
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