Gene-Immune Therapy of Cancer: Approaches and Problems

Tumor heterogeneity and constant selection of therapy-resistant cancer cells in the tumor require combinatorial approaches to the treatment of cancer that affect various vital processes in the tumor. Immunotherapy made a revolution among approaches to cancer treatment. Today, many combinatorial methods are grouped around this type of treatment. Most antitumor immunotherapeutic agents are administered intravenously, which cause serious, often life-threatening, side effects due to the accumulation of these agents in nontarget tissues. Side effects can be reduced using local therapy, which is limited to the tumor, but at the same time causes systemic antitumor immune response. Localization of the action can be achieved by intratumoral introduction of therapeutic genes. These genes can encode a variety of therapeutic products, ranging from checkpoint inhibitors and immunomodulators to enzymes that mediate intratumoral conversion of prodrugs into chemotherapeutic agents (gene-directed enzyme prodrug therapy, GDEPT). In this review, we will consider approaches that use intratumoral introduction of therapeutic genes encoding molecules of immune checkpoints, cytokines, danger signals, and GDEPT enzymes, as well as their combination for gene-immune therapy of cancer.