title: Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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: Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USA.
authors: Christopher A
authors: CA
authors: Klebanoff
authors: Luca
authors: L
authors: Gattinoni
authors: Douglas C
authors: DC
authors: Palmer
authors: Pawel
authors: P
authors: Muranski
authors: Yun
authors: Y
authors: Ji
authors: Christian S
authors: CS
authors: Hinrichs
authors: Zachary A
authors: ZA
authors: Borman
authors: Sid P
authors: SP
authors: Kerkar
authors: Christopher D
authors: CD
authors: Scott
authors: Steven E
authors: SE
authors: Finkelstein
authors: Steven A
authors: SA
authors: Rosenberg
authors: Nicholas P
authors: NP
authors: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012044:Regression Analysis; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D000098546:Interleukin-21