Invisible Army Rouses Home Guard

Writing this blog – perhaps any blog – is an odd pastime because you never really know who, if anyone, reads it or what they get out of it. Regardless of that, one person that it certainly helps is me. That is, trying to make sense of the latest cancer news is one of the best possible exercises for making you think clearly – well, as clearly as I can manage!

But over the years one other rather comforting thing has emerged: more and more often I sit down to write a story about a recent bit of science only to remember that it picks up a thread from a piece I wrote months or sometimes years ago. And that’s really cheering because it’s a kind of marker for progression – another small step forward.

Thus it was with this week’s headline news that a ‘cancer vaccine’ might be on the way. In fact this development takes up more than one strand because it’s about immunotherapy – the latest craze – that we’ve broadly explained in Self Help Part-1Gosh! Wonderful GOSH and Blowing-up Cancer and it uses artificial nanoparticles that we met in Taking a Swiss Army Knife to Cancer.

Arming the troops

What Lena Kranz and her friends from various centres in Germany described is yet another twist on the idea of giving our inbuilt defence – i.e. the immune system – a helping hand to tackle tumours. They made small sacs of lipid called nanoparticles (they’re so small you could get 300 in the width of a human hair), loaded them with bits of RNA and injected them into mice. This invisible army of fatty blobs was swept around the circulatory system whereupon two very surprising things happened. The first was that, with a little bit of fiddling (trying different proportions of lipid and RNA), the nanoparticles were taken up by two types of immune cells, with very little appearing in any other cells. This rather fortuitous result is really important because it means that the therapeutic agent (nanoparticles) don’t need to be directly targetted to a tumour cell – thus avoiding one of the perpetual problems of therapy.

The second event that was not at all a ‘gimme’ was that the immune cells (dendritic cells and macrophages) were stimulated to make interferon and they also used the RNA from the nanoparticles as if it was their own to make the encoded proteins – a set of tumour antigens (tumour antigens are proteins made by tumour cells that can be useful in identifying the cells. A large number of have now been found: one group of tumour antigens includes HER2 that we met as a drug target in Where’s That Tumour?)

The interferon was released into the tumour environment in two waves, bringing about the ‘priming’ of T lymphocytes so that, interacting via tumour antigens, they can kill target cells. By contrast with taking cells from the host and carrying out genetic engineering in the lab (Gosh! Wonderful GOSH), this approach is a sort of internal re-wiring achieved by giving a sub-set of immune system cells a bit of genetic code (in the form of RNA).

TAgs RNA Nano picNanoparticle cancer vaccine. Tiny particles (made of lipids) carry RNA into cells of the immune system (dendritic cells and macrophages) in mice. A sub-set of these cells releases a chemical signal (interferon) that promotes the activation of T lymphocytes. The imported RNA is translated into proteins (tumour antigens) – that are presented to T cells. A second wave of interferon (released from macrophages) completes T cell priming so that they are able to attack tumour cells by recognizing antigens on their surface (Kranz et al. 2016; De Vries and Figdor, 2016).

So far Kranz et al. have only tried this method in three patients with melanoma. All three made interferon and developed strong T-cell responses. As with all other immunotherapies, therefore, it is early days but the fact that widely differing strategies give a strong boost to the immune system is hugely encouraging.

Other ‘cancer vaccines’

As a footnote we might add that there are several ‘cancer vaccines’ approved by the US Food and Drug Administration (FDA). These include vaccines against hepatitis B virus and human papillomavirus, along with sipuleucel-T (for the treatment of prostate cancer), and the first oncolytic virus therapy, talimogene laherparepvec (T-VEC, or Imlygic®) for the treatment of some patients with metastatic melanoma.

How was it for you?

As we began by pointing out how good writing these pieces to clarify science is for me, the question for those dear readers who’ve made it to the end is: ‘How did I do?’

References

Kranz, L.M. et al. (2016). Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature (2016) doi:10.1038/nature18300.

De Vries, J. and Figdor, C. (2016). Immunotherapy: Cancer vaccine triggers antiviral-type defences.Nature (2016) doi:10.1038/nature18443.

 

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Blowing Up Cancer

To adapt the saying of the sometime British Prime Minister Harold Wilson, a month is a long time in cancer research. {I know, you’ve forgotten – as well you might. He was PM from 1964 to 1970 and again from 1974 to 1976. His actual words were “A week is a long time in politics”}. When I started to write the foregoing Self Helps (Parts 1 & 2) I had absolutely no intention of mentioning the subject of today’s sermon – viral immunotherapy. But how times change and a recent report has hit the headlines – so here goes.

The reason for my reticence is that this is not a new field – far from it. Folk have been trying to target tumour cells with active viruses for twenty years but efforts have foundered to the extent that the new report is the first time in the western world that a phase III trial (when a drug or treatment is first tested on large groups of people) of cancer “virotherapy” has definitively shown benefit for patients with cancer, although a virus (H101) made by the Shanghai Sunway Biotech Co. was licensed in China in 2005 for the treatment of a range of cancers.

Hard bit already done

I appreciate that getting the hang of immunotherapy in the two Self Helps wasn’t a total doddle – but it was worth it, wasn’t it, bearing in mind we’re dealing with life and death here. My friend and correspondent Rachel Bown had to resort to her GCSE biology notes (since she met me I think she keeps them on the coffee table) but is now up to speed.

