Engineering T cells for cancer therapy

Abstract

It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting.

Activating Systemic T-Cell Immunity Against Self Tumor Antigens to Support Oncolytic Virotherapy with Vesicular Stomatitis Virus

“…In addition to direct activity against the local tumor, this will also provide direct in vivo vaccinating effects, provided that supra-threshold levels of TAA-specific T-cell responses can be achieved. In addition, these VSV-TAA could be used in patients who have previously undergone adoptive transfer of their own T cells with specificity for their tumor cells, either with or without preconditioning chemotherapy (Mansoor et al, 2005;Morgan et al, 2006;Powell et al, 2006;Rosenberg et al, 2008;Hawkins et al, 2010). This would allow for the activation and expansion of antitumor T cells in the same way that we have observed in our preclinical models here.…”

Antitumor activity of dual-specific T cells and influenza virus

“…In attempts to generate tumor reactive T cells, genetic modification techniques have been employed resulting in the generation of T cells reactive with ovarian, colon, kidney, breast and other cancers. [19][20][21][22][23][24][25][26] Despite demonstrations of tumor reactivity of genetically redirected T cells, they do not expand or persist in vivo even in the continued presence of antigen. In this respect, these previously described gene-modified T cells can be considered to be poorly responsive to antigen.…”

Redirected Activity of Human Antitumor Chimeric Immune Receptors is Governed by Antigen and Receptor Expression Levels and Affinity of Interaction

“…T umor-associated antigens (TAA) rarely lead to immune activation 1 ; therefore, many clinically relevant Ab-based adoptive immunotherapeutic strategies have been designed to destroy tumors by redirecting immune effector functions. [2][3][4] Strategies based on chimeric immune receptor (CIR) have been proposed as Ab-based immunotherapeutic reagents 5 that have recently reached clinical application. 6 CIRs combine the Ab specificity for a surface TAA with the effector activity of T lymphocytes.…”