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Superior Antitumor In vitro Responses of Allogeneic Matched Sibling Compared with Autologous Patient CD8⁺ T Cells

¹ Department of Medicine III, Hematology and Oncology, ² Department of Urology, and ³ Department of Medicine I, University of Mainz, Mainz, Germany; ⁴ Department of Nephrology, University of Bari, Bari, Italy; and ⁵ Institute of Molecular Immunology, GSF National Research Center for Environment and Health, Munich, Germany

Requests for reprints: Wolfgang Herr, Department of Medicine III, Hematology and Oncology, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. Phone: 49-6131-17-2710; Fax: 49-6131-17-6678; E-mail: w.herr{at}3-med.klinik.uni-mainz.de.

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. (Cancer Res 2006; 66(23): 11447-54)