Gene therapy for cancer: present status and future perspective

Abstract

Advancements in human genomics over the last two decades have shown that cancer is mediated by somatic aberration in the host genome. This discovery has incited enthusiasm among cancer researchers; many now use therapeutic approaches in genetic manipulation to improve cancer regression and find a potential cure for the disease. Such gene therapy includes transferring genetic material into a host cell through viral (or bacterial) and non-viral vectors, immunomodulation of tumor cells or the host immune system, and manipulation of the tumor microenvironment, to reduce tumor vasculature or to increase tumor antigenicity for better recognition by the host immune system. Overall, modest success has been achieved with relatively minimal side effects. Previous approaches to cancer treatment, such as retrovirus integration into the host genome with the risk of mutagenesis and second malignancies, immunogenicity against the virus and/or tumor, and resistance to treatment with disease relapse, have markedly decreased with the new generation of viral and non-viral vectors. Several tumor-specific antibodies and genetically modified immune cells and vaccines have been developed, yet few are presently commercially available, while many others are still ongoing in clinical trials. It is anticipated that gene therapy will play an important role in future cancer therapy as part of a multimodality treatment, in combination with, or following other forms of cancer therapy, such as surgery, radiation and chemotherapy. The type and mode of gene therapy will be determined based on an individual's genomic constituents, as well as his or her tumor specifics, genetics, and host immune status, to design a multimodality treatment that is unique to each individual's specific needs.

Keywords: Adenoviruses; Clinical trials; Electroporation; Gene silencing; Gene transfer technique; Immunomodulation; Molecular targeted therapy; Oncolytic viruses; Retroviruses; Suicide transgenes.

Figure 1

Genetically-modified adenovirus acting as a suicide gene. The above mode of action represents an example of a modified virus acting as a suicide gene, namely OBP-301 (Telomelysin) (Courtesy Oncolys BioPharma Company, Tokyo, Japan).

Figure 2

Mechanism of action of monoclonal antibody ipilimumab. Generation of an immune signal requires presentation of tumor antigen by major histocompatibility complex (MHC) class I or II molecules, on an antigen presenting cell (APC) such as dendritic cell. However, T-cell activation and proliferation requires a second signal, typically generated by CD28 antigen. When CD28 antigen on T-cell surface simultaneously binds to costimulatory B7-1/B7- ligand on the antigen presenting cell (APC), T-cell upregulate and translocate CTLA-4 receptor molecules to the surface, which binds B7 with a higher avidity than CD28, leading to suppressor effects, with T-cell inhibition, reduction of interleukin-2 (IL-2) secretion, and prevention of immune response against malignant cell. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor, thus prevents such inhibitory effect, and allows T-cell to proliferate and mediate an immune reaction against malignant cells. Other regulatory checkpoints with the potential for modulation include the coinhibitory molecule PD-1, as well as costimulatory molecules such as OX40 and 4-1BB. Abbreviations: APC, antigen presenting cells; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility antigen; TCR, T-cell receptor. (Courtesy of Annals of New York Academy of Science and Wiley, Hoboken, New Jersey, Publisher) [86].

Figure 3

Analysis of overall survival comparing monoclonal antibody ipilimumab plus dacarbazine to placebo plus dacarbazine in metastatic melanoma patients. Kaplan–Meier analysis of overall survival in the phase III study CA184-024. Survival analysis of overall survival in treatment-naive patients with advanced melanoma who received ipilimumab at 10 mg/kg plus DTIC or placebo plus DTIC in the phase III trial, CA184-024. The survival curves reach a plateau beginning at approximately three years after initiation of treatment. Continued survival follow-up of more than four years demonstrates a long-term survival benefit that is consistent with the results of other ipilimumab studies. Abbreviations: DTIC, dacarbazine; Ipi, ipilimumab, Plac, placebo (Courtesy of Annals of New York Academy of Science and Wiley, Hoboken, New Jersey, Publisher) [86].

Figure 4

Chimeric antigen receptor modified T-lymphocyte therapy for B-cell malignancies. Generation of tumor-specific T cells by repeated antigen stimulation or genetic modification to express a tumor-targeting receptor. PBMC collected from a patient or healthy individual can be stimulated in vitro with tumor antigen at regular intervals to induce gradual enrichment of antigen-specific T cells (blue). Multiple stimulations followed by additional enrichment or expansion strategies are required to ensure sufficient antigen-specific T cells are generated. The entire process may take 2–3 months. In contrast, approaches that utilize genetic modification to redirect T cell specificity to a tumor antigen are much more rapid. PBMC can be collected from a patient or healthy donor and retrovirally or lentivirally transduced to express a tumor-reactive CAR (or TCR). The enriched CAR-modified tumor-reactive T cells (red) can be infused into the patient in as little as 1–2 weeks. Abbreviations: PBMC: Peripheral blood mononuclear cells, CAR: Chimeric antigen receptor modified T-lymphocytes. (Courtesy of The International Journal of Hematology, and Springer-Tokyo, Publisher) [102].