Prospects and Limitations of T Cell Receptor Gene Therapy

Abstract

Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining molecule in T cell function, adoptive transfer of TCR genes into patient T cells may be used as an alternative approach for the transfer of tumor-specific T cell immunity. On theoretical grounds, TCR gene therapy has two substantial advantages over conventional cellular transfer. First, it circumvents the demanding process of in vitro generation of large numbers of specific immune cells. Second, it allows the use of a set of particularly effective TCR genes in large patient groups. Conversely, TCR gene therapy may be associated with a number of specific problems that are not confronted during classical cellular therapy. Here we review our current understanding of the potential and possible problems of TCR gene therapy, as based on in vitro experiments, mouse model systems and phase I clinical trials. Furthermore, we discuss the prospects of widespread clinical application of this gene therapy approach for the treatment of human cancer.

Engineered T cells for cancer treatment

“…Transferred α and β chains can cross-pair with endogenous TCR chains, forming hybrid TCRs with either loss of activity or gain of new and unwanted (autoimmune) specificity. The frequency of this problem can be reduced by incorporating a murine-derived transmembrane region in the transgenic TCR, though this is not ideal given the potential immunogenicity (26) , or through the introduction of sequences encoding cysteine residues to form additional disulfide bonds that stabilize pairing of the transgenic TCR and minimize cross pairing with endogenous α and β chains (27–29) . Alternatively, selective disruption of the endogenous αβTCR using zinc-finger nucleases (ZFNs) (30,31) , or the substitution of γδ T cells as the platform for αβ transgenic TCR transduction may prevent this problem (32) .…”

Genetic engineering of T-cell receptors: TCR takes to titin

“…1 E xpression of many developmentally important genes is associated with the activities of distal enhancers, which often each drive target gene expression in distinct, specific cell types. 2 Particularly in vertebrates, these enhancers can be separated by large genomic intervals from their target promoter(s),…”

“…To improve the activity of tumor-directed T cells, investigators have therefore isolated high-affinity TCRs specific for tumor peptides from the T cells of patients who responded to immunotherapy and have used these constructs to genetically modify T cells. 2 When T cells expressing these TCRs specific for tumor antigens such as MART are adoptively transferred, they have induced dramatic clinical responses in a subset of patients, with no evidence of off-target activity. 3 Several investigators have tried to further improve T-cell activity by artificially enhancing the affinity of the transferred tumor antigen-directed TCRs.…”

Will T-cell therapy for cancer ever be a standard of care?

“…Thus, the past decade has seen major, and widely applicable, improvements both in the vectors used to transfer the genes of interest (for example, using lentiviral vectors) 20,21 and in optimizing the expression of the transgenes they encode, for example by introducing appropriate spacer elements to enhance CAR expression or by manipulating the expression of native a and b TCRs to limit cross-pairing of introduced transgenic TCR. 3,22,23 Such technologies are applicable for essentially all planned uses of T cells for cancer therapy. Similarly, the development of countermeasures to tumor immune evasion strategies can be widely introduced into therapies targeting a multiplicity of different cancers since there is considerable conservation of evasion techniques between tumors.…”