Fortunately this bit is pretty easy to follow – it’s just an extension of the viral jiggery-pokery we met in Self Help Part 2. There we saw that using ‘disabled’ viruses is a neat way of getting new genetic material into cells. The viruses have key bits of their genome (genetic material) knocked out – so they don’t have any nasty effects and don’t replicate (make more of themselves) once inside cells. Inserting new bits of DNA carrying a therapeutic gene turns them into a molecular delivery service.

Going viral

In virotherapy there’s one extra wrinkle: the viruses, though ‘disabled’, still retain the capacity to replicate – and this has two effects. First, more and more virus particles (virions) are made in an infected cell until eventually it can hold no more and it bursts. The cell is done for – but a secondary effect is that the newly-made virions spill out and drift off to infect other cells. This amplifies the effect of the initial injection of virus and, in principle, will continue as long as there are cells to infect.

A new tool

The virus used is herpes simplex (HSV-1) of the relatively harmless type that causes cold sores and, increasingly frequently, genital herpes. The reason for this choice is that sometimes, not very often, science gets lucky and Mother Nature comes up with a helping hand. For HSV-1 it was the completely unexpected discovery that when you knock out one of its genes the virus becomes much more effective at replicating in tumour cells than in normal cells. That’s a megagalactic plus because, in effect, it means the virus targets tumour cells, thereby overcoming one of the great barriers to cancer therapy. In this study another viral gene was also deleted, which increases the immune response against infected tumour cells.

All this cutting and pasting (aka genetic engineering) is explained in entertaining detail in Betrayed by Nature but for now all that matters is that you end up with a virus that:

  1. Gets into tumour cells much more efficiently than into normal cells,
  2. Makes the protein encoded by the therapeutic gene, and
  3. Replicates in the cells that take it up until eventually they are so full of new viruses they go pop.

The finished product, if you can get your tongue round it, goes by the name of talimogene laherparepvec, mercifully shortened by the authors to T-VEC (made by Amgen). So T-VEC mounts a two-pronged attack – what the military would call a pincer movement. Infected tumour cells are killed (they’re ‘lysed’ by viral overload) and the inserted gene makes a protein that soups up the immune response – called GM-CSF (granulocyte macrophage colony-stimulating factor). The name doesn’t matter: what’s important is that it’s a human signaling molecule that stimulates the immune system, the overall result being production of tumour-specific T cells.

Fig. 1 Viral Therapy

Virotherapy. Model of a virus (top). The knobs represent proteins that enable the virus to stick to cells. Below: sequence of injecting viruses that are taken up by tumour cells that eventually burst to release new virions that diffuse to infect other tumour cells.

And the results?

The phase III trial, led by Robert Andtbacka, Howard Kaufman and colleagues from Rutgers Cancer Institute of New Jersey, involved 64 research centres worldwide and 436 patients with aggressive, inoperable malignant melanoma who received either an injection of T-VEC or a control immunotherapy. Just over 16% of the T-VEC group showed a durable response of more than six months, compared with 2% given the control treatment. About 10% of the patients treated had “complete remission”, with no detectable cancer remaining – considered a cure if the patient is still cancer-free five years after diagnosis.

Maybe this time?

We started with Harold Wilson and it was in between his two spells in Number 10 that President Nixon declared his celebrated ‘War on Cancer’, aimed at bringing the major forms of the disease under control within a decade or two. It didn’t happen, as we might have guessed. Back in 1957 in The Black Cloud the astrophysicist Sir Fred Hoyle has the line ‘I cannot understand what makes scientists tick. They are always wrong and they always go on.’ To be fair, it was a science fiction novel and the statement clearly is only partly true. But it’s not far off and in cancer there’s been rather few of the media’s beloved ‘breakthroughs’ and a great deal of random shuffling together with, overall, some progress in specific areas. Along the bumpy highway there have, of course, been moments of high excitement when some development or other has briefly looked like the answer to a maiden’s prayer. But with time all of these have fallen, if not by the wayside, at least into their due place as yet another small step for man. The nearest to a “giant leap for mankind” has probably been coming up with the means to sequence DNA on an industrial scale that is now having a massive impact on the cancer game.

When Liza Minnelli (as Sally Bowles in Cabaret) sings Maybe this time your heart goes out to the poor thing, though your head knows it’ll all end in tears. But this time, maybe, just maybe, the advent of cancer immunotherapy in its various forms will turn out to be a new era. Let us fervently hope so but, even if it does, the results of this Phase III trial show that a long struggle lies ahead before treatments arrive that have most patients responding.

We began Self Help – Part 1 with the wonderful William Coley and there’s no better way to pause in this story than with his words – reminding us of a bygone age when the scientist’s hand could brandish an artistic pen and space-saving editors hadn’t been invented:

“While the results have not been as satisfactory as one who is seeking perfection could wish, … when it comes to the consideration of a new method of treatment for malignant tumours, we must not wonder that a profession with memories overburdened with a thousand and one much-vaunted remedies that have been tried and failed takes little interest in any new method and shows less inclination to examine into its merits. Cold indifference is all it can expect, and rightly too, until it has something beside novelty to offer in its favour.”

References

Mohr, I. and Gluzman, Y. (1996). A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. The EMBO Journal 15, 4759–66.

Andtbacka, R.H.I. et al. (2015). Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. 10.1200/JCO.2014.58.3377