Ex vivo gene transfer for improved adoptive immunotherapy of cancer

Abstract

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.

Figure 1.

(A) Tumor evasion mechanisms. (1) Downregulation of HLA; (2) lack of co-stimulation; (3) lack of homing signals for effector T cells; (4) recruitment of Treg and Th2 subsets; (5) secretion of immunosupressive molecules; (6) expression of inhibitory ligands. (B) Genetic modifications of adoptive T cells to overcome tumor evasion. (1) Redirecting T cell antigen specificity with transgenic TCRs or bypassing the need for HLA with CARs; (2) intrinsic co-stimulatory signals; (3) expression of homing signals; (4) expression of transgenic cytokines or their receptors; (5) expression of dominant-negative receptors; (6) downregulation of negative effectors’ signaling cascade.