E Nicholson

CD8 T Cell Tolerance to a Tumor-Associated Self-Antigen Is Reversed by CD4 T Cells Engineered To Express the Same T Cell Receptor

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR–engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8+ T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR–engineered CD4+ T cells provided help and restored cytotoxic function of CD8+ T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4+ T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I–restricted TCR responsible for Ag recognition and tolerance induction in CD8+ T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I–restricted CD4+ T cells may enhance the efficacy of therapeutic TCR-engineered CD8+ T cells and can be readily generated with the same TCR.

Improving TCR Gene Therapy for Treatment of Haematological Malignancies

Adoptive immunotherapy using TCR gene modified T cells may allow separation of beneficial Graft versus tumour responses from harmful GvHD. Improvements to this include methods to generate high avidity or high affinity TCR, improvements in vector design and reduction in mispairing. Following adoptive transfer, TCR transduced T cells must be able to survive and persist in vivo to give most effective antitumour responses. Central memory or naive T cells have both been shown to be more effective than effector cells at expanding and persisting in vivo. Lymphodepletion may enhance persistence of transferred T cell populations. TCR gene transfer can be used to redirect CD4 helper T cells, and these could be used in combination with CD8+ tumour specific T cells to provide help for the antitumour response. Antigen specific T regulatory T cells can also be generated by TCR gene transfer and could be used to suppress unwanted alloresponses.

Cytomegalovirus-specific T-cell therapies: current status and future prospects.

Adoptive transfer of T cells specific for viral pathogens offers an attractive method for hastening immune reconstitution and protective immunity in patients following stem cell transplantation. The largest experience to date has been in the context of treatment or prevention of cytomegalovirus or Epstein-Barr virus. A number of technical hurdles have now been overcome allowing consideration of more widespread application of products compliant with Good Manufacturing Practice regulations, and of the development of commercialization pathways for these products. This review summarizes progress to date and highlights some of the areas that remain problematic and that require further innovation and evaluation before more widespread adoption is considered.

T cell gene-engineering to enhance GVT and suppress GVHD

Gene-engineering of T cells offers the possibility of uniformly changing the characteristics of their immune responses. The ability to direct polyclonal T cells to a single antigenic specificity is a powerful tool with which to probe anti-tumour immune responses, and in turn ask which tumour antigens represent the best targets for immune therapy. The intracellular components of TCR signalling pathways can also be manipulated to optimise anti-tumour responses. Such manipulated T cells may in the future represent an important adjunctive therapy alongside allogeneic haematopoietic stem cell transplantation (ASCT), in order to specifically boost a graft versus leukaemia (GVL) effect. In addition, the ability to confer a suppressive phenotype to CD4 cells or to engineer a susceptibility gene into effector cells provides new therapeutic avenues for graft versus host disease (GVHD), the most challenging adverse effect arising post ASCT. Within this review, mechanisms of GVL and GVHD are discussed and we consider how they may be separated through T cell gene engineering. In addition, we highlight recently investigated safety issues which will impact the future clinical application of gene-manipulated immune cells.