Gene Therapy in Oncology

Abstract Gene therapy is any treatment in which a replacement gene is added to a patient’s cells or body; a disease causing gene is inactivated; or a gene is added to cells to stimulate, activate, target, or expand a cellular process associated with disease modification. Gene therapy was initially tested clinically in 1989, but toxicities provided developmental challenges. In recent years, several have been approved including ones in the United States for cancer therapy. These include an oncolytic herpes vector genetically modified to preferentially replicate in tumor cells with a GM-CSF transgene (Talimogene laherparepvec, October 2015) for advanced melanoma. Another approach, with two FDA regulatory approvals, reprograms T-lymphocytes to kill tumor cells (chimeric antigen receptor [CAR] T-cells). These include a cellular therapeutic to treat B-cell lymphomas (Yescarta, October 2017) and a second targeting acute lymphoblastic leukemia (Kymriah, August 2017). While these approaches are associated with toxicities, they have demonstrated significant therapeutic activity. Perhaps the most encouraging approval (Europe) is a therapy for children with adenosine deaminase - severe combined immunodeficiency, in combination with stem cell transplantation, which results in 100% disease remission. In this approach the patient’s own stem cells are removed, the cells are treated with a viral vector that inserts the ADA gene into cellular DNA, and gene-corrected cells are infused into the patient (Strimvelis, May 2016). Recent approaches are combining immune checkpoints inhibitors, to enhance the efficacy of the viral/cellular therapies. Overall, gene therapy is rapidly progressing with regulatory approval of various vectors and targets supporting future development and regulatory approval.