Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice

Christopher A. Klebanoff, Luca Gattinoni, Douglas C. Palmer, Pawel Muranski, Yun Ji, Christian S. Hinrichs, Zachary A. Borman, Sid P. Kerkar, Christopher D. Scott, Steven E. Finkelstein, Steven A. Rosenberg, Nicholas P. Restifo

Research output: Contribution to journalArticle

Abstract

Purpose: Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γc) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified. Experimental Design: Tosystematically and quantitatively appraise each of these variables,weemployed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (TCM), effector memory (TEM), and stem cell memory (TSCM) subsets on the strength of tumor regression as well as the dose and type of clinically available γc cytokines, including IL-2, IL-7, IL-15, and IL-21. Results: We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γc cytokine only moderately correlated with response. Conclusion: Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γc cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo.

Original languageEnglish (US)
Pages (from-to)5343-5352
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number16
DOIs
StatePublished - Aug 15 2011
Externally publishedYes

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Adoptive Immunotherapy
T-Lymphocytes
Neoplasms
Cytokines
Adoptive Transfer
Interleukin-2
Viral Vaccines
Antigens
Interleukin-15
Interleukin-7
Experimental Melanomas
Aptitude
Cell- and Tissue-Based Therapy
Immunotherapy
Cell Differentiation
Research Design
Stem Cells
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Klebanoff, C. A., Gattinoni, L., Palmer, D. C., Muranski, P., Ji, Y., Hinrichs, C. S., ... Restifo, N. P. (2011). Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. Clinical Cancer Research, 17(16), 5343-5352. https://doi.org/10.1158/1078-0432.CCR-11-0503

Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. / Klebanoff, Christopher A.; Gattinoni, Luca; Palmer, Douglas C.; Muranski, Pawel; Ji, Yun; Hinrichs, Christian S.; Borman, Zachary A.; Kerkar, Sid P.; Scott, Christopher D.; Finkelstein, Steven E.; Rosenberg, Steven A.; Restifo, Nicholas P.

In: Clinical Cancer Research, Vol. 17, No. 16, 15.08.2011, p. 5343-5352.

Research output: Contribution to journalArticle

Klebanoff, CA, Gattinoni, L, Palmer, DC, Muranski, P, Ji, Y, Hinrichs, CS, Borman, ZA, Kerkar, SP, Scott, CD, Finkelstein, SE, Rosenberg, SA & Restifo, NP 2011, 'Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice', Clinical Cancer Research, vol. 17, no. 16, pp. 5343-5352. https://doi.org/10.1158/1078-0432.CCR-11-0503
Klebanoff, Christopher A. ; Gattinoni, Luca ; Palmer, Douglas C. ; Muranski, Pawel ; Ji, Yun ; Hinrichs, Christian S. ; Borman, Zachary A. ; Kerkar, Sid P. ; Scott, Christopher D. ; Finkelstein, Steven E. ; Rosenberg, Steven A. ; Restifo, Nicholas P. / Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 16. pp. 5343-5352.
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AU - Hinrichs, Christian S.

AU - Borman, Zachary A.

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