Overview of Gene Therapy as a Treatment Strategy in Cancer

An overview of gene therapy strategies to treat cancer


Cancer is a complex genetic disease that evolves through a multistage process in which inherited and somatic mutations transform a normal cell into a cancer cell1,2

Gene Mutations

Mutations in genes affecting proteins involved in cell cycle control have been identified as the main drivers for the transformation of normal cells into cancer cells1,3,4

The involvement of gene mutations in the development of cancer makes cancer a good candidate for gene therapy1

Immune Response

In addition, the immune response in cancer patients plays a critical role in regulating cancer pathogenesis5

  • During the early stages of cancer development, the immune system can help to fight cancer6
  • But, as the tumor develops, cancer cells evolve different mechanisms that allow them to evade or escape their destruction by the immune attack6,7

The interactions between cancer cells and host immune cells create a tumor microenvironment that is highly immunosuppressive and can impair tumor-specific immune responses through different mechanisms, which involve:8-10

  • Elimination of immune cells and suppression of their function
  • Evasion of recognition by immune cells

As a treatment strategy for cancer, gene therapy introduces genes into immune or cancer cells with the aim to either:1

  • Enhance the immune response against the cancer cells (i.e. used as immunotherapy)
  • Address the altered function of cancer cells due to their genetic abnormalities

Gene Therapies

A range of gene therapy strategies have been identified for the treatment of cancer, including:2,4,11

  • Genetic modulation of immune cells
  • Gene addition of a tumor suppressor gene
  • Gene-directed enzyme prodrug therapy (GDEPT)

CAR, chimeric antigen receptor; TCR, T-cell receptor.

Genetic Modulation of Immune Cells

Genetic modulation of immune cells involves the introduction of modified genes to promote a stronger immune response to kill the cancer cells12-17

There are various approaches by which genetic modulation of immune cells has been investigated to treat cancer, including:17,18

  • Chimeric antigen receptor (CAR) T-cell therapy
  • T-cell receptor (TCR) therapy
  • Cytokine gene transfer

Chimeric antigen receptor (CAR) T-cell therapy

The capacity of T cells for antigen-directed cytotoxicity has become a central focus for engaging the immune system to fight cancer19

One of the standout gene therapy approaches designed to target the naturally occurring antigens on the surface of cancer cells is the use of CAR T cells18

  • CAR T-cell therapy involves genetically engineering a patient’s T cells to express CARs that bind to specific antigens on cancer cells in order to kill cells containing the antigen17,20
  • A CAR is a recombinant receptor with both antigen-binding and T-cell-activating functions21

CAR, chimeric antigen receptor.

CAR T-cell therapies rely on ex vivo modification and expansion of T cells harvested from individual patients.17

CAR T-cell therapy has achieved unparalleled success for the treatment of hematologic malignancies17

A few examples of the CAR T-cell therapies that were the first to be approved in Europe and in the US for the treatment of hematologic malignancies include:22-30

Between 2017 and 2018, axicabtagene ciloleucel received approval by the FDA and EMA for the treatment of adult patients with r/r large B-cell lymphoma after ≥2 other lines of systemic, including DLBCL and PMBCL22,30

Between 2017 and 2018, tisagenlecleucel received approval by the FDA and EMA for the treatment of patients ≤25 years of age with B-cell precursor ALL that is refractory or in second or later relapse, or adults with relapsed or refractory (r/r) large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL and high-grade B-cell lymphoma24,26,27,31

In 2020, brexucabtagene autoleucel received approval by the FDA and EMA for the treatment of adult patients with r/r MCL23,28,29,32

In February 2021, lisocabtagene maraleucel received approval by the FDA for the treatment of adult patients with r/r large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, PMLBL and follicular lymphoma Grade 3B25,33

While CAR T-cell therapy has achieved dramatic results for the treatment of some types of leukemia and lymphoma, its success has been associated with severe side effects, which include:34-37


CAR, chimeric antigen receptor; CD, cluster of differentiation.

Many clinical trials are underway that are investigating the use of CAR T-cell therapy for several cancer-associated targets in both hematologic malignancies and solid tumors17



Figure adapted from Zhao L, Cao YJ. 2019.17
The figure represents the percentage of investigated CAR T-cell targets for hematologic malignancies in clinical trials (Phase I or II) registered on ClinicalTrials.gov (as per 2019 publication17).
BCMA, B-cell maturation antigen; CD, cluster of differentiation; ROR1R, receptor tyrosine kinase-like orphan receptor.



