7th Annual Symposium
Physics of Cancer
Leipzig, Germany
October 4-6, 2016
Invited Talk
Gene Therapy Come of Age
Dietger Niederwieser
University Hospital Leipzig, Department of Hematology and Medical Oncology, Johannisallee 32 A, 04103 Leipzig, Germany
Contact:  | Website
The ability to introduce genes into mammalian cells has contributed much to our knowledge of the mechanism and regulation of gene expression. A variety of methods have been used to transfer foreign genetic material into cells ranging from calcium-phosphate-mediated gene-transfer, micro-injection into target cells and the use of viral vectors to direct gene expression. The SV40 vectors used in the 80ties had a number of limitations, many of which were overcome with the development of retrovirus packaging mutants that could be used to produce helper-free, defective retrovirus. These more efficient delivery systems offered the first real promise of gene therapy. This may be used to restore the function of defect genes, to mark cells and even to treat cancer. The first attempt to modify human cells in this way was performed in 1980, but the first successful procedure to be reported involved the marking of infiltrating lymphocytes with a G418 resistant gene in 1989. Treatment of ADA deficient patients was reported in 1990. Since then, over 2300 clinical trials have been conducted, more than half of them in phase I studies. This intense period of investigation into gene therapy and the successful treatment of a number of patients served to demonstrate both the high potential benefits and the risks involved. The high potential is obvious: Natural and chimeric genes can produce products to restore homeostasis and provide clinical benefit. The question now is how to reduce the risk and broaden the appeal so that gene therapy can enter into the mainstream of clinical practice.

Important developments in this respect include the recent use of lentiviral vectors to replace mutated genes in blood stem cells of patients with leukodystrophy and Wiskott Aldrich syndrome, apparently without causing harmful side effects, and the introduction of chimeric antigen receptors (CAR) in T-cells to treat hematological cancer.

The introduction of chimeric antigen receptors into T-cells has been of interest for decades. However it was only recently that scientists recognized that the intracellular T-cell receptor wasn’t enough to induce cell death of the antigen-bearing tumor cell. The early clinical trials using CAR T cells showed only modest results. However, after modifying the intracellular domain, several trials of CD19-targeted CAR T-cells in the treatment of patients with B-cell malignancies have reported impressive outcomes, resulting in increased enthusiasm for this approach. Unprecedented remission rates of 70%–90% have been observed in adult and pediatric patients with relapsed and refractory acute lymphoblastic lymphoma. Remissions have been sustained in many patients without subsequent therapy, a phenomenon often correlating with CAR T-cell persistence. In other CD19+ malignancies including chronic lymphocytic leukemia and B cell Non-Hodgkin Lymphomas, response rates of 50%–80% have been observed even in heavily pretreated and refractory patients. Cytokine release syndrome is the most significant treatment related toxicity. Neurologic toxicity with encephalopathy is another important side effect. On target, off tumor effects of CD19-CAR T-cells are fortunately limited to B-cells and B-cell aplasia occurs in patients with CAR T-cell persistence. Given the successes of these early phase trials, larger Phase II studies are underway to assess the feasibility of expanding this treatment modality to multiple centers and to evaluate outcomes among larger numbers of patients. Important lessons have been learned from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. However questions regarding the persistence of transduced cells and tumor escape remain to be solved in the future.
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