The broad applicability of adoptive immunotherapy in cancer: optimization through host conditioning and target selection

Open Access
Author:
Ward-kavanagh, Lindsay Kate
Graduate Program:
Cell and Molecular Biology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
May 19, 2015
Committee Members:
  • Todd Schell, Dissertation Advisor/Co-Advisor
  • Todd Schell, Committee Chair/Co-Chair
  • Kristin Ann Eckert, Committee Member
  • Christopher Charles Norbury, Committee Member
  • Clare E Sample, Committee Member
  • Jianxun Song, Committee Member
Keywords:
  • Immunotherapy
  • Cancer
  • Adoptive Cell Therapy
  • Radiation
  • Anti-CD40
  • Conditioning
  • SV40 T Antigen
  • CD8+ T cell
Abstract:
Adoptive cell therapy (ACT) holds the potential to cure advanced cancer through selective elimination of tumor cells with cytotoxic T lymphocytes, yet this approach has shown strong clinical efficacy in only a few cancer types. Improving adoptive immunotherapy for solid tumors requires a clearer understanding of the immunosuppressive tumor microenvironment (TME) and the characteristics of effective tumor targets. To assess the efficacy of applying ACT and whole body irradiation (WBI) conditioning to solid tumors of distinct tissue origin, we treated mice bearing established SV40 T antigen-induced, autochthonous prostate or pancreatic neuroendocrine tumors with the same protocol. The results demonstrate that WBI-enhanced ACT targeting the immunodominant Site IV epitope of T antigen was insufficient to regress tumors in either model. However, we discovered that treatment of established prostate tumors with a second round of WBI-enhanced ACT regressed established prostate tumors through an IFNγ-independent mechanism, indicating that the first round of immunotherapy substantially changed the TME to promote an anti-tumor response. In contrast, treatment of pancreatic tumors with T cells targeting Site IV could not be optimized to drive development of an effector T cell population or eliminate disease. Instead, tumor regression required targeting the subdominant Site I epitope, and application of both WBI and an agonist anti-CD40 antibody to overcome the suppressive TME. Tumor regression was associated with infiltration of the pancreas by PD-1lo donor T cells capable of producing IFNγ, indicating that the TME’s suppressive networks were sufficiently disrupted to prevent exhaustion of donor T cells. Incomplete differentiation of Site IV-specific T cells in mice bearing pancreatic tumors may be explained by decreased availability of Site IV in vivo, since priming of Site IV-specific T cells in vivo required higher amounts of T antigen-expressing cells than did priming of site I-specific T cells. Analysis of peptide-MHC binding demonstrated that the Site I peptide exhibited greater relative affinity for MHC than Site IV peptide. Thus, effective adoptive immunotherapy of solid tumors of distinct tissue origins requires optimization of host conditioning, and selection of a target antigen that allows sufficient effector T cell differentiation in vivo.