The Betrayal: turning cancer against itself

I honestly believe that we’re living in the most exciting time for cancer therapeutics. The past few years (dare I say decades, even?) have pushed the boundaries of cancer treatment from radiation and chemotherapy to the use of cancer-targeted antibodies, oncolytic viruses and the more recent approval of CAR-T cells (see my previous post on CAR-T cells).

And now we have yet another possible approach to add to this list: reprogramming cancer cells to target and kill their fellow cancer cells.

This month, Dr. Khalid Shah and his team at Brigham and Women’s Hospital, Harvard Medical School published a paper in Science Translational Medicine: “CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors.”

The authors are quick to point out that their study is not the first to use cancer cells against a tumour. Cancer cells have long been shown to exhibit a self-homing property that seems to bring them to each other and the tumour bulk (mothership, if you will), making them ideal vehicles to deliver an anti-tumour payload. Previous methods have had some good results (read about examples here, here, and here), but their limitation is that the repurposed cancer cells often die from their own payloads, reducing the duration of their therapeutic effects.

Knowing this, Shah’s team had two main goals:

1. Develop a system that wouldn’t kill the repurposed cancer cells before they could have a therapeutic effect; and,
2. Build in a ‘fail-safe’ that would prevent the modified cancer cells from starting tumours of their own (having made them resistant to therapy).

Capitalizing on the cell-surface receptors of cancer cells and the subsequent built-in signaling pathways, the authors chose to use S-TRAIL (secretory variant of tumor necrosis factor-related apoptosis-inducing ligand) as their anti-tumour agent of choice, knowing that the ligand affects cancer cells significantly more than normal cells (based off their previous research).

Their plan was to engineer treatment-resistant (more on that later) cancer cells to express large amounts of S-TRAIL and allow the engineered cancer cells to use their homing capacity to get close to the tumour, where the secreted S-TRAIL would bind with tumour death receptors (DRs), triggering apoptosis: programmed cell death.

Their cancer models of choice were glioblastoma (GBM, the aggressive primary brain tumour that killed Gord Downie) and brain metastases (brain tumours that arise from tumours elsewhere in the body) – both of which are fatal diagnoses, with few treatment options for patients.

The authors performed experiments on what they hope will evolve into two different treatment options for cancer patients. There are risks and limitations with both options, but do they ever sound exciting!

The study presents compelling data based on in vitro (cell-in-dish) and in vivo (animal) models, demonstrating that the genetically engineered therapeutic cancer cells preferentially target cancer cells, home to the tumour, and prolong survival for both proposed “Off-the-Shelf” and “Self-Targeting” approaches (see infographic). While the initial experiments are done with brain tumour models, the plan would be to expand to other cancers. These are only early laboratory studies, but these promising results have huge clinical implications for future cancer treatment.

True to their initial goal of using cancer cells that would be resistant to the S-TRAIL signaling pathway, the team used CRISPR techniques (see my previous post on CRISPR) to knockout the DRs in the therapeutic cells (GBM and brain metastasis cell lines), rendering them ‘deaf’ to S-TRAIL-mediated apoptosis.

As promised, they also made sure to build in a fail-safe. Therapeutic cells were also engineered to express the prodrug-converting enzyme HSV-TK (herpes simplex virus thymidine kinase). HSV-TK converts the drug ganciclovir into an active form that causes incomplete or incorrect DNA replication, triggering apoptosis in the cell (read more about the HSV-TK-ganciclovir system here).

The authors noted two findings of interest about their fail-safe system:

1. When ganciclovir was added to both in vitro and in vivo systems, it not only killed off the therapeutic cancer cells, but there was a substantial “bystander effect” as well; and,
2. In control groups (in vivo) where ganciclovir was not administered after injection of the therapeutic cells, despite initial regression of the tumour, there was no difference in the survival of the mice, suggesting the therapeutic cells were now making tumours. This further solidified the authors’ imperative that any therapeutic cells must have a fail-safe, and even suggested having a backup would be a good idea in future endeavours (agreed!).

panCELLa

Shah and colleagues are not the first to realize that the biology of one’s creation can lead to betrayal.

In 2011 Dr. Andras Nagy, as part of the International Stem Cell Initiative (ISCI), showed that over one hundred frequently used embryonic stem (ES) cell and induced pluripotent stem cell (iPSC) lines had the potential to quickly evolve into cancer if not kept in check. In October 2016, the ISCI discussed the implications of this inherent potential risk to patients as ES and iPSC-based therapies made their way to clinical trials. The result was to create an advisory panel to further review the issue, and initiate guidelines for clinical translation.

Drs. Nagy and Armand Keating have gone a step further and have created a Toronto-based company (hooray for the local team!) called panCELLa. Its mission is “to provide ‘FailSafe Cell Therapy’ for the treatment of degenerative and malignant diseases.” panCELLa uses the HSV-TK and ganciclovir system, but with an added layer of security. They have linked the expression of HSV-TK to that of an enzyme critical for cell division. This essentially reduces the risk of the HSV-TK gene being edited out to zero: it is part of a critical and protected area of the genome, and will always be expressed.

As this latest study has shown, it’s definitely an exciting time for cancer therapy research. It’s hard not to want to push for things to move forward even more quickly – it feels like we’re so close. But both cancer researchers and embryonic scientists alike are pleading for caution with cell-based therapies, and we should listen.

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Sara M. Nolte

Sara Nolte holds a Bachelor of Health Sciences and Masters of Science in Biochemistry & Biomedical Sciences from McMaster University. Her MSc research focused on developing a cancer stem model to study brain metastases from the lung. She then spent a year working on developing cell-based cancer immunotherapies. Throughout a highly productive graduate career, Sara became interested in scientific communication and education, and later pursued a career as a Physician Assistant (PA) in order to build medical expertise. Working as a PA in Emergency Medicine helps her find ways to bridge the gaps between laboratory and clinical science, and to improve scientific and health-related communication with the public. Outside of science, Sara enjoys participating in a variety of sports, and is a competitive Olympic weightlifter hoping to compete at the National level soon!

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