Date Published: January 26, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Emma Nicholson, Sara Ghorashian, Hans Stauss.
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.
Allogeneic haematopoietic stem cell transplantation (HSCT) is an effective treatment for many haematological malignancies. In addition, unselected donor lymphocyte infusions (DLIs) can be utilized to successfully treat relapsed leukaemia after HSCT . Depending on the degree of HLA mismatch, donor T cells recognize alloantigens derived from allogeneic MHC or from polymorphic minor histocompatibility antigens (mHags) expressed by the host. Whilst able to deliver beneficial Graft versus Tumour effects (GvT), alloreactive T cells may also direct their response against normal tissues resulting in Graft versus Host Disease (GvHD), and this is one of the leading causes of transplant-related morbidity and mortality. The incidence of GvHD can be reduced by utilizing T-cell-depleted transplants-but this also leads to an increase in disease relapse rate [2–4]. How best to deliver effective GvT responses whilst minimizing harmful GvHD remains a significant challenge.
Improving the therapeutic GvT effect may be achieved by an increase in the functional avidity of the transduced T cell for its specific tumour antigen. Increasing T cell avidity has been correlated with improved elimination of tumour cells in vivo . Avidity of the TCR is a function of the level of expression of the TCR on the T-cell surface and the individual affinity of the TCR for its cognate peptide-MHC (pMHC). High-avidity CTLs specific for TAA may be absent from the peripheral T cell repertoire as a result of deletion during thymic selection or tolerance induction following encounter of TAA in the periphery.
The ability of transduced T cells to persist long-term, mount robust memory responses and migrate to the site of response following adoptive transfer is key to successful antitumour responses. Persistence of transferred tumour reactive T cells has been shown to correlate with an effective therapeutic effect in adoptive immunotherapy utilizing TIL for treatment of metastatic melanoma . From the earliest trials of adoptive cellular therapy, it has been demonstrated that “younger” TIL- that is, those subjected to fewer rounds of stimulation delivered better antitumour responses. In mouse models, tumour-specific CD8+ T cells that had undergone a number of in vitro stimulations and acquired effector functions were less effective at mediating tumour regression after adoptive transfer [42, 43]. Cells that had a prolonged period in culture acquired a T effector cell phenotype with decreased expression of cell surface markers associated with trafficking to secondary lymphoid organs, for example, CCR7 and CD62L and also downregulation of costimulatory receptors such as CD27 and CD28 . Shorter telomeres were also associated with a reduction in clinical response and reduced in vivo persistence . It is becoming increasingly apparent that the transfer of end stage effector CD8 T cells may not be desirable for adoptive immunotherapy but that transfer of naive or memory cell subsets may be more effective.
Most adoptive immunotherapy protocols have focused on the transfer of CD8+ tumour-specific T cells. However, in the absence of CD4 help, CD8+ T cells have impaired function, persistence, and cannot mount effective memory responses [66–68]. The generation of both TCR-transduced CD8+ and CD4+ T helper cells may have a beneficial effect on sustained tumour control (Figure 1).
In order to develop effective adoptive immunotherapy protocols, it is important that the correct TAA or epitope is targeted. The use of high throughput screening of cancer genomes can identify large numbers of novel TAA, and it is important that research is focused, leading to more effective translation of TCR gene therapy and vaccine strategies into clinical practice. An ideal tumour antigen would be one that is widely expressed in different tumour types and not unique to individual patients. Targeting tumour antigens that are essential to the oncogenic process or cancer cell survival may induce sustained tumour regression. Specifically targeting a single epitope, however, may lead to the selection of tumour variants that lack the target antigen as a result of antigen loss or aberrant presentation via MHC loss [81–83]. Selecting a target that does not lead to autoimmune damage will also be of paramount importance. This has been recently demonstrated in a study where lymphocytes transduced with a high-avidity TCR specific for carcinoembryonic antigen (CEA) were administered to 3 patients with metastatic colorectal cancer. All patients in the study developed severe inflammatory colitis as a result of the TCR gene-modified T cells recognizing CEA expressed within normal colonic epithelium .
In addition to reducing the efficacy of TCR transduced T cells, mispairing is also a concern with regards to safety of TCR-transferred T cells for clinical use. Bendle et al. have demonstrated that TCR-transduced T cells can induce GVHD following adoptive transfer. This is not a result of the on-target toxicity of the introduced TCR but is a result of the formation of new heterodimers that have off-target toxicity directed against normal tissues . This stresses the importance of utilizing mechanisms to prevent mispairing of the introduced alpha and beta chains.
TCR gene transfer to produce antigen-specific T cells represents a targeted approach to treatment of haematological malignancies which may generate more specific GvT responses whilst reducing harmful GvHD responses. In addition to using TCR-transduced T cells to enhance GvT, we can also generate antigen-specific T regs to directly suppress harmful GVHD responses. Experience from clinical trials of melanoma antigen-specific TCR-transduced T cells has highlighted areas where this technique can be further refined and improved. Improvements in vector design, generation of high-avidity TCR, and reduction of TCR mispairing has all led to improvements in preclinical models. The importance of phenotype and subtype of the transferred population and the host environment into which they are transferred is becoming increasingly evident. Clinical trials utilizing WT1 TCR-transduced lymphocytes for treatment of haematological malignancies are due to commence in the near future hopefully leading to progress translating this technique into wider clinical use.