Gene Transfer
Gene transfer for cancer represents a cutting-edge and promising strategy aimed at introducing foreign genetic material into cancer cells or normal cells, thereby modifying their functions and achieving therapeutic effects. This technique holds immense potential in manipulating the expression or activity of genes pivotal to cancer initiation, progression, or resistance, including tumor suppressor genes, oncogenes, apoptosis genes, and drug metabolism genes. Additionally, it can bolster the immune system's capability to recognize and eliminate cancer cells by transferring genes encoding cytokines, antigens, or receptors. The concept of gene transfer for cancer treatment has evolved significantly over the past three decades. The maiden clinical trial, conducted in 1989, utilized retroviral vectors to deliver tumor necrosis factor genes to melanoma patients, marking a pivotal milestone in this field.
Features of Gene Transfer for Cancer
The main features and characteristics of gene transfer for cancer are its versatility, flexibility, specificity, and potentiality. Gene transfer for cancer is versatile because it can be applied to various types of cancer, genes, vectors, and cells, depending on the needs and goals of each case. Gene transfer for cancer is flexible because it can be combined or integrated with other conventional or emerging cancer therapies, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc., to achieve additive or synergistic effects. Gene transfer for cancer is specific because it can target cancer cells or tissues with high precision and selectivity, minimizing damage to normal cells or organs. Gene transfer for cancer has potential because it can offer new possibilities and opportunities for the diagnosis, treatment, prevention, and prognosis of cancer. Gene transfer for cancer can also be compared and contrasted with other cancer therapies in terms of their efficacy, safety, cost, availability, and acceptability. For example, gene transfer for cancer may have higher efficacy and safety than chemotherapy or radiotherapy but lower cost and availability than immunotherapy or targeted therapy. Gene transfer for cancer may also have different ethical, social, and legal implications than other cancer therapies, such as the risks of gene mutation, integration, dissemination, or misuse. These issues need to be carefully considered and addressed before gene transfer for cancer can be widely applied and accepted in clinical practice.
Research or Clinical Progress of Gene Transfer for Cancer
Gene therapy for cancer has undergone extensive exploration in both preclinical and clinical environments across a spectrum of cancer types. Notable approaches include:
- P53 Gene Therapy: P53, a pivotal tumor suppressor gene regulating critical cellular functions, experiences mutations or loss in numerous cancers. P53 gene therapy seeks to restore its normal function by introducing a wild-type or modified P53 gene via viral or non-viral vectors. Encouraging outcomes have been observed in diverse cancers, including head and neck, lung, liver, and ovarian cancers.
- Suicide Gene Therapy: This innovative technique involves delivering a gene encoding an enzyme that transforms a harmless prodrug into a potent toxin. Administered systemically, the prodrug selectively targets cancer cells expressing the enzyme, resulting in their demise. Suicide gene therapy achieves precise cancer cell eradication while preserving healthy cells. Its application spans various cancers, such as prostate, glioma, melanoma, and pancreatic cancers.
- CAR-T Cell Therapy: Representing a paradigm shift in immunotherapy, CAR-T cell therapy employs genetically modified T cells expressing a chimeric antigen receptor (CAR) recognizing specific cancer cell antigens. Once infused, these CAR-T cells selectively attach to and eliminate cancer cells expressing the target antigen. Remarkable efficacy has been demonstrated in hematological malignancies like acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL).
Table 1. Summary of Gene Therapy Examples for Cancer
Type of gene therapy | Gene | Vector | Cancer type | Clinical trial | Outcome |
P53 gene therapy | P53 | Adenovirus | Head and neck cancer | Phase III trial of Gendicine | Higher response rate and survival rate than radiotherapy alone |
Suicide gene therapy | Cytosine deaminase (CD) | Retrovirus | Glioma | Phase III trial of Toca 511 and Toca FC | Improved overall survival and quality of life |
CAR-T cell therapy | CD19-specific CAR | Lentivirus | ALL, CLL, NHL | Phase II trials of tisagenlecleucel and axicabtagene ciloleucel | High remission rate and response rate |
References
- Bennett J, et al. Gene therapy for inherited retinal degenerations. Annu Rev Vis Sci. 2019 Sep 15;5:361-386.
- Crudele JM, et al. Gene therapy for Duchenne muscular dystrophy: AAV leads the way. Acta Neuropathol. 2020 Mar;139(3):503-525.
- Duan D, et al. Gene therapy for cancer: Challenges and future perspectives. Cancer Lett. 2020 Jan 1;469:8-18.
- Escors D, et al. Lentiviral vectors in gene therapy: their current status and future potential. Arch Immunol Ther Exp (Warsz). 2010 Apr;58(2):107-19.
- Fajardo CA, et al. Oncolytic immunotherapy: conceptual evolution, current strategies, and future perspectives. Front Immunol. 2017 May 8;8:555.
- Ginn SL, et al. Gene therapy clinical trials worldwide to 2017: An update. J Gene Med. 2018 Mar;20(5):e3015.
- Grada A, et al. Next-generation sequencing: methodology and application. J Invest Dermatol. 2013 Aug;133(8):e11.
- Kim YJ, et al. Therapeutic strategies for targeting cancer stem cells. J Biomed Sci. 2016 Nov 24;23(1):87.
- Maus MV, et al. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res. 2016 Apr 15;22(8):1875-84.
- Naldini L. Gene therapy returns to centre stage. Nature. 2015 Oct 15;526(7573):351-60.
- Park SJ, et al. CRISPR/Cas9-mediated gene knockout for the identification of molecular targets and pathways involved in tumorigenesis and drug resistance of human ovarian clear cell carcinoma cells (Review). Oncol Rep. 2020 Jan;43(1):1-12.
- Wang Y, et al. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA. Cancer Sci. 2018 Mar;109(3):629-641.
- Yla-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther. 2012 Oct;20(10):1831-2.