Regional Gene Therapy for Cancer

Abstract

Two successful regional gene therapies have emerged in recent years: chimeric antigen receptor (CAR) T-cell therapy and oncolytic virus therapy. Coupled with the recent advances in the understanding of solid tumor immunology, the success of these therapies illustrates how regional therapy can be combined with efficient gene transfer and immune stimulation to treat solid tumors. CAR T cells and oncolytic viruses leverage the fundamental advantages of regional delivery to accomplish the following three objectives: 1. Enhance delivery of therapeutics to the tumor. Cancer-targeted gene therapy can be inefficient when infused intravenously, owing to the increased volume of distribution, sequestration in other organs, and poor or altered vascularity, which limit drug perfusion into tumor tissue. Regional CAR T-cell administration can bypass these limitations. Oncolytic viruses can be regionally infused or intralesionally injected. 2. Enhance targeting of cancer cells, thereby limiting normal-tissue toxicity. CAR T cells and oncolytic viruses are genetically modified to optimize cancer-specific targeting. The flexibility afforded by genetic engineering allows preferential targeting, infection of cancer cells, and sparing of normal tissues. 3. Generate both a local and a systemic immune response that can target metastatic disease and prevent tumor recurrence. Perhaps, the most impressive feature of these local therapies is their ability to generate an immune response that extends beyond the primary tumor to establish systemic immune surveillance. This immune response follows the tenets of the adaptive immune system: it establishes circulating immune memory that is capable of self-renewal and is long-lasting. Regional delivery of CAR T cells elicits a robust local immune response and establishes systemic immunity. Oncolytic viruses not only target tumors via local cancer cell destruction but also generate a local and systemic immune response. The regression of metastatic lesions following local delivery of oncolytic virus exemplifies the potential to generate systemic immune responses.