Figure adapted from Zhao L, Cao YJ. 2019.17 

The figure represents the percentage of frequently investigated CAR T-cell targets for solid tumors in clinical trials (Phase I or II) registered on ClinicalTrials.gov (as per 2019 publication17).
EGFR, epidermal growth factor receptor; GPC3, glypican-3; MUC1, mucin 1; CEA, carcinoembryonic antigen; EpCAM, epithelial cell adhesion molecule; PSCA, prostate stem cell antigen.

T-cell receptor (TCR) therapy

TCR therapy involves genetically modifying T cells to express a specific TCR on the T-cell surface17,38,39

  • TCRs only recognize antigens presented by the major histocompatibility complex (MHC) found on cancer cells, rather than surface antigens on cancer cells
  • Upon recognition of the target antigen, modified T cells expressing specific TCRs become activated to attack the cancer cell

MHC, major histocompatibility complex; TCR, T-cell receptor.

While there are no approved TCR therapies for cancer treatment, there are several trials in early stages investigating the use of TCR therapy in cancer.17,40 Examples of cancer or tumor types currently under investigation in Phase I or II clinical trials include:40


Cytokine Gene Transfer

Cytokine gene transfer involves the transfer and expression of an immune-stimulating cytokine to induce an immune response to attack cancer cells15,41

Stimulating cytokines are considered an ideal target for antitumor therapies due to their ability to modulate the host immune response towards cancer cells and to induce tumor cell death42-44


Figure adapted from Lan T, et al. 2021.44
IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; GM-CSF, granulocyte–macrophage colony-stimulating factor.

The following are examples of tumor types currently under investigation in Phase II or III clinical trials:44


In all of these studies, an adenovirus vector is used to deliver the cytokine gene under investigation to treat the patient.44 In addition, an oncolytic virus-based therapy has been successfully used and approved for the treatment of melanoma.45,46

Cytokine gene transfer is being investigated in combination with other approaches, such as:

  • CAR T-cell and TCR therapies to prolong survival and promote their penetration into the cancer tissue17,47,48
  • Gene-based vaccines and oncolytic viruses to augment the immune response against cancer cells15,49

Oncolytic viral therapy utilizes cytokine gene transfer as part of its mechanism of action15,41,50,51

  • Oncolytic viral therapy uses recombinant oncolytic viruses that are capable of selectively replicating within tumor cells, leading to the lysis of the tumor cells
  • As the infected cancer cells are lysed, replicated virus is released into the surrounding tissue where it infects and lyses the neighboring tumor cells
  • The recombinant oncolytic virus can also be engineered to express a cytokine-encoding gene that helps to promote an immune response against the tumor cells

In 2015, talimogene laherparepvec was the first genetically modified oncolytic virus-based therapy approved by the EMA and FDA for the treatment of melanoma45,46

  • Talimogene laherparepvec is a genetically modified herpes simplex virus 1 designed to replicate within tumors and produce an immunostimulatory cytokine called GM-CSF
  • Induction of GM-CSF expression triggers a systemic immune response allowing effector T cells to attack and kill the cancer cells

In addition, the herpes simplex virus-based vector is delivered with certain viral gene deletions so that it preferentially replicates in tumor cells and leads to oncolysis.15

Gene Addition of Tumor Suppressor Genes

Tumor suppressor genes are important genes that code for proteins involved in restricting cell growth and division, DNA repair mechanisms and inducing apoptosis3

Inactivation of tumor suppressor genes is a well-known mechanism contributing to the development of cancer52


The tumor suppressor gene 53 (TP53) is a nuclear transcription factor that, in response to cellular stresses such as DNA damage, activates genes involved in the cell cycle and/or cell death53

The TP53 gene is mutated in ~60% of solid tumors, and it is one of the most commonly transferred tumor-suppressor genes under investigation in clinical trials1,18


Addition of TP53 via viral vector-mediated expression of wild-type TP53 is an approved treatment for cancer:

  • In October 2003, in China, recombinant human p53 became the first gene therapy product in the world to be approved for clinical use54-57
    • Recombinant human p53 is a replication-incompetent, human adenovirus of serotype 5 designed to contain the human wild-type TP53
    • It was approved by China’s State Food and Drug Administration (now called the National Medical Products Administration) for the treatment of head and neck squamous cell carcinoma
  • Other tumor-suppressor genes are also being studied as potential targets for gene addition of tumor suppressor genes, including:2,58
    • Retinoblastoma gene Rb: Regulates cell cycle and differentiation
    • Cyclin-dependent kinase inhibitor 2A (also known as p16INK or CDKN2): Regulates the cell cycle
    • Phosphatase and tensin homolog (PTEN): Regulates cell survival

