Exploiting T cell receptor genes for cancer immunotherapy

Abstract

Adoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for 'unconventional' antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8(+) and CD4(+) lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.

Fig. 1

Retroviral TCR gene transfer. Retroviral DNA constructs are transfected into packaging cells to produce viral particles. Peripheral blood lymphocytes are polyclonally activated, using anti-CD3 antibodies or beads coated with anti-CD3/CD28 antibodies. Two days after activation lymphocytes are exposed to viral particles, and 5 days after activation TCR expression can be demonstrated by FACS analysis. Antigen-stimulation (in vitro or in vivo) leads to the expansion of cells expressing the introduced TCR.

Fig. 2

Pairing of TCR chains in TCR-transduced lymphocytes. In principle, each TCR-transduced T cell can express four TCR specificities, two of which are novel specificities with a risk of displaying reactivity towards patient MHC molecules. As discussed in the text, experimental observations suggest that most transduced T cells do not express two novel specificities.

Fig. 3

The function of CD4⁺ helper T cells in tumour immunity. (a) Conventional CD4⁺ T cells recognize tumour antigens presented by MHC class II molecules on the surface of DCs. TCR engagement and signals derived from the interaction of co-stimulatory molecules such as B7·1, B7·2 and CD40 trigger the production of cytokines, including IL-2, which is required for proliferation. IFN-γ can have direct effects by inhibiting cells of the tumour stroma, or it can activate antitumour effector function of macrophages, NK cells and CTL. (b) CD4⁺ T cells expressing an MHC class I-restricted TCR can interact directly with tumour cells. In this case, the interaction is dominated by the TCR and is not assisted by co-stimulatory signals. It is currently not known if this will trigger full effector function and T cell expansion, or if TCR signal without co-stimulation may lead to lack of IL-2 production, the development of anergy or even the triggering of apoptosis.