An Impressive Performance in Clearing Cancer from Mice via Immunotherapy

Immunotherapy is a cut above chemotherapy and radiotherapy: at its best, it is significantly more effective and significantly less harmful to the patient. It has still required years, a great deal of funding, and many failures for those best approaches to arise. Nonetheless, the report here is a cheering example for the sizable fraction of us expected to suffer cancer at some point in the years ahead if the condition is not soon brought under medical control. This immunotherapy appears highly effective, and just importantly, adaptable to many types of cancer. This potential for broad application is the most important aspect of any potential new cancer therapy. There are hundreds of subtypes of cancer, and the research community cannot make acceptably rapid progress by dealing with them one at a time - too many years and too much funding has gone to that type of strategy in the past. The only viable way forward towards the control of cancer in our lifetime is the production of very general anti-cancer technologies, those that are effective and easily, quickly, and cheaply adapted to each type of cancer.

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases. The approach works for many different types of cancers, including those that arise spontaneously. The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient's immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides - from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times. Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

The new method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are "prescreened" by the body to recognize only cancer-specific proteins. Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors. "This is a very targeted approach. Only the tumor that shares the protein targets displayed by the treated site is affected. We're attacking specific targets without having to identify exactly what proteins the T cells are recognizing."



WOW! Very impressive result!

Posted by: Antonio at February 2nd, 2018 6:34 AM

This seems similar to the 2015 work using Cowpea Mosaic virus for in situ cancer vacination, although that seemed to work through the unusual route of stimulating a neutrophil response against the cancer, and then a T cell response to tumor antigens in the dying tumor.

" We recently demonstrated, that virus-like particles (VLPs) from plants induce a potent anti-tumor immune response when introduced into the tumor microenvironment after tumors are established [Nature Nanotechnology 2016]. The idea pursued is an "in situ vaccination" immunotherapy strategy to manipulate tumors to overcome local tumor-mediated immunosuppression and subsequently stimulate systemic anti-tumor immunity to treat metastases. The VLPs exhibited clear treatment efficacy and systemic anti-tumor immunity in melanoma, ovarian, colon, and breast tumor models in multiple anatomic locations. Our data indicate that anti-tumor immune-stimulation generates immune memory to prevent tumor progression,metastasis, and most importantly recurrence. While treatment and diagnosis can improve patient outcome, the prevention of cancer development (before physicians are able to detect its onset) represents a vertical leap in the field. "

You have to wonder if this result and the one reported today could be combined for a synergistic effect?

Posted by: Jim at February 2nd, 2018 6:46 AM

Great news. How long will it take from mouse to human?

Posted by: Chris at February 2nd, 2018 11:37 AM

Usually I have a long-winded inspirational diatribe.

Not today.

Today I'll just stare with my mouth agape.

Posted by: Mark Borbely at February 2nd, 2018 2:17 PM

"He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2."

So undergoing surgery is still necessary?

Posted by: Chris at February 2nd, 2018 3:24 PM

I think the reason cancers are such bastards, and have such dastardly variation is because, once they have immortalised, they maintain short telomeres and enough genomic instability to evolve at a much accelerated rate in order to overcome any challenge (such as a cancer treatment).

This reported treatment has much promise because one such adaption(putting T Cells to sleep) has been overcome. I'm always cautious however, as it only takes one cancer cell to evolve a counter, and you're back to square one. Ultimately you want to avoid cancers ever reaching that stage (having immortalised) and I think the only way to do that is to keep the body young. With youthful length telomeres and strong immune system, plus fully functioning tumour suppression genes, the likelihood of cancer reaching a clinical stage is much reduced. I'm not sure on the incidence rate of cancer in those under say 40, but even without any further cancer breakthroughs, if we could keep people young biologically, i suspect they'd tend to stay cancer free a long time.

Posted by: Mark at February 3rd, 2018 3:38 AM

Mark: Long telomeres can't prevent mutations. You need just the opposite, ablation of TERT.

Posted by: Antonio at February 3rd, 2018 6:02 AM

Indeed, the highest mutation rate occurs when we are young.

Posted by: Antonio at February 3rd, 2018 6:04 AM

That's just because there is faster replication of cells when you're young, Antonio. The fact that faster replication leads to more mutations but doesn't lead to a higher cancer rate shows that the background mutation rate is not the decisive factor. The mutation rate does become important once a cell has turned cancerous however, because this is what allows it to outsmart the body and cancer treatments. And it does this with short telomeres (typically). So it's a bit more nuanced than long or short telomeres are good or bad; though generally spwaking i'd much rather have long ones for the reasons I've given above.

WILT is a completely different approach that kind of sidesteps all the various issues. We're a long way from being able to implement that, however.

Posted by: Mark at February 4th, 2018 12:25 PM
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