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

Self Help – Part 1

It’s not easy to find good things to say about cancer and humour is equally elusive, as those of us who lecture on the subject know very well. But most people are aware of one cheering fact: cancers aren’t transmissible between humans – that is, they’re not like ’flu, venereal diseases and lots of other nasty things we pass around. Thus, if you transplant tumours from one animal to another of the same species (usually mice) generally they don’t grow – in much the same way that transplanted organs (livers, etc.) are rejected by the recipient’s immune system. Transplant rejection occurs because the body mounts an immune response to the foreign (i.e. ‘non-self’) organ: transplantation works when that is reduced by matching donor to recipient as closely as possible and combining that with immunosuppressant drugs.

But here’s an obvious thought: if tumours transferred between animals don’t grow, their immune systems must be doing a pretty good job of recognizing them as ‘non-self’ and killing them off. If that’s true, how about trying to boost the immune response in cancer patients as a therapeutic strategy? It’s such a good idea it’s become the trendiest thing in cancer science, the field being known as immunotherapy.

Immunotherapy

The aim is to give a patient’s immune response a helping hand so it can kill their tumours. The stars of the show are a subset of white blood cells called T lymphocytes: that’s because some of them have the power to kill – they’re ‘cytotoxic T cells’. So the simple plan is to boost either the number or the efficiency of these tumour-killing T cells. The story is complicated by there being lots of sub-types of T cells – most notably T Helper cells (that do what their name suggests: activate cytotoxic T cells) and Suppressor T cells that shut down immune responses.

To get the hang of immunotherapy we need only focus on ways of boosting T Helpers but in passing we can hardly avoid asking “why so complicated?” Well, the immune system has evolved on a tight-rope, trying on the one hand to kill invading organisms whilst, on the other, leaving the cells and tissues of the host untouched. It works amazingly well but it can fall off both ways when either it’s overcome by the genomic gymnastics of cancer or when it exceeds its remit and causes auto-immune diseases – things like type 1 diabetes in which the immune system destroys the cells in the pancreas that make insulin.

Shifting the balance

We’ve seen that T cells (of all varieties) are among the ‘groupies’ attracted to the scene of growing solid tumours (in Cooperative Cancer Groupies and Trouble With The Neighbours) and so the name of the game is how to tweak the balance in that environment towards more efficient tumour cell killing.

Broadly speaking, there are two forms of cancer immunotherapy. In one T cells are removed from the patient, grown to large numbers and then put back into the circulation – called ‘adoptive cell therapy’, we’ll come to it in Part 2. The more widespread approach, sometimes called ‘checkpoint blockade’, uses agents that block inhibitory pathways switched on by tumours – in effect releasing molecular brakes that prevent T cell hyperactivity and autoimmunity. So ‘checkpoint blockade’ is a systemic method – drugs are administered that diffuse throughout the body to find their targets, whereas next time we’ll be talking about ‘personalized medicine’ – using the patient’s own cells to fight his cancer.

There’s one further method – viral immunotherapy – which I wasn’t going to mention but has been in the news lately to the extent that I feel obliged to make a trio with “Blowing Up Cancer” to follow Parts 1 & 2.

There’s nothing new about this general idea. Over 100 years ago the New York surgeon William Coley noticed that occasionally tumours disappeared when patients accidentally picked up post-operative bacterial infections and, from bugs grown in the lab, he made extracts that, injected into solid tumours, caused about one in ten of them to regress, with some patients remaining well for many years thereafter.

A new era

Even so, it took until 1996 before it was shown that blocking an inhibitory signal could unleash the tumour killing power of T cells in mice and it was not until 2011 that the first such agent was approved by the U.S. Food and Drug Administration for treating melanoma. In part the delay was due to the ‘agent’ being an antibody and the time taken to develop ‘humanized’ versions thereof. Antibodies (aka immunoglobulins) are large, Y-shaped molecules made by B lymphocytes that bind with high specificity to target molecules – antigens – humanized forms being engineered so that they are made almost entirely of the human protein sequence and therefore do not provoke an immune response.

92 FigCheckpoint Blockade Activates Anti-Tumour Immunity

Interactions between Receptors A and a suppress T cell activity. Antibodies to these receptors block this signal and restore immune activity against tumour cells.

Unblocking the block

We picture the tumour microenvironment as a congregation of various cell types with chemical messengers whizzing to and fro between them. In addition, some protein (messenger) receptors on cell surfaces talk to each other. The receptors themselves become messengers thus drawing the cells together – essential to bring killer cells into contact with their target. You can think of all these protein-protein interactions as keys inserting into locks or as molecular handshakes – a coming together that passes on information. Antibodies come into their own because they bind to their targets just as avidly as the normal signaling molecules – so they’re great message disruptors.

The sketch shows in principle how this works for two interacting receptors, A and a. The arrival of a specific antibody (anti-A or anti-a) puts a stop to the conversation – and if the upshot of the chat was to decrease the immune response, bingo, we have it! Targeting a regulatory pathway with an antibody enhances anti-tumour responses.

Putting names to targets, CTLA-4 and PD-1 are two key cell-surface receptors that, when engaged, trigger inhibitory pathways and dampen T-cell activity. Antibodies to these (ipilimumab v. CTLA-4; pembrolizumab and nivolumab v. PD-1) have undergone a number of clinical trials and the two in combination have given significant responses, notably for melanoma. So complex is immune response control that it presents many targets for manipulation and a dozen or so agents (mostly antibodies) are now in various clinical trials.

Déjà vu

So the era of immunotherapy has well and truly arrived but, as ever with cancer, it is not quite time to break open the champagne and put our feet up. Whilst combinations of antibodies have given sustained responses, with some patients remaining disease-free for many years, at the moment immunotherapy has only been shown to work in subsets of cancers and even then only a small fraction (about 25%) of patients respond. My correspondent Dr. Markus Hartmann has pointed out that the relatively limited improvements in survival rates following immunotherapy might be significantly enhanced if we took into account the specific genetic background of patients and determined which genes of interest are expressed or switched off. This information should reveal why some patients benefit from immunotherapy whilst others with clinically similar disease do not.

The challenge, therefore, is to characterise individual tumours and their supporting bretheren in terms of the cell types and messengers involved so that the optimal targets can be selected – and, of course, to make the necessary agents. It’s a tough ask, as the sporting fraternity might put it, but that’s what science is about so onwards and upwards with William Coley’s words of 105 years ago writ large on the lab notice board: “That only a few instead of the majority showed such brilliant results did not cause me to abandon the method, but only stimulated me to more earnest search for further improvements in the method.”

I’m grateful to Dr. Markus Hartmann  (Twitter: @markus2910) for constructive comments about this post.

References

Coley, W. B. (1910). The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proceedings of the Royal Society of Medicine  3, 1-48.

Twyman-Saint Victor, C. et al. (2015). Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377.

Wolchok, J.D. et al. (2013). Nivolumab plus Ipilimumab in Advanced Melanoma. N. Eng. J. Med., 369, 122-133.