Gene-Directed Enzyme Prodrug Therapy (GDEPT)

GDEPT, also known as ‘suicide gene therapy’, utilizes a gene encoding a foreign enzyme delivered to the cancer cell. The enzyme is then expressed within the cancer cell where it converts an administered inactive/prodrug into a cytotoxic drug11,59

Mechanism of GDEPT Systems11,60



The gene encoding the enzyme is delivered via a vector to the cancer cell where it is expressed11


A prodrug is administered systemically and absorbed by the targeted cancer cell60


The prodrug is converted to a cytotoxic drug by the enzyme60

By utilizing tumor cell-specific promoters, the gene encoding the enzyme can be targeted to the cancer cells. This allows for the enzymatic reaction to occur specifically in the tumor cells, leaving other noncancerous cells unaffected60

Some examples of the most investigated GDEPT systems that have been investigated for the treatment of cancer include:60-66


Examples of cancer types that are being investigating in Phase II/III and III clinical trials include high-grade glioma and high-risk acute leukemia60,64,65

Inhibition of DNA synthesis and formation of DNA cross-links are the main mechanisms by which these cytotoxic drugs induce cell death of the cancer cells60


  1. Akbulut M, et al. Chapter 1 – Cancer gene therapy. In: Gene Therapy – Principles and Challenges. Hashad D (ed). Rijeka, Croatia: InTech, 2015:1-36.
  2. Das SK, et al. J Cell Physiol 2015; 230: 259-271.
  3. Chow AY. Nature Education 2010; 3: 7.
  4. Heo DS. Genet Med 2002; 4: 52S-55S.
  5. Pandya PH, et al. J Immunol Res 2016; 2016: 4273943.
  6. Gonzalez H, et al. Genes Dev 2018; 32: 1267-1284.
  7. Vinay DS, et al. Semin Cancer Biol 2015; 35 Suppl: S185-S198.
  8. Amer MH. Mol Cell Ther 2014; 2: 27.
  9. Chambers WH, et al. Mechanisms of Immunosuppression. In: Holland-Frei Cancer Medicine. 6th edition. Kufe DW, Pollock RE, Weichselbaum RR, et al., (eds). Hamilton (ON), US: BC Decker; 2003.
  10. de Souza AP, Bonorino C. Expert Rev Anticancer Ther 2009; 9: 1317-1332.
  11. Ohana P, et al. Chapter 8 - Toxin-Based Cancer Gene Therapy: Under the Control of Oncofetal H19 Regulatory Sequences. In: Gene Therapy of Cancer (Third Edition). Elsevier Inc., 2014.
  12. Majhen D, et al. Hum Gene Ther 2014; 25: 301-317.
  13. Pearl TM, et al. Mol Ther Oncolytics 2019; 13: 14-21.
  14. Strachan T, Read A. Genetic approaches to treating disease. In: Human Molecular Genetics. 4th edn. Boca Raton, FL: CRC Press, 2018:696-699.
  15. Wang D, Gao G. Discov Med 2014; 18: 151–161.
  16. Zhang C, et al. Front Immunol 2019; 10: 594.
  17. Zhao L, Cao YJ. Front Immunol 2019; 10: 2250.
  18. Ginn SL, et al. J Gene Me 2018; 20: e3015.
  19. Waldman AD, et al. Nat Rev Immunol 2020; 20: 651-668.
  20. Titov A, et al. Cancers (Basel) 2020; 12: 125.
  21.  Sadelain M, et al. Cancer Discov 2013; 3: 388-398.
  22. Yescarta® [Product Information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/yescarta-epar-product-information_en.pdf. Accessed June 14, 2021.
  23. Tecartus® [Product Information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/tecartus-epar-product-information_en.pdf. Accessed June 14, 2021.
  24. Kymriah® [Product Information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf. Accessed June 14, 2021.
  25. U.S. FDA. Approval letter. February 5, 2021. Available at: https://www.fda.gov/media/145712/download. Accessed June 14, 2021.
  26. U.S. FDA. Approval letter. August 30, 2017. Available at: https://www.fda.gov/media/106989/download. Accessed June 14, 2021.
  27. U.S. FDA. Approval letter. May 1, 2018. Available at: https://www.fda.gov/media/112803/download. Accessed June 14, 2021.
  28. U.S. FDA. Approval letter. July 24, 2020. Available at: https://www.fda.gov/media/140415/download. Accessed June 14, 2021.
  29. EMA. Tecartus. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/tecartus. Accessed June 14, 2021.
  30. U.S. FDA. Approval letter. October 18, 2017. Available at: https://www.fda.gov/media/108458/download. Accessed June 14, 2021.
  31. Kymriah® [package insert]. 2018. Available at: https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf. Accessed June 14, 2021.
  32. Tecartus® [package insert]. 2020. Available at: https://www.fda.gov/media/140409/download. Accessed June 14, 2021.
  33. Brenyanzi® [Product Information]. 2021. Available at: https://www.fda.gov/media/145711/download. Accessed June 14, 2021.
  34. American Cancer Association. CAR T-cell Therapy and Its Side Effects. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html. Accessed June 14, 2021.
  35. Bonifant CL, et al. Mol Ther Oncolytics 2016; 3: 16011.
  36. Kennedy LB, Salama AKS. CA Cancer J Clin 2020; 70: 86-104.
  37. Srivastava IK, Liu MA. Ann Intern Med 2003; 138: 550-559.
  38. Gascoigne NR, et al. Front Immunol 2011; 2: 72.
  39. Morris EC, Stauss HJ. Blood 2016; 127: 3305–3311.
  40. Zhang J, Wang L. Technol Cancer Res Treat 2019; 18: 1533033819831068.
  41. Qian C, et al. Cell Res 2006; 16: 182-188.
  42. Berraondo P, et al. Br J Cancer 2019; 120: 6-15.
  43. Chulpanova DS, et al. Front Cell Dev Biol 2020; 8: 402.
  44. Lan T, et al. Cells 2021; 10.
  45. Imlygic® [package insert]. 2019. Available at: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/imlygic/imlygic_pi.ashx Accessed June 14, 2021.
  46. Imlygic® [product information]. 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/imlygic-epar-product-information_en.pdf. Accessed June 14, 2021.
  47. Dwyer CJ, et al. Front Immunol 2019; 10: 263.
  48. Uchibori R, et al. Mol Ther Oncolytics 2019; 12: 16-25.
  49. Kutzler MA, Weiner DB. Nat Rev Genet 2008; 9: 776-788.
  50. Marelli G, et al. Front Immunol 2018; 9: 866.
  51. Matar P, et al. J Biomed Sci 2009; 16: 30.
  52. Joyce C, et al. Tumor-Suppressor Genes. In: StatPearls [Internet].
  53. Wang LH, et al. Cell Physiol Biochem 2018; 51: 2647-2693.
  54. Daley D. Gene therapy arrives. Available at: https://www.nature.com/articles/d41586-019-03716-9. Accessed June 14, 2021.
  55. EMERGO. NMPA - National Medical Products Administration. Available at: https://www.emergobyul.com/resources/china/china-food-drug-administration. Accessed June 14, 2021.
  56. Qu J, et al. Experimental and therapeutic medicine 2020; 20: 18.
  57. Zhang WW, et al. Hum Gene Ther 2018; 29: 160-179.
  58. NCBI. CDKN2A cyclin dependent kinase inhibitor 2A [Homo sapiens (human)]. Available at: https://www.ncbi.nlm.nih.gov/gene/1029. Accessed June 14, 2021.
  59.  Zarogoulidis P, et al. J Genet Syndr Gene Ther 2013; 4.
  60. Zhang J, et al. AAPS J 2015; 17: 102-110.
  61. deaminase C. ClinicalTrials.gov. NCT01172964. Available at: https://clinicaltrials.gov/ct2/show/NCT01172964. Accessed June 14, 2021.
  62. deaminase C. ClinicalTrials.gov. NCT01562626. Available at: https://clinicaltrials.gov/ct2/show/NCT01562626. Accessed June 14, 2021.
  63. deaminase C. ClinicalTrials.gov. NCT01470794. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01470794. Accessed June 14, 2021.
  64. HSV-Tk. ClinicalTrials.gov. NCT00914628. Available at: https://clinicaltrials.gov/ct2/show/NCT00914628. Accessed June 14, 2021.
  65. HSV-Tk. ClinicalTrials.gov. NCT02414165. Available at: https://clinicaltrials.gov/ct2/show/NCT02414165. Accessed June 14, 2021.
  66. HSV-Tk. ClinicalTrials.gov. NCT01913106. Available at: https://clinicaltrials.gov/ct2/show/NCT01913106. Accessed June 14, 2021.