Adoptive immunotherapy with tumor-specific T lymphocytes generated from cytokine gene-modified tumor-primed lymph node cells.
Adoptive immunotherapy with immune T cells mediates regression of established tumors in animal models. We previously demonstrated that precursor lymphocytes of sensitized T cells can develop into mature effector cells after in vitro activation with anti-CD3 mAb and IL-2. We demonstrate here that tumor cells genetically modified to secrete IL-2 can enhance the precursor response in the tumor-bearing host and subsequently augment the antitumor efficacy of adoptive immunotherapy. MCA205 and MCA203, weakly immunogenic fibrosarcomas, were transfected in vitro with cDNA encoding for IL-2, IL-4, or IL-6. Lymph nodes (LN) draining these cytokine-producing tumors for 7 days were harvested, activated in vitro with anti-CD3/IL-2, and adoptively transferred into mice bearing established parental MCA205 pulmonary metastases. The effector cells generated from LN draining the IL-2 producing tumor exhibited enhanced antitumor activity compared with cells from LN draining parental, IL-4-producing, or IL-6-producing tumor. Phenotype analysis of cells from LN draining the IL-2-producing tumor revealed selective expansion of V beta 8+ cells. Depletion of V beta 8+ effector cells abrogated the antitumor efficacy indicating that V beta 8+ cells constituted the majority of antitumor reactivity and that secretion of IL-2 from tumor cells promoted the priming of V beta 8+ precursor cells, which can develop into mature effector cells. These results have important clinical implications that the method presented here could be applicable to the treatment of human cancer as more effective immunotherapy.
Ohno
K
K
Department of Medicine (II), Niigata University Medical School, Japan.
Yoshizawa
H
H
Tsukada
H
H
Takeda
T
T
Yamaguchi
Y
Y
Ichikawa
K
K
Maruyama
Y
Y
Suzuki
Y
Y
Suzuki
E
E
Arakawa
M
M
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D005434:Flow Cytometry; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*
D017252:CD3 Complex; D016207:Cytokines; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell