title: Superior antitumor in vitro responses of allogeneic matched sibling compared with autologous patient CD8+ T cells.
abstract: Allogeneic cell therapy as a means to break immunotolerance to solid tumors is increasingly used for cancer treatment. To investigate cellular alloimmune responses in a human tumor model, primary cultures were established from renal cell carcinoma (RCC) tissues of 56 patients. In three patients with stable RCC line and human leukocyte antigen (HLA)-identical sibling donor available, allogeneic and autologous RCC reactivities were compared using mixed lymphocyte/tumor cell cultures (MLTC). Responding lymphocytes were exclusively CD8(+) T cells, whereas CD4(+) T cells or natural killer cells were never observed. Sibling MLTC populations showed higher proliferative and cytolytic antitumor responses compared with their autologous counterparts. The allo-MLTC responders originated from the CD8(+) CD62L(high)(+) peripheral blood subpopulation containing naive precursor and central memory T cells. Limiting dilution cloning failed to establish CTL clones from autologous MLTCs or tumor-infiltrating lymphocytes. In contrast, a broad panel of RCC-reactive CTL clones was expanded from each allogeneic MLTC. These sibling CTL clones either recognized exclusively the original RCC tumor line or cross-reacted with nonmalignant kidney cells of patient origin. A minority of CTL clones also recognized patient-derived hematopoietic cells or other allogeneic tumor targets. The MHC-restricting alleles for RCC-reactive sibling CTL clones included HLA-A2, HLA-A3, HLA-A11, HLA-A24, and HLA-B7. In one sibling donor-RCC pair, strongly proliferative CD3(+)CD16(+)CD57(+) CTL clones with non-HLA-restricted antitumor reactivity were established. Our results show superior tumor-reactive CD8 responses of matched allogeneic compared with autologous T cells. These data encourage the generation of antitumor T-cell products from HLA-identical siblings and their potential use in adoptive immunotherapy of metastatic RCC patients.
authors.affiliation: Department of Medicine III, Hematology and Oncology, University of Mainz, Mainz, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kausche
authors.forename: Thomas
authors.initials: T
authors.lastname: Wehler
authors.forename: Elke
authors.initials: E
authors.lastname: Schnürer
authors.forename: Volker
authors.initials: V
authors.lastname: Lennerz
authors.forename: Walburgis
authors.initials: W
authors.lastname: Brenner
authors.forename: Sebastian
authors.initials: S
authors.lastname: Melchior
authors.forename: Mark
authors.initials: M
authors.lastname: Gröne
authors.forename: Marion
authors.initials: M
authors.lastname: Nonn
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.forename: Ralf
authors.initials: R
authors.lastname: Meyer
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D035781:Siblings; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016827:CD8 Antigens; D006680:HLA Antigens; D019041:L-Selectin