Gene Therapy in the Treatment of Cancer

Introduction

The application of efficient gene-transfer techniques to lymphocyte populations has opened new pathways in the therapy of neoplastic disease. Genetically engineered lymphocytes possess unique functional characteristics which can be exploited in novel treatment protocols. The ability of lymphocytes to traffic to tumor deposits can be harnessed to effect the delivery of therapeutically active molecules to the tumor microenvironment. Specific changes in the local tumor milieu may augment the host immune response, while avoiding the toxicity associated with high-dose systemic administration of cytokines. In addition, the construction of chimeric T cell receptors has led to the direct coupling of the recognition and effector phases of the immune response. In addition, advances in the isolation and propagation of specific hematopoietic stem cell (HSC) populations may enable researchers partially to reconstitute the hematolymphoid system with genetically engineered precursor cells possessing specific antitumor activity. Targeting of HSC may allow the indirect transfer of genes into lymphocytic effector populations, while overcoming some of the limitations associated with direct gene insertion into mature lymphocytes. This chapter reviews methods of gene transfer into lymphocytes and HSC and the in-vivo characteristics of these cells following adoptive transfer. Strategies for using genetic modification of lymphocytes and HSC to enhance the antitumor immune response are discussed, and the relative merits of using either the mature lymphocyte or HSC populations for gene therapy of cancer are examined.