Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go?
In a recent clinical trial involving patients with metastatic melanoma, immunosuppressive conditioning with fludarabine and cyclophosphamide resulted in a 50% response rate in robust long-term persistence of adoptively transferred T cells. Experimental findings indicate that lymphodepletion prior to adoptive transfer of tumor-specific T lymphocytes plays a key role in enhancing treatment efficacy by eliminating regulatory T cells and competing elements of the immune system ('cytokine sinks'). Newly emerging animal data suggest that more profound lymphoablative conditioning with autologous hematopoetic stem-cell rescue might further enhance treatment results. Here we review recent advances in adoptive immunotherapy of solid tumors and discuss the rationale for lymphodepleting conditioning. We also address safety issues associated with translating experimental animal results of total lymphoid ablation into clinical practice.
Muranski
Pawel
P
Clinical Research Center, National Institutes of Health, Room 3-5762, Bethesda, MD 20892, USA. muranskp@mail.nih.gov
Boni
Andrea
A
Wrzesinski
Claudia
C
Citrin
Deborah E
DE
Rosenberg
Steven A
SA
Childs
Richard
R
Restifo
Nicholas P
NP
D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*