Robert Coffin: Inventor, IMLYGIC®

Harnessing Viruses to Help the Body Beat Cancer
Dr. Robert Coffin, inventor of Amgen’s IMLYGIC, will be one of the honorees for Inventor of the Year at the IPO Education Foundation’s Annual Awards Dinner in Washington, DC on 6 December. Dr. Coffin began his journey into the field of virology at Imperial College London, where he was initially focused on viruses of agricultural importance that infect plants. During his post-doctoral research at University College London on basic herpes virus virology, he established his own research group focused on developing herpes simplex virus-based vectors for the delivery of genes to the nervous system, and eventually started a company around that technology.

The company was ultimately called BioVex (acquired by Amgen in 2011) and was initially looking at gene therapy for diseases such as Parkinson’s, chronic pain, and spinal cord injury repair. However, “a couple of years in we decided there was a great opportunity to develop new and better oncolytic viruses,” Dr. Coffin says. Oncolytic viruses are viruses that can replicate selectively in tumors, thereby killing the tumors. The group also focused on combining that technology with activating the immune system against the tumor at the same time, which led to the development of IMLYGIC, an “oncolytic immunotherapy.”

Here, Dr. Coffin—who today is the founder and CEO of Replimune, another company developing technology in the oncolytic immunotherapy space—explains the exciting technology behind IMLYGIC, and how combining it with other existing immunotherapies could hold promising possibilities for the future of cancer treatment.

What is IMLYGIC and how does it work?

IMLYGIC is potentially broadly applicable to solid tumors in general.

IMLYGIC is an example of what is called an oncolytic immunotherapy—a virus that either selectively replicates in tumor tissue naturally, or has been engineered to selectively replicate in tumor tissue and thereby kill the tumor. It aims to treat cancer by taking advantage of the ability of viruses to naturally kill cells, in this case tumor cells. The virus is injected into tumors so that the virus can then replicate in those tumors and kill them. You can see pretty easily that if you can directly kill tumors that could be useful for patients, but unless you’re having a truly systemic effect, i.e., killing tumors that the virus doesn’t necessarily come into contact with as well as those it does, you may not have a great overall effect because cancer is a systemic disease throughout the body. A patient often will have small tumors that can’t be seen on imaging, which unless these are also eradicated will grow and spread to ultimately kill the patient. So in addition to the direct effect of the virus in killing the tumors with which it comes into contact, it’s also very important to have a systemic effect too.

That’s where the immunotherapy side of IMLYGIC comes into play. In addition to directly killing tumors in which the virus is replicating IMLYGIC also produces a potent immune response to those tumors. That immune response can impact the patient’s cancer systemically, in particular to treat uninjected tumors, where it may kill the small deposits that may not be seen on imaging, and also vaccinate against relapse. So, it’s a two-pronged approach to killing cancer: one is directly killing the tumor and the other is inducing a potent vaccine effect against the cancer that can treat tumors which have not themselves come into contact with the virus. This includes potentially mopping up micro metastatic disease and vaccinating against relapse. Therefore, IMLYGIC is defined as an oncolytic immunotherapy because it has both of those two modes of action. IMLYGIC is based on herpes simplex virus 1, the virus which naturally causes cold sores, and in addition to having been engineered to have the property of replicating selectively in tumors, it also expresses a potent immune stimulatory cytokine called GM-CSF, the gene that augments the anti-tumor immune response further.

In which types of cancers has it been most effective?

Treatment with IMLYGIC should be applicable to really any type of solid tumor; there’s no specificity or selectivity for particular tumor types. So far, IMLYGIC has been approved in the U.S., Europe, Australia, and New Zealand for the treatment of advanced melanoma, where it was tested successfully in a phase III study, but it’s also being or has been tested in other cancer types too, including head and neck cancer and pancreatic cancer. So IMLYGIC is potentially broadly applicable to solid tumors in general, even though currently its approved just in melanoma.

What makes IMLYGIC unique?

The “immune checkpoint blockade” drugs release the brakes from a pre-existing immune response that a patient might have to the cancer, and therefore lets the patient’s own immune response to the cancer provide therapeutic benefit. I think one of the great things about IMLYGIC is not only that it works on its own, but that it’s also been found in both animal models and early clinical trials to be highly synergistic with these other approaches. This is because it can itself induce an immune response to the tumor, exactly as is needed for immune checkpoint blockade drugs to work. If you then combine it with something that further releases the brakes from that response, you’d expect to see a synergistic effect. Early clinical trials in melanoma conducted by Amgen in combination with Merck’s KEYTRUDA® and in combination with BMS’ YERVOY® have shown that synergy is probably occurring. And because of the exciting data already seen with IMLYGIC in combination with KEYTRUDA, there is already a phase III trial in 660 patients to test that combination. Hopefully, if that’s successful, it will lead to the routine use of the drugs together if the combination is then approved by the FDA.

What is the significance of cancer immunotherapies generally?

These new types of treatment have already rendered a number of very hard to treat or untreatable tumor types treatable, at least in some proportion of patients.

Undoubtedly these new types of treatment have been transformational for cancer patients. They add a completely new modality of treatment for oncologists to use. They have already rendered a number of very hard to treat or untreatable tumor types treatable, at least in some proportion of patients. This includes patients with melanoma and lung cancer and will no doubt include other tumor types soon. In relative terms, they’re also generally of low toxicity, which is great, although there are still problems when some of these drugs are combined together, which does seem to give the best therapeutic results.

How have patents been important to your research and career?

Filing and obtaining patents was absolutely critical. As a startup coming out of UCL in 1999, having patents filed was critical to obtaining the funding to start the company, and then continued to be critical for obtaining further rounds of venture capital funding over the years. Ultimately, prior to the acquisition of BioVex by Amgen, $140 million in venture capital funding was raised. Having strong patents was also critical to potential acquirers or partners for the technology as otherwise there would have been no monopoly position for the product, and others would have been able to directly copy it. Of course, in addition to having our own patents for IMLYGIC, it was also critical to have freedom to operate with respect to other company’s patents too, which is a completely different thing—negotiating that and carving out our own IP area was therefore critical in IMLYGIC ultimately being approved for use in cancer patients.

What do you think the next five to ten years holds for cancer treatment?

Carving out our own IP area was critical in IMLYGIC ultimately being approved for use in cancer patients.

I think the next five to ten years will be largely focused on working on the myriad of combinations of immuno-oncology drugs and targets that are possible, developing new drugs in the area, and teasing out which combinations provide the best balance of efficacy and lack of toxicity in different tumor types. The best combination for use in one tumor type may turn out to be very different to other tumor types, and in some cases combination of more than two of the drugs together, i.e., three or four drugs, may be needed. I also expect that eventually these drugs will be used earlier and earlier in a patient’s cancer, and I expect that we’ll end up with far more patients being cured of their cancer in an early stage, or at the very least making cancer more of a manageable chronic disease rather than a death sentence. This also means that fewer patients will be treated when they have extensive metastatic disease, particularly in organs such as the lung or the liver or brain, by which point the opportunity to effectively treat them has often been lost. In my view, we’re in the early days of the immuno-oncology era and there’s a long way to go, but I think the future is very bright.