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Borrowed Immune Cells to Fight Cancer

It is an unfortunate fact of life that many promising avenues of medical research languish partially developed and unfunded. It isn't unusual to see potentially transformative medical technologies linger with little further progress for a decade or more after their first triumphant discovery. The innovative antiviral DRACO technology is one such, offering the potential of therapies for persistent infections that cannot currently be treated. Another is the use of immune cell transplants to attack cancer, presented in its initial form of granulocyte infusion therapy (GIFT) with accompanying compelling animal data at the third SENS conference in 2007, but under development for years prior to that point. Where is this approach to cancer treatment today, nearly a decade down the line? Little advanced beyond that point, I'm sorry to say. In fact so little progress has occurred and so little attention has been given to this style of cancer treatment that other researchers are now and then independently finding their way to the same place from different directions, as noted in the paper and publicity materials that are linked below.

Why does this waste of potential continue to happen over and again in the field of medical research and development? One challenge is that a life in the fairly rigid hierarchy of the sciences is typically poor preparation for the cut and thrust of bringing a new technology into the marketplace, raising funding outside the established channels of grants, and working with businesses. That is an entirely different set of skills and talents. Some scientists have those skills and talents, and you'll tend to see those people starting companies or leading laboratories. Most do not - just as there are few entrepreneurs and leaders in the general population, there are also few entrepreneurs and leaders within the scientific community. There are only so many hours in the day, time spent on one set of skills is not spent on another, and science is a demanding partner. Just because a team makes a solid advance in their field doesn't mean they are well positioned or qualified to make it a success after that point.

Another issue, important in this case, is that the combination of heavy regulation of medicine, regulatory capture, and the consequent dominance of very conservative large developers and very expensive development processes means that medicine rarely moves forward for any potential treatment in which the biochemical mechanisms cannot be explained. Ten years ago, there was no good explanation for why GIFT was so good at defeating cancer in mice. Progress within the system and the present cultural edifice of cancer research required that explanation - the idea of moving ahead based purely on great results doesn't win you support from Big Pharma, and without that support there are few organizations with deep enough pockets to move ahead through the burdensome FDA processes as they stand these days. So while there have been trials of immune infusion therapies for cancer, these were small and funded from other sources. That backing is not extensive. There have been some signs of availability in the medical tourism space, but without more of a mainstream interest in the field that is also so far anemic.

An entirely different class of problem contributing to the existence of moribund fields of research is the lack of funding and attention given to medical research in general. Very little of medical research is funded to anywhere near a reasonable level given the potential expectations for resulting benefits. To a first approximation, no-one cares about medical research and medical progress, or at least not until it is far too late to do anything about it. Research survives on the scraps and margins of philanthropy of this wealthy society. Bread and circuses before progress, and near all of the money in medicine goes towards using the technology that exists, even when there are much better alternatives within reach, just a few years of development away.

Fighting cancer with the help of someone else's immune cells

Researchers decided to test whether a "borrowed immune system" could "see" the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments - also known as neo-antigens - on their surface, much in the way virus-infected cells express fragments of viral proteins. To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient's tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients' T cells. "In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens. The receptor that is used by these donor T-cells can then be used to genetically modify the patient's own T cells so these will be able to detect the cancer cells. Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput."

Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen specific T cell responses are therefore attractive. Here, we demonstrate that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11/57 predicted HLA-A2-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes. Finally, T cells re-directed with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such "outsourced" immune responses in cancer immunotherapy.

Comments

So an analogy to the current situation with medical drugs is perhaps Black Cab drivers in London? They have to sit a super tough (and unnecessary) test called the knowledge, which takes about three years to learn. They probably don't enjoy having to pay the cost (in time) of doing this, but once they are registered this barrier prevents other taxi drivers from easily entering the London market, creating an oligopoly.

Medicine is perhaps even worse off as the regulators have little incentive to contain the cost of testing.

Posted by: Jim at May 27th, 2016 11:07 AM

What I don't understand is why respective scientists don't move abroad and offer their experimental therapies via medical tourism. If these therapies work, money will be no issue anymore.

Posted by: Claus Elser at May 27th, 2016 11:57 AM

@Jim: Haha and spot on. We now just really need a biomedical Uber.

Posted by: Barbara T. at May 27th, 2016 2:00 PM

@Claus - I'd guess that once scientists take the overseas path they'd lose funding for research from the institute they are at (if it is publicly funded).

Also, I doubt many people would buy medical treatments that have only been tested in animals. Loads of drugs fail to make the leap from animals to humans. Using better animal models such as pigs may help with the leap. But you'd still need to get a stage 1 safety trial done.

On the other hand, if clinical trials are over the top at present, why do so many drugs seem to flame out in stage 3 trials?

Posted by: Jim at May 27th, 2016 4:18 PM

@Jim: Yes, moving abroad and offering experimental treatment will likely get you excommunicated from the scientific community. On the other side it should not be forgotten that many patients still die from cancer and many of them don't care about the risk of experimental treatment since their disease is fatal anyway. In addition to this, chemotherapy is not very pleasant and often not very effective and we already have lots of medical tourism to other countries. Unfortunately, the therapies that are offered abroad, often don't work. As soon as this changes, the whole field of medical tourism will change.

Posted by: Claus Elser at May 28th, 2016 4:28 PM

We all recognize the problem of restrictive regulation slowing down medical progress. I'm just not sure how to bring about a change to it. That issue is not important to any of the political parties in the US (I believe it's a similar non-issue in much of Europe). I'm not trying to be defeatist about it, I'm just wondering what is a realistic path to actually changing it? Or is attempting to sidestep the whole process by private funding and medical tourism the only option?

Posted by: KC at June 1st, 2016 2:21 PM

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