A Glance at the State of Virotherapy as a Cancer Treatment

The future of cancer treatments is, one way or another, all about two things: (a) the ability to identify and target common mechanisms in a broad range of cancers so that one technology platform, one research initiative, can be useful for many patients rather than just a few, and (b) targeting cancer cells so that treatments are far more effective and have few and negligible side-effects. Today's cancer treatments are highly specific to cancer types and subtypes, the result of a large number of parallel lines of development undertaken at great cost, and are also damaging to the patient's healthy tissue. At the most blunt even the application of the best of chemotherapies are an art that involves finding the optimal point in the range lying between too little to degrade the cancer and too much for the patient to bear. Yet the transition is underway to a world in which cancer treatments are something you walk into a clinic to obtain, and walk right out again a hour later feeling no worse for the experience.

There are many ways in which this goal might be achieved, coupling the knowledge needed to distinguish the chemistry of cancer cells from ordinary cells with any one of a number of possible delivery systems. Over the past decade researchers have demonstrated the use of nanoparticle assemblies that glue together sensors for cancer cell characteristics and cell-killing compounds, but why build new molecular machinery when there so much of the stuff is already evolved and waiting to be used as raw materials? Take immune cells, for example, which already handily perform the function of attacking and destroying unwanted cells and other invaders. The use of engineered and trained immune cells is prevalent in modern cancer research, and trials of immunotherapies for cancer are in some cases a fair way along the road to widespread clinical availability. This may well win out to be the basis for most of the next generation of cancer treatment technology.

Beyond immunotherapies, however, there are bacteria and viruses to consider. These can also be engineered to attack cancer cells in a discriminating fashion, and self-replication is a powerful weapon in the therapeutic arsenal if it can be harnessed and controlled. While receiving less attention than immunotherapy these days, there are still a goodly number of impressive demonstrations in the laboratory of the ability of bacteria and viruses to mop up cancer when everything goes right. In clinical trials, there are still hurdles to overcome far more often than not, but it is perhaps encouraging that the same was true for immunotherapies not so very long ago.

Personalized virotherapy in cancer

The use of engineered oncolytic viruses (OVs) is a promising new therapy for cancer treatment. Different OVs have been engineered to express immune stimulatory molecules indicating that OVs can act at two levels, by directly killing malignant cells in concurrence with the simultaneous activation of the host anti-tumor immunity. OVs can be also combined with chemotherapeutic agents providing an aggressive platform for cancer attack. One of these OVs, a Herpes Simplex virus named T-VEC armed with GM-CSF has just completed a phase III trial in advanced melanoma with promising results and might reach the clinic after FDA approval.

Conditionally Replicative Adenoviruses are oncolytic adenoviruses (OAV) engineered to selectively replicate within and kill tumor cells. Selectivity is obtained through the use of ''cancer cell''-specific promoters (CCSP) that are selected to replace viral promoters and drive the expression of genes essential for OAV replication. OAVs replicate essentially in malignant cells with positive expression of the gene from which the CCSP was selected. OAVs efficacy can be also improved through the exchange of the capsid fiber of the virus or addition of specific moieties that will retarget vectors to enter the cell through alternative receptors.

As for other therapeutic modalities, viral spread and therapeutic efficacy is hampered by the extracellular matrix (ECM) barrier. The high resistance to conventional and targeted therapies in desmoplastic tumors of adults is largely due to the dense ECM. The ECM distorts blood and lymphatic vessels structure that hampers the possibility of systemically delivered therapies to reach the tumor mass. With this in mind, we started engineering OAVs whose replication was driven by CCSPs active both in the stroma and in the malignant compartment of the tumor mass. More recently we have shown that the OAV AV25CDC combined with gemcitabine exhibited a large efficacy and complete absence of toxicity in preclinical models of pancreatic cancer in mice and syriam hamsters. AV25CDC was able to disrupt tumor architecture by inducing an increase in MMP-9 activity that would have facilitated gemcitabine penetration deeply inside the tumor mass.

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