Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health

Abstract

Gene therapy manipulates or modifies a gene that provides a new cellular function to treat or correct a pathological condition, such as cancer. The approach of using gene manipulation to modify patient’s cells to improve cancer therapy and potentially find a cure is gaining popularity. Currently, there are 12 gene therapy products approved by US-FDA, EMA and CFDA for cancer management, these include Rexin-G, Gendicine, Oncorine, Provange among other. The Radiation Biology Research group at Henry Ford Health has been actively developing gene therapy approaches for improving clinical outcome in cancer patients. The team was the first to test a replication-competent oncolytic virus armed with a therapeutic gene in humans, to combine this approach with radiation in humans, and to image replication-competent adenoviral gene expression/activity in humans. The adenoviral gene therapy products developed at Henry Ford Health have been evaluated in more than 6 preclinical studies and evaluated in 9 investigator initiated clinical trials treating more than100 patients. Two phase I clinical trials are currently following patients long term and a phase I trial for recurrent glioma was initiated in November 2022. This systematic review provides an overview of gene therapy approaches and products employed for treating cancer patients including the products developed at Henry Ford Health.

Designing cytochrome P450 enzymes for use in cancer gene therapy

“…In the realm of cancer gene therapy, various strategies have been explored, including the transfer of tumor suppressor genes, suicide genes, enzyme/pro-drug approach (like GDEPT), inhibition of dominant oncogenes, immunomodulation approaches, and expression of molecules affecting angiogenesis, tumor invasion, and metastasis ( Seth, 2005 ). The use of recombinant adeno-associated viruses (rAAV2) for intraperitoneal gene delivery to cancer cells, besides bacteria-mediated cancer gene therapy and the development of new vector systems, exemplifies the continuous progress and advanced strategies being employed in this field ( Cao et al, 2010 ; Malecki et al, 2010 ; Zu and Gao, 2021 ; Bulcha et al, 2021 ; Thoidingjam et al, 2023 ). Of utmost importance remains bridging the gap between research and clinical application for successful clinical translation of recent advances.…”

Genome Engineering as a Therapeutic Approach in Cancer Therapy: A Comprehensive Review

“…From replacing non‐functional genes with normal ones, to silencing mutated genes, and enhancing the expression of healthy ones, gene therapy has come a long way. [ 117 ] Herein we review some of the gene therapy tools including Oncolytic Virotherapy, Imlygic, Gendicine, Oncorine, and Rexin‐G.…”

Long-Term Follow-Up of Phase I Trial of Oncolytic Adenovirus-Mediated Cytotoxic and Interleukin-12 Gene Therapy for Treatment of Metastatic Pancreatic Cancer

“…A significant advantage of employing oncolytic adenoviruses lies in their capacity to transform "immunologically cold" tumors into "immunologically hot" ones. Pancreatic tumors, often characterized as "cold" due to their lack of infiltrating immune cells and low mutational burden, stand to benefit from this therapeutic paradigm shift [10].…”

“…The upgraded second-generation adenovirus featured enhancements in its enzyme components, including cytosine deaminase from yeast (yCD), a mutant HSV-TK with superior catalytic activity, and the adenovirus death protein (ADP), which allowed for higher oncolytic capabilities. This advancement laid the groundwork for the development of the third-generation vector, Ad5-yCD/mutTKSR39rep-mIL12, which carried dual suicide genes alongside mouse IL-12 [10]. This vector has shown promising results in preclinical models, demonstrating improved tumor control and survival rates compared to earlier versions lacking IL-12 [11].…”