The Great Fire of London started 350 years ago in September 1666 following a fire in a Pudding Lane bakery. It highlights the potential of what a small fire can do once it takes hold – over the course of 3 days, 13,000 houses and 436 acres were destroyed. It forever changed the landscape of medieval London.
The Monument (pictured right) to commemorate the Great Fire was designed by Sir Christopher Wren. Constructed from 1671 – 1677, it is 202 feet in height, the distance to the bakery where the fire started. You can even walk up it, if you are in the area.
When we think about cancer immunotherapy, one of the emerging important trends is the need to “inflame” or set fire to the immune system, especially in those cancer patients who don’t have a pre-existing immune response.
We want to ignite the immune system, in the hope that it will create the equivalent of the Great Fire…
In this post we’re starting at mini-series looking at neoantigens, beginning with a primer on what they are and why they matter in cancer immunotherapy. In subsequent posts we’ll look at some of the innovative ways companies are identifying and targeting them.
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Much has been written about the impact of cancer immunotherapies, particularly the twin pillars of checkpoint blockade and CAR T cell therapies, but beyond that lies a huge wealth of alternative approaches that may come in very useful indeed.
Just as we have seen oncogenic escape witth targeted therapies, there is also a related phenomenon called immune escape. Likewise, this can occur as either primary or secondary resistance.
It’s very important to consider this issue, because, after all, the vast majority of cancer patients with solid tumours do NOT see durable clinical benefit with immunotherapies when given as single agents. Some don’t respond at all (primary resistance), while others may see an initial response, then relapse (secondary resistance).
Understanding the mechanisms involved in resistance may help us design better combination trials to address the underlying biology as well as develop biomarkers to help select appropriate patients for each regimen. Clearly resistance can vary, not only by tumour type, but also by lesion and patient, making it a very complex situation to research.
Some interesting new information has recently come to light that is worthy of futher discussion and analysis, particularly in the context of other published data in this niche.
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There were so many posters worthy of further analysis and discussion at ASCO this year that we may well need to write a longer series than usual on some of these hidden gems!
If you’re anything like me, just getting round the massive poster hall melée each day in one piece to nab the QR codes and chat to some KOLs felt like an achievement in itself, never mind having the time to read and digest them properly. This is why it’s nice to sit down and process some of the findings afterwards because there was actually quite a lot to learn on the nuances with later reflection.
So what’s on deck in the hot seat today?
Here, we focus on the importance of the tumour microenvironment and how that can be manipulated so that subsequent therapy can be more effective.
Fortunately, there are a number of different approaches that can potentially achieve this lofty goal, at least preclinically, but what happens in the real world when these concepts are actually tested in people with cancer?
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We’ve noticed for a while now that trials involving immunotherapies have not just standard adverse events reported, but also immune related adverse events (irAEs). We saw these articulately in combination trials at ASCO earlier this month.
Most of these have involved colitis, hepatitis, pneumonitis and such like. If the signs and symptoms are picked up early through careful monitoring and education, these can be more easily managed and controlled.
What about auto-immune diseases?
Is there a risk of auto-immune disease with long term use usage of checkpoint blockade, especially in situations where patients may be treated until progression, which could be a long time if the patient is one of the lucky ones who get a durable complete response?
In today’s post we take a look at these issues. To learn more, subscribers can log in or you can sign up in the blue box below:
Continuing part two of our mini-series on colorectal cancer, today we move from the big scale Immunoscore study to small subsets of disease that are looking interesting in several ways.
For years, advanced colorectal cancer has been dominated by chemotherapy (FOLFOX or FOLFIRI) with and without targeted therapies (VEGF and EGFR antibodies), with very little new to talk about. Part of the challenge here is how do you add something the existing standard of care and move the needle significantly. In front-line, for example, the OS is already out 2-plus years, so these are long and risky trials to undertake. Not surpisingly, many companies have sought to evaluate their agents in tumour types where they consider the risk of development to be lower.
Unless… we can find creative approaches that turn the paradigm on its head and identify a clearly defined niche that can be carved out separately from allcomers.
This is where we’re at now – identifying subsets that might respond exquisitely to novel approaches based on a rational understanding of the underlying biology. One obvious subset might be BRAF, which can be treated with a BRAF inhibitor with or without other targeted therapies as Dr Pietrantonio and colleagues (2016) literally just showed for example, but what about others of potential interest?
Colorectal cancer with microsatellite stable (MSS) disease represents 95% of metastatic patients. These are people whose mismatched repair system is proficient and actively functional in fixing the DNA strand breaks that occur during the course of life.
In contrast, those with microsatellite instability (MSI) are the minority of people with colon cancer (and some other cancers too) whose mismatched repair system is deficient and unable to adequately repair the DNA strand breaks. Ironically, this leads to thousands of mutations that can be recognised by the immune system to help detect the presence of cancer. It also tends to occur in hereditary cancers such as Lynch Syndrome.
We’ve been following the MSI vs MSS story for a while now, but at ASCO this year there was more data available and things appear to be getting clearer on the commercial front too.
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The 10 abstracts selected here are actually not in order of magnitude, preference or weight… with the lone exception #1, an incredible piece of work that was a decade in the making.
Few of these choices are in the press briefing, none are in the Plenary session – they’re often hidden gems that many will miss in the hurly burly of the data drop and noise.
They’re also 10 abstracts that I feel are worthy of highlighting with some additional commentary.
Some of the ideas here illustrate some intriguing trends that are emerging, others may have a big impact on the cancer immunotherapy space, either because of the novel concept idea, or because the data are very compelling, if you understand the science.
You can decide for yourselves – which ones would you pