Retroviral Vectors for Cancer Gene Therapy

Abstract

Advances in molecular technologies have led to the discovery of many disease-related genetic mutations as well as elucidation of aberrant gene and protein expression patterns in several human diseases, including cancer. This information has driven the development of novel therapeutic strategies, such as the utilization of small molecules to target specific cellular pathways and the use of retroviral vectors to retarget immune cells to recognize and eliminate tumor cells. Retroviral-mediated gene transfer has allowed efficient production of T cells engineered with chimeric antigen receptors (CARs), which have demonstrated marked success in the treatment of hematological malignancies. As a safety point, these modified cells can be outfitted with suicide genes. Customized gene editing tools, such as clustered regularly interspaced short palindromic repeats-CRISPR-associated nucleases (CRISPR-Cas9), zinc-finger nucleases (ZFNs), or TAL-effector nucleases (TALENs), may also be combined with retroviral delivery to specifically delete oncogenes, inactivate oncogenic signaling pathways, or deliver wild-type genes. Additionally, the feasibility of retroviral gene transfer strategies to protect the hematopoietic stem cells (HSC) from the dose-limiting toxic effects of chemotherapy and radiotherapy was demonstrated. While some of these approaches have yet to be translated into clinical application, the potential implications for improved cellular replacement therapies to enhance and/or support the current treatment modalities are enormous.

Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy

“…Thus, autologous T-helper cells become resistant against HIV-1 [42]. Although such an application is restricted to the in vitro manipulation of T-helper cells, these experiments demonstrate that engineered retroviruses are excellent gene delivery systems and, therefore, provide important tools for therapeutic anti-tumor strategies [43].…”

“…With the emergence of the new neurotropic ZIKV with its unexpected preference for infecting GSCs, a new research area for glioma virotherapy opened up [26,[28][29][30]43,44]. In regard to Flaviviridae, recombinant reporter viruses, for example, for West Nile and Dengue virus, were constructed using the original flavivirus genome as a packaging template [45,46].…”

Viral Vectors in Gene Therapy

“…Deletion of HSV genes has generated expression vectors with low toxicity and an excellent packaging capacity of >30 kb foreign DNA [ 13 ]. In contrast to HSV, retroviruses possess a ssRNA genome with an envelope structure [ 14 ]. Typically, retroviruses are randomly integrated into the host genome, which has been problematic, as previously described, in the therapy of SCID patients [ 2 , 3 ].…”

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

“… 73 In attempts to improve the safety of retrovirus-based therapy for hematological malignancies, T cells with chimeric antigen receptors have been engineered. 74 Additionally, deletion of oncogenes and inactivation of oncogenic signaling pathways have been achieved by introduction of Cas9, zinc finger nucleases (ZFNs), or transcription activator-like effector nucleases (TALENs) into retrovirus vectors.…”

“… 70 Moreover, retroviruses have been subjected to chimeric antigen-receptor engineering to provide safe treatment of hematological malignancies. 74 …”