Harnessing the Natural Biology of Adeno-Associated Virus to Enhance the Efficacy of Cancer Gene Therapy

Abstract

Adeno-associated virus (AAV) was first characterized as small “defective” contaminant particles in a simian adenovirus preparation in 1965. Since then, a recombinant platform of AAV (rAAV) has become one of the leading candidates for gene therapy applications resulting in two FDA-approved treatments for rare monogenic diseases and many more currently in various phases of the pharmaceutical development pipeline. Herein, we summarize rAAV approaches for the treatment of diverse types of cancers and highlight the natural anti-oncogenic effects of wild-type AAV (wtAAV), including interactions with the cellular host machinery, that are of relevance to enhance current treatment strategies for cancer.

Adding recombinant AAVs to the cancer therapeutics mix

“…As many rAAVs are being designed and tested in several cancers to cause a controlled, focused response to target the tumor, it is key that the AAV itself does not influence the host immune system in a way that could compromise the effects of the therapy. 5 , 8 , 9 , 101 , 102 , 103 Even in reports of hemophilia A where a high dose of an rAAV driving expression of factor VIII is inducing immune responses, such as neutralizing antibodies toward the AAV capsid, strategies to dampen the immune response to the virus or enhance the efficacy of the rAAV are showing promise and could be broadly applicable. 97 , 104 , 105 , 106 Other types of viral vectors and nucleic acid-based methods of gene therapy being explored do not consistently exhibit these characteristics of low immunogenicity or no links to human pathology, making AAVs an attractive vehicle for gene therapy.…”

“…NSE, neuron-specific enolase. TnC, tenascin-C. 5 , 6 , 8 , 9 , 53 , 55 , 58 , 61 , 101 , 102 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 …”

“…In addition to targeting the many cells and factors that comprise and influence cancer progression, approaches combining rAAVs with current cancer therapies are being explored pre-clinically. 5 , 7 Many of the combinations include a chemotherapeutic agent such as platinum-based drugs, 5-fluorouracil, and doxorubicin that supplements the rAAV gene therapy that is targeting a specific aspect of the tumor. 5 , 16 These combinations apply cell cycle stress on the tumor cells that lead to toxicity and cell death.…”

“…Gene therapy treatments designed to target mutated DNA sequences and correct them to restore proper function are being explored and are having a positive impact on multiple disease outcomes, including cancer. 5 , 6 , 7 , 8 , 9 , 10 , 11 In this review, we provide a brief overview of the cancer therapeutics landscape before focusing on the various types of gene therapy yielding encouraging results in preclinical and clinical settings for cancer, including advantages and limitations of these therapies. Finally, we concentrate on the biology and application of adeno-associated viruses (AAVs), one type of viral gene therapy with the potential to make a major impact on the cancer field due to their versatility, low immunogenicity, and long-lasting effects.…”

“…Indeed, reported therapeutic regimens being tested pre-clinically that contain a gene therapy like AAV and established drugs like immunotherapy or chemotherapy are showing promise in cancers such as ovarian, hepatocellular carcinoma, and triple-negative breast cancer. 5 , 7 , 9 , 26 …”