Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells

Claudia Wrzesinski, Chrystal M. Paulos, Andrew Kaiser, Pawel Muranski, Douglas C. Palmer, Luca Gattinoni, Zhiya Yu, Steven A. Rosenberg, Nicholas P. Restifo

Research output: Contribution to journalArticle

Abstract

Lymphodepletion before adoptive cell transfer (ACT)-based immunotherapies can enhance anti-tumor responses by augmenting innate immunity, by increasing access to homeostatic cytokines, and by depressing the numbers of regulatory T cells and myeloid-derived suppressor cells. Although it is clear that high-dose total body irradiation given together with hematopoietic stem cell (HSC) transplantation effectively enhances ACT, the relationship between the intensity of lymphodepletion and tumor treatment efficacy has not been systematically studied. Using the pmel-1 mouse model of self/tumor-reactive CD8 T cells, we observed a strong correlation between the intensity of the conditioning regimen and the efficacy of ACT-based treatments using linear regression analysis. This was the case for preparative total body irradiation administered either as a single dose (R=0.97, P+ cells (potentially T regulatory cells); Gr1 cells (which are capable of functioning as myeloid-derived suppressor cells); and endogenous CD8 and natural killer 1.1 cells (that can act as "sinks" for homeostatic cytokines in the postablative setting). With increasing ablation, we also observed elevated lipopolysaccharide levels in the sera and heightened levels of systemic inflammatory cytokines. Thus, increased intensity lymphodepletion triggers enhanced tumor treatment efficacy and the benefits of high-dose total body irradiation must be titrated against its risks.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalJournal of Immunotherapy
Volume33
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

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Adoptive Transfer
Whole-Body Irradiation
T-Lymphocytes
Regulatory T-Lymphocytes
Cytokines
Neoplasms
Hematopoietic Stem Cell Transplantation
Innate Immunity
Natural Killer Cells
Immunotherapy
Lipopolysaccharides
Linear Models
Regression Analysis
Serum
Myeloid-Derived Suppressor Cells
Therapeutics

Keywords

  • Adoptive immunotherapy
  • Total body irradiation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Wrzesinski, C., Paulos, C. M., Kaiser, A., Muranski, P., Palmer, D. C., Gattinoni, L., ... Restifo, N. P. (2010). Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. Journal of Immunotherapy, 33(1), 1-7. https://doi.org/10.1097/CJI.0b013e3181b88ffc

Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. / Wrzesinski, Claudia; Paulos, Chrystal M.; Kaiser, Andrew; Muranski, Pawel; Palmer, Douglas C.; Gattinoni, Luca; Yu, Zhiya; Rosenberg, Steven A.; Restifo, Nicholas P.

In: Journal of Immunotherapy, Vol. 33, No. 1, 01.2010, p. 1-7.

Research output: Contribution to journalArticle

Wrzesinski, C, Paulos, CM, Kaiser, A, Muranski, P, Palmer, DC, Gattinoni, L, Yu, Z, Rosenberg, SA & Restifo, NP 2010, 'Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells', Journal of Immunotherapy, vol. 33, no. 1, pp. 1-7. https://doi.org/10.1097/CJI.0b013e3181b88ffc
Wrzesinski, Claudia ; Paulos, Chrystal M. ; Kaiser, Andrew ; Muranski, Pawel ; Palmer, Douglas C. ; Gattinoni, Luca ; Yu, Zhiya ; Rosenberg, Steven A. ; Restifo, Nicholas P. / Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. In: Journal of Immunotherapy. 2010 ; Vol. 33, No. 1. pp. 1-7.
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