The Shape of Things to Come?

One of the problems of trying to keep up with cancer – and indeed helping others to do so – is that you (i.e. ‘I’) get really irritated with the gentlemen and ladies of the press for going over the top in their efforts to cover science. I have therefore been forced to have a few rants about this in the past – actually, when I came to take stock, even I was a bit shocked at how many. Heading the field were Not Another Great Cancer Breakthough, Put A Cap On It and Gentlemen… For Goodness Sake. And not all of these were provoked by The Daily Telegraph!

If any of the responsible reporters read this blog they probably write me off as auditioning for the Grumpy Old Men tv series. But at least one authoritative voice says I’m really very sane and balanced (OK, it’s mine). Evidence? The other day I spotted the dreaded G word (groundbreaking) closely juxtaposed to poor old Achilles’ heel – and yes, it was in the Telegraph – but, when I got round to reading the paper, I had to admit that the work referred to was pretty stunning. Although, let’s be clear, such verbiage should still be banned.

A Tumour Tour de Force

The paper concerned was published in the leading journal Science by Nicholas McGranahan, Charles Swanton and colleagues from University College London and Cancer Research UK. It described a remarkable concentration of current molecular fire-power to dissect the fine detail of what’s going on in solid tumours. They focused on lung cancers and the key steps used to paint the picture were as follows:

1. DNA sequencing to identify mutations that produced new proteins in tumour cells (called tumour-associated antigens or ‘neoantigens’ – meaning molecular flags on the cell surface that can provoke an immune response – i.e. the host makes antibody proteins that react with (stick to) the antigens). Typically they found just over 300 of these ‘neoantigens’ per tumour – a reflection of the genetic mayhem that occurs in cancer.

2 tumoursVariation in neoantigen profile between two multi-region sequenced non-small cell lung tumours. There were approximately 400 (left) and 300 (right) neoantigens/tumour

  • Blue: proportion of clonal neoantigens found in every tumour region.
  • Yellow: subclonal neoantigens shared in multiple but not all tumour regions.
  • Red: subclonal (‘private’) neoantigens found in only one tumour region.
  • The left hand tumour (mostly blue, thus highly clonal) responded well to immunotherapy (from McGranahan et al. 2016).

2. Screening the set of genes that regulate the immune system – that is, make proteins that detect which cells belong to our body and which are ‘foreign.’ This is the human leukocyte antigen (HLA) system that is used to match donors for transplants – called HLA typing.

3. Isolating specialised immune cells (T lymphocytes) from samples of two patients with lung cancer, growing them in the lab to expand the population and testing how good these tumour-infiltrating cells were at recognizing the abnormal proteins (neo-antigens) on cancer cells.

4. Detecting proteins released by different types of infiltrating T cells that regulate the immune response. These include so-called immune checkpoint molecules that limit the extent of the immune response. This showed that T cell subsets that were very good at recognizing neo-antigens – and thus killing cancer cells (they’re CD8+ T cells or ‘killer’ T cells) also made high levels of proteins that restrain the immune response (e.g., PD-1).

5. Showing that immunotherapy (using the antibody pembrolizumab that reacts with PD-1) could significantly extend survival of patients with advanced non-small cell lung cancer. We’ve already met this approach in Self-help Part 1.

The critical finding was that the complexity of the tumour (called the clonal architecture) determines the outcome. Durable benefit from this immunotherapy requires a high level of mutation but a restricted range of neo-antigens. Put another way, tumours that are highly clonal respond best because they have common molecular flags present on every tumour cell.

6. Using the same methods on some skin cancers (melanomas) with similar results.

What did this astonishing assembly of results tell us?

It’s the most detailed picture yet of what’s going on in individual cancers. As one of the authors, Charles Swanton, remarked “This is exciting. This opens up a way to look at individual patients’ tumours and profile all the antigen variations to figure out the best ways for treatments to work. This takes personalised medicine to its absolute limit where each patient would have a unique, bespoke treatment.”

He might have added that it’s going to take a bit of time and a lot of money. But as a demonstration of 21st century medical science it’s an absolute cracker!

References

McGranahan et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 10.1126/science.aaf490 (2016).

 

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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.