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

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 (γ(c)) 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:

To systematically and quantitatively appraise each of these variables, we employed 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 (T(CM)), effector memory (T(EM)), and stem cell memory (T(SCM)) subsets on the strength of tumor regression as well as the dose and type of clinically available γ(c) 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 γ(c) 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 γ(c) cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 16 Pg. 5343-52 (Aug 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21737507 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2011 AACR.

Chemical References

• Cancer Vaccines
• Cytokines
• Interleukin-15
• Interleukin-2
• Interleukin-7
• Interleukins
• interleukin-21

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, transplantation)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Differentiation (immunology)
• Cell Line, Tumor
• Cytokines (immunology, therapeutic use)
• Dose-Response Relationship, Drug
• Immunologic Memory (immunology)
• Immunotherapy, Adoptive (methods)
• Interleukin-15 (immunology, pharmacology)
• Interleukin-2 (immunology, pharmacology)
• Interleukin-7 (immunology, pharmacology)
• Interleukins (immunology, pharmacology)
• Melanoma, Experimental (immunology, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Regression Analysis
• Treatment Outcome
• Tumor Burden (drug effects, immunology)