Adoptive Antigen-Specific Immunotherapy Manuscript Review:

Adoptive Antigen-Specific Immunotherapy

Manuscript review: Xue, S., Gillmore, R., Downs, a., Tsallios, a., Holler, a., Gao, L., et al. (2005). Exploiting T cell receptor genes for cancer immunotherapy. Clin Exp Immunol, 139(2), 167-172.

Article Summary (Xue et al., 2005)

Adoptive antigen-specific immunotherapy is a potential cancer therapy because immunocompetence is not required and lymphocyte specificity can be targeted against tumour-associated antigens. T cell receptor (TCR) genes isolated from antigen-specific T cells may be therapeutically used for antigen-specific immunotherapy. TCR gene therapy may provide an appealing strategy to develop antigen-specific immunotherapy. Examples of this type of therapy include retroviral TCR gene transfer, TCR gene modified lymphocytes, and TCR gene expression.

Article Purpose

The purpose of this article was to review various cancer treatment options with T cell receptor immunotherapy. Monoclonal TCRs may be used as generic reagents on the surface of CTL and T. helper cells. They may initiate a variety of functions including cytotoxicity and cytokine production. Modified TCR chains may provoke immune responses and trigger rejection of injected lymphocytes. There is no requirement for histocompatibility between donor T cells and patients, and cloned TCR genes become generic molecules for therapy of all patients with a malignancy that expresses the TCR-recognized antigen and HLA allele required for antigen presentation.

Article Results

Vaccination is an effective form of immune prevention with major health benefits for human populations worldwide. Effective vaccines are immunogenic, stimulate potent antibody responses, and are administered prior to exposure to the disease-causing pathogen. However, the therapeutic benefit of vaccines is inconclusive when administered for chronic infections. Immune responses are dampened by weak immunogenicity of tumour-associated antigens, which may fail to yield strong immune responses when expressed in normal tissues. The weak immunogenicity of tumor antigens, the existence of tolerance mechanisms, and the compromised immunocompetence exhibited in many cancer patients may provide a strong incentive for adoptive immunotherapy approaches that are not dependent on the patient's own immune responses.

It is important to increase the avidity of CTL responses against tumor-associated antigens. Although CTL are specific for a self-antigen, they are functionally tumor-reactive and do not show any signs of normal tissue damage when transferred adoptively in murine model experiments. The isolation of CTL specific for tumour-associated antigens is a time-consuming and labour-intensive process that fails on many occasions. Hence, it is hugely attractive to exploit the specificity of a well-characterized, tumour antigen-specific CTL line and use it for therapy in many cancer patients.

Novel TCR pairs are not readily assembled and expressed due to preferential pairing of TCR / combinations that were naturally selected during thymic T cell selection. The retroviral transfer of TCR genes into polyclonally activated lymphocytes can rapidly produce T cell populations of desired antigen-specificity. TCR transduced human CTL display long-term antigen-specific activity in vitro, and murine TCR transduced CTL mediate disease protection in vivo.

The current protocols of T cell transduction involve in vitro activation to achieve T cell proliferation that is required for effective retroviral infection. Adoptive transfer of such minimally stimulated cells will reveal whether in vivo transfer of TCR transduced resting T cells provides more effective protection from disease and better memory development than transfer of fully activated T cells.

TCR gene transfer can also be used to produce antigen-specific CD4+ helper T cells. The in vivo interaction of conventional CD4+ T cells is restricted to MHC class II-positive professional antigen-presenting cells. Recognition of DC presented antigen triggers the production of cytokines by conventional CD4+ T cells. IL-2 has a direct effect on the CD4+ T cells and triggers proliferation and can prevent anergy induction. Other cytokines, such as IFN-, can activate macrophages and natural killer (NK) cells and enhance the functional activity of CTL. In addition, IFN- can have antitumor effects by inhibiting the formation of new blood vessels in the tumour stroma.

Unlike conventional CD4+ T cells, MHC class I-restricted helper cells can recognize peptide epitopes presented by MHC class II-negative non-professional APCs. This is a critical issue as anergic class I-restricted helper T cells may inhibit ongoing antitumor immune responses and thus promote tumur growth in cancer patients. Class I-restricted helper cells activated upon peptide recognition on the surface of tumour cells may also enhance antitumor immunity in these individuals.

Article Conclusions

The isolation and expansion of monoclonal T cells of defined antigen specificity is technically difficult. However, it is appealing to use monoclonal TCRs. TCRs may trigger a wide spectrum of effector functions and can have long-lasting therapeutic effects in cancer patients. The TCR approach has an advantage of no immunogenicity requirements. High-avidity TCRs are isolated readily from human T cells and can be introduced reliably into patient lymphocytes.