Targeting Cancer With Engineered Viruses and Immune Cells

Targeting is the future of cancer treatment. The fact that treatments can be targeted to cancer cells with even a moderate level of precision is the important factor, not the nature of the mechanism used to destroy those cells. Targeting means few or no side effects, which in turn means that more potent attacks can be conducted on cancerous cells: no more will cancer therapy be a matter of finely juggling whole-body chemical infusions to kill as much of the cancer as possible without killing or crippling the patient.

Many different cell killing mechanisms have been demonstrated in the laboratory in conjunction with forms of targeting - there are any number of ways to sabotage a cell to the point at which it self-destructs, such as by dumping in enough heat, or radiation, or toxic molecules, or carefully selected sabotaging proteins that throw a spanner into cellular machinery. When nanoparticles are used as the delivery platform, researchers can even load them up with old-school chemotherapy drugs: minute amounts attached to each nanoparticle, but enormous doses for each individual cancer cell in comparison to what would be received in the standard form of presently widespread chemotherapy.

Here are two examples of other methods of targeting cancer presently under development: a gene therapy delivered by engineered virus, and altered immune cells that are programmed to attack and destroy cells with cancerous surface markers.

Targeted viral therapy destroys breast cancer stem cells in preclinical experiments

A promising new treatment for breast cancer [has] been shown in cell culture and in animal models to selectively kill cancer stem cells at the original tumor site and in distant metastases with no toxic effects on healthy cells, including normal stem cells. Melanoma differentiation associated gene-7 (mda-7), also known as interleukin (IL)-24, has been shown to directly impact two forms of cell suicide known as apoptosis and toxic autophagy, regulate the development of new blood vessels and also play a role in promoting cancer cell destruction by the immune system. In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.

Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer "terminator" viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.

Modified immune cells seek and destroy melanoma

All cells express a complex known as the proteasome, which acts as the garbage disposal for the cell. There are two types of proteasomes: constitutive proteasomes (cPs), which are found in normal tissues, and immunoproteasomes (iPs), which are found in stressed or damaged cells. In a damaged cell, the iP generates protein fragments that are displayed on the surface of the distressed cells, triggering recognition by dendritic cells and subsequent destruction by the immune system.

Most cancers, including melanoma, exclusively express cPs, making it impossible for them to express the protein fragments that are recognized by the immune system. To make it easier for the immune system to find cancer cells, [researchers] engineered a specific type of immune cell, known as a dendritic cell, that recognizes protein fragments of cancer specific antigens made by cPs. The engineered dendritic cells were then injected into patients that were in remission from melanoma.

The trial consisted of 4 patients that were vaccinated with regular dendritic cells, 3 patients that received cells that underwent a control treatment, and 5 patients that received dendritic cells that recognized cancer-made protein fragments. Vaccination with all three types of dendritic cells elicited an immune response, which peaked after 3-4 vaccinations with dendritic cells. Patients that received the specially modified dendritic cells had a longer lasting immune response and fewer circulating melanoma cells. Of the two patients that had active disease, treatment with modified dendritic cells resulted in a partial clinical response in one and a complete clinical response in the other.

A number of other forms of targeting are further ahead in the process of development than the two examples above: there is a lot of variety in the approaches used, and that is a very good thing. Competition drives progress. It is not unreasonable to think that cancer will be a controllable part of our biology twenty years from now, gone the way of tuberculosis to become something that can only seriously harm you if you do not have access to clinical medicine.

Comments

I see almost on a daily basis some new way of killing cancer cells selectively for at least the last 5 years if not 10 years now. Yet, I have not seen any clinical studies using actual patients.

I am very disappointed if it is the FDA holding up getting some of these targeted drugs to the patient. What happened to the so called accelerated drug approval system? I was hopefully we would see statistics showing death by cancer start to go down directly caused by using the nanoparticles.

Posted by: Robert Church at June 24th, 2013 10:18 PM

We work on it and we hope we can find a better way to kill and down cancer cells.

Posted by: Ghader Ahmadi at September 30th, 2014 1:56 AM

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