Adoptive immunotherapy of advanced tumors with CD62 L-selectin(low) tumor-sensitized T lymphocytes following ex vivo hyperexpansion.
Tumor-draining lymph nodes (TDLN) contain sensitized T cells with the phenotype CD62 L-selectin(low) (CD62L(low)) that can be activated ex vivo with anti-CD3 mAb and IL-2 to acquire potent dose-dependent effector function manifested upon adoptive transfer to secondary tumor-bearing hosts. In this study advanced tumor models were used as a stringent comparison of efficacy for the CD62L(low) subset, comprising 5-7% of the TDLN cells, vs the total population of TDLN cells following culture in high dose IL-2 (100 U/ml). During the 9-day activation period the total number of CD8+ T cells increased 1500-fold, with equivalent proliferation in the CD62L(low) vs the total TDLN cell cultures. Adoptive transfer of activated CD62L(low) cells eliminated 14-day pulmonary metastases and cured 10-day s.c. tumors, whereas transfer of maximally tolerated numbers of total TDLN cells was not therapeutic. Despite their propagation in a high concentration of IL-2, the hyperexpanded CD62L(low) subset of TDLN cells functioned in vivo without exogenous IL-2, and CD8+ T cells demonstrated relative helper independence. Moreover, the anti-tumor response was specific for the sensitizing tumor, and long term memory was established. The facile enrichment of tumor-reactive TDLN T cells, based on the CD62L(low) phenotype, circumvents the need for prior knowledge of the relevant tumor Ags. Coupling the isolation of pre-effector T cells with rapid ex vivo expansion to >3 logs could overcome some of the shortcomings of active immunotherapy or in vivo cytokine treatment, where selective robust expansion of effector cells has been difficult to achieve.
Wang
Li-Xin
LX
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510, USA.
Chen
Bing-Guan
BG
Plautz
Gregory E
GE
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002455:Cell Division / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006649:Histocompatibility Antigens / Q000276:immunology; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019041:L-Selectin / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D012074:Remission Induction; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D006649:Histocompatibility Antigens; C029237:tumor-associated transplantation antigen; D019041:L-Selectin