Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells.
T-cell adoptive immunotherapy for stringent murine tumor models, such as intracranial, s.c., or advanced pulmonary metastases, routinely uses lymphodepletive conditioning regimens before T-cell transfer, like recent clinical protocols. In this study, we examined whether host lymphodepletion is an obligatory component of curative T-cell therapy; we also examined the mechanism by which it augments therapy. Mice bearing intracranial, s.c., or 10-day pulmonary metastases of MCA 205 received total body irradiation conditioning or were nonirradiated before i.v. transfer of tumor-reactive T cells. Total body irradiation was not required for immunologically specific curative therapy and induction of memory provided that a 3- to 12-fold higher T-cell dose was administered. The mechanism involved enhanced intratumoral proliferation of T-effector cells in total body irradiation-conditioned recipients. In this tumor model, intratumoral T(reg) cells were not detected; consequently, intratumoral T-effector cells produced identical amounts of IFN-gamma upon ex vivo antigen stimulation irrespective of total body irradiation conditioning. Thus, host lymphodepletion augments T-cell immunotherapy through enhanced antigen-driven proliferation of T-effector cells, but curative therapy can be achieved in nonconditioned hosts by escalation of T-cell dose. These data provide a rationale for dose escalation of T-effector cells in situations where single or repeated lymphodepletion regimens are contraindicated.
Wang
Li-Xin
LX
Center for Surgery Research, Division of Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Shu
Suyu
S
Plautz
Gregory E
GE
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D017252:CD3 Complex / Q000276:immunology; D003131:Combined Modality Therapy; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000556:secondary / Q000628:therapy; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects*; D014916:Whole-Body Irradiation
D017252:CD3 Complex; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D015851:Interleukin-7