Gene Therapy in Combination: A Promising Avenue for Cancer Treatment
Gene therapies (GTs) are a rapidly growing field of cancer treatment, with almost 2000 active clinical trials worldwide representing 65% of total gene therapies. There is particular interest in the use of GTs in combination with existing drug treatments for cancers to provide more effective therapies. Some of the reasons behind this optimism include:
Improving response rates… Immune checkpoint inhibitors (IHIs) like PD-1 work by blocking the shutdown of the normal immune response to cancer cells, promoting tumor clearance by the immune system. IHI drugs like pembrolizumab and nivolumab have relatively high response rates (33 and 40% respectively), but remain ineffective in over half of patients. Gene therapies that work in parallel with IHIs to boost immune response offer attractive targets. A recent Phase Ib study has shown that pembrolizumab in combination with an oncolytic viral therapy (T-VAC) boosted response rate to 62% in metastatic melanoma patients. Psioxus Therapeutics currently has a Phase I trial for Enadenotucirev in combination with PD-1 inhibitors to treat Advanced Epithelial tumors.
Tackling redundancy… A major barrier to effective cancer treatment is the ability for tumors to use multiple redundant signaling pathways to the same end. For example, both EGFR and AKT signaling pathways can help cancer cells escape apoptotic cell death signals, meaning blocking only one pathway can be ineffective. Genprex has developed a non-viral means to deliver the TUSC2 gene into tumors. TUSC2 is a tumor suppressor gene that promotes apoptosis by targeting EGFR and AKT pathways. Phase I/II trials of Oncoprex in combination with EGFR inhibitors in lung cancer patients are ongoing, but initial data suggests a 78% control rate of the disease. In another example, a recent publication in Gene Therapy showed that p53 expression in combination with chemotherapy led to 100% survival rate in a preclinical model of prostate cancer.
More bang for your buck… New gene delivery vectors are being developed that can introduce multiple genes into tumors. In a multifaceted disease like cancer, having the ability to introduce as many interventions as possible is critical. This approach has a long history, with the first trial in 1995 for two interleukin-12 (IL-12) genes to treat kidney cancer. More recently, IL-12 was added in combination with a suicide gene and showed an improved response in a preclinical model of prostate cancer.
Shared learnings… Advances in gene therapies in other disease fields have important implications for future cancer treatment. Last year, the FDA approved the first ever siRNA therapy for the treatment of a rare hereditary neuropathy. siRNAs offer the ability to silence gene expression. Many cancers are driven by expression of mutated or over-active ‘oncogenes’. siRNAs are a promising way to enable inhibition of targets that are not amenable to pharmacological intervention and could provide attractive therapies when combined with other GTs or drugs.
Looking forward, gene therapies are only going to become more commonplace in the treatment of cancer. Absorption Systems’ Cell and Gene Therapy platform is supporting these therapies to reach the market safely and expediently through a wide range of in vitro and in vivo services.