title: Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy.
abstract: To date, lung cancer is one of the leading causes of cancer mortality with short overall survival despite adequate therapy. New immunotherapeutic strategies using peptides derived from tumor-associated antigens (TAAs) can induce a specific cytotoxic T cell (CTL) response leading to a targeted tumor cell death. In the present study, we addressed whether there are further significant immunogenic candidate targets that may induce strong immune reactions with a high frequency in lung cancer patients eligible for cellular immunotherapeutic approaches, such as in a polyvalent vaccination approach. In this study, we investigated specific CTL responses of 14 HLA-A*0201-positive patients (of 33 screened patients) with non-small cell lung cancer (NSCLC; n=12) or small cell lung cancer (SCLC; n=2) against several known and novel TAA-derived peptides from lung cancer and/or other tumor entities, by measuring granzyme B (GrB) and/or interferon γ (IFNγ) secretion using enzyme-linked immunospot (ELISpot) analysis. Specific T cell responses could be detected for hTERT (4/13), two MAGE-A3-derived peptides (4/13 and 3/13, respectively), RHAMM (4/14), PRAME (8/14), G250 (7/12), survivin (3/13), HER2 (5/10) and WT1 (2/14), but also novel epitopes derived from Aurora kinase A (4/13) and B (5/13). Additionally, simultaneous CTL responses against the different peptides were examined and specific T cell responses against at least one of these TAAs could be detected in 13/14 (93%) patients. It could be shown that all patients with immune reactions against RHAMM and hTERT showed also immune responses against PRAME. Furthermore, patients with CTL responses against the Aurora kinase A peptide (Aura A1) also demonstrated a response against the Aurora kinase B peptide (Aura B1). Taken together, we showed that these TAA-derived peptides induce frequent specific T cell responses in patients with metastatic lung cancer and are, therefore, novel candidates for targeted immunotherapies and polyvalent approaches.
authors.affiliation: Department of Internal Medicine III, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Babiak
authors.forename: Max
authors.initials: M
authors.lastname: Steinhauser
authors.forename: Marlies
authors.initials: M
authors.lastname: Götz
authors.forename: Cornelia
authors.initials: C
authors.lastname: Herbst
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Jochen
authors.initials: J
authors.lastname: Greiner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D055752:Small Cell Lung Carcinoma / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D053804:Granzymes