Welcome to National Colorectal Cancer Awareness Month!
That month is this month March 2002. The annual public information drive aims to educate Americans about the major malignancy. This year approximately 148,300 people in the U.S. will be diagnosed with colorectal cancer and 56,600 will die from the disease.
However, observed molecular oncologist Richard Vile, “Patients who get colorectal carcinoma do not usually die of the tumor in their colon, but they die when that tumor metastasizes or spreads to their liver.”
Vile is a consultant at the Mayo Clinic in Rochester, Minn., in the department of molecular medicine. This month’s issue of Nature Biotechnology carries an article of which he is senior author. Its title: “Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells.”
This gene therapy approach to killing colorectal tumor cells, Vile told BioWorld Today, has been preceded by a host of such dry-hole attempts in human trials. “Previously, people have used adoptive transfer of T cells to patients with tumors, but nobody has used the specificity that is conferred by the T cells’ recognition of the tumor to produce viral vectors in the way that we have done here. Essentially,” he continued, “the field as it stands at the moment is that people have made viral vectors, and those viral vectors have various levels of tumor targeting. The problem that has really blocked the field is that although one can inject those vectors locally into an accessible tumor site, nobody has found the way yet of using those vectors to reach systemic metastatic disease. The main reason for that failure is that the patient’s immune system will destroy those vectors if you just inject them intravenously.
“What we’ve shown here,” Vile pointed out, “is that we can take gene delivery viral vectors, and now we have a means to inject them systemically through the blood stream, and get them to disease sites which previously has not been possible.”
Big Advance Over Prior Art’
“Caveats and so on aside,” he explained, “we can use immune system T cells to get to tumor sites, and there liberate viral vectors, which carry cytotoxic genes. And the big advance over prior art,” he went on, “which just puts the vectors into the blood stream without chaperoning them by the T cells, [is that] those viral vectors would be destroyed before they ever got to the tumor. Our strategy protects viral vectors until they’re actually located at tumors, and gets them to be effective in situ there. The novelty in it comes from linking viral production locally with the binding of T cells, which are specific for tumor cells.
“We hope that within a relatively short period of time,” Vile said, “we will be able to use targeted T cells to deliver viral vectors to patients with systemic disease, as opposed to localized disease. And to me the biggest achievement is trying to get genes out there away from the local arena into the arena of patients with genuinely systemic metastatically spread cancer. And this sort of cell chaperoning method, I think, provides some hope that that strategy may be reality in the future.”
Meanwhile, in the here and now, Vile and his co-authors have tested their complex gene therapy in mice.
“We took immune-incompetent nude mice and injected into their blood stream human colorectal tumor cells, which then lodged in the livers of those animals. Seven days after injecting the tumor cells, we injected the modified T cells. And then we treated the mice with the anticancer prodrug ganciclovir. What we showed was that in the control mice, the human colorectal tumor cells lodged in the liver grew. At the end of the in vivo experiment, most of the control animals had typically over 50 metastases per liver. We terminated the trial when it started to make the mice sick.
“However,” Vile recounted, “the treated mice, which received the T cells and the prodrug, reduced the number of metastases which were viable in those livers by up to 80 [percent] or 90 percent. Typically, most mice had between zero and five metastases, showing that [in] animals with liver metastases which is in some ways analogous to the human situation in colorectal cancer administration of these armed T cells could reduce the metastatic burden by significant levels.”
An Armory Of Gene Therapy Weapons
Arming those T cells drew on a veritable arsenal of gene therapy-supporting molecules.
The T cell receptor recognizes tumor antigen on the tumor.
That activates NF-kB, a transcription factor released from an inhibitor when T cells are triggered.
CEA carcinoembryonic antigen is a tumor marker specific for colorectal tumors. The T cells have a receptor that recognizes CEA on the surface of colorectal tumor cells. CEA binds to the tumor, triggering NF-kB activation, and therefore viral-vector production within the T cells.
So the virus that is released will go into tumor cells, which, if they are colorectal recognized by CEA will express the cytotoxic gene, and be killed.
For the killing proper, Vile explained, “We incorporated into the virus that is released from T cells a so-called suicide gene the herpes simplex virus thymidine kinase gene. It converts ganciclovir into a toxic metabolite, which kills the tumor cells.”
This elaborate mechanism here simplified Vile stated, “lends itself very much so to treat other types of tumors. Our aim is to use T cells that are specific for antigens on, say, melanoma tumors, prostate tumors and other malignancies besides colorectal carcinoma.” The Mayo Clinic applied to patent this invention “about eight months ago,” Vile noted. “It’s a single patent related to cell-based delivery of therapeutic genes for cancer.” Several of the co-authors are co-inventors.
“I think that some of the problems with what we’re hoping to do,” he observed, “is just the logistics of getting T cells out of patients, with a wide specificity. Modifying them in vitro, then putting them back into patients. We would like to think,” he concluded, “that in a year’s time we would go into human trials.”