Making cancer fight itself

CRISPR used by researchers to make cancer cells into turncoats that attack tumors

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BOSTON—Immuno-oncology is pretty well established in science circles as having great potential, and it is gaining ground via mass media with the populace at large in terms of awareness and recognition. And the theory is a good one: boost or re-educate the immune system to be able to recognize cancer cells as the enemy and to attack them aggressively.
Basically, take the armed forces already in place and give them better weapons and better surveillance so they can wage war more effectively.
But what if we took another analogy related to fighting foreign powers—this time looking to spycraft and sabotage instead?
Well, at Brigham and Women’s Hospital (BWM), researchers did just that when they decided to explore whether cancer cells could be re-engineered to turn against their own kind. And, as noted in a new study in Science Translational Medicine, those researchers used (in part) the gene-editing technology known as CRISPR (clustered regularly interspaced short palindromic repeats)—which has been gaining scientific acclaim and public recognition for about as long as immuno-oncology now—to “convince” cancer cells to kill other cancer cells.
According to BWM, the team reported promising results in preclinical models across multiple types of cancer cells, establishing a potential roadmap toward clinical translation for treating primary, recurrent and metastatic cancer.
“This is just the tip of the iceberg,” said corresponding author Dr. Khalid Shah, director of the Center for Stem Cell Therapeutics and Imaging in the BWH Department of Neurosurgery and faculty at Harvard Medical School and Harvard Stem Cell Institute. “Cell-based therapies hold tremendous promise for delivering therapeutic agents to tumors and may provide treatment options where standard therapy has failed. With our technique, we show it is possible to reverse-engineer a patient’s own cancer cells and use them to treat cancer. We think this has many implications and could be applicable across all cancer cell types.”
As BWM explains, the new approach capitalizes on cancer cells’ self-homing ability, whereby cancer cells can track the cells of their kind that have spread within the same organ or to other parts of the body.
One of the reasons this is such an attractive option to turn cancer against cancer is that there is one critical limitation that so often limits promising anticancer therapeutics: getting the gene- or antibody- or drug-based payload to the sites of tumors.
BWM further explains that the team developed and tested two techniques to harness the power of cancer cells. The “off-the-shelf” technique used pre-engineered tumor cells that would need to be matched to a patient’s HLA phenotype (essentially, a person’s immune fingerprint). The “autologous” approach used CRISPR technology to edit the genome of a patient’s cancer cells and insert therapeutic molecules. These cells could then be transferred back into the patient.
Mouse models of brain cancer and breast cancer (both primary and recurrent) were used in the published research to test both methods.
Noted BWM: “The team saw direct migration of engineered cells to the sites of tumors and found evidence that the engineered cells specifically targeted and killed recurrent and metastatic cancer in the mice. The researchers report that the treatment increased the survival of the mice. Engineered cells were equipped with a ‘kill switch’ that could be activated after treatment—PET imaging showed that this kill switch worked to eliminate the cells.”
“Our study demonstrates the therapeutic potential of using engineered tumor cells and their self-homing properties for developing receptor-targeted therapeutics for various cancers,” concluded Shah.
But, as with so many promising therapeutic strategies, this is not a cure-all, even if it turns out to work in humans as well as it does in mice. Nor is it without potential risks, because the “rehoming” that the researchers are taking advantage of is part of a phenomenon noted by researchers more than a decade ago in which cancer cells migrate back to the original tumor after metastasizing to distant sites.
As noted in a Scientific American article about the published BWM research on July 12, “A key unanswered question is what happens to distant metastases even if CRISPR’d rehoming cells successfully attack the original tumor. As far as biologists know, they make a one-way trip, to the primary tumor but not to distant metastases, which can occur in multiple organs. Those metastases, not the original tumor, are responsible for upwards of 90 percent of cancer deaths. Another question is how to keep CRISPR’d rehoming cells from going rogue and initiating new tumors rather than killing the original one; CRISPR’d or not, they’re still cancer cells.”

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