Adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer.
Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated in vitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell transfer between congenic hosts demonstrated that anti-4-1BB administration increased the survival of adoptively transferred TDLN cells. Using STAT4(-/-) mice, we found that modulated IFN gamma secretion in wt TDLN cells after anti-CD3/CD28/4-1BB activation in vitro was lost in similarly stimulated STAT4(-/-) TDLN cells. Additionally, anti-4-1BB administration failed to augment the therapeutic efficacy of T cell therapy in STAT4(-/-) mice. Together, these results indicate that administered anti-4-1BB mAb can serve as an effective adjuvant to augment the antitumor reactivity of adoptively transferred T cells by recruiting the host NK cells; increasing the persistence of infused effector T cells, and modulating the STAT4 molecular signaling pathway.
Li
Qiao
Q
Division of Surgical Oncology, University of Michigan, Ann Arbor, MI 48109-5932, USA. qiaoli@umich.edu
Iuchi
Takekazu
T
Jure-Kunkel
Maria N
MN
Chang
Alfred E
AE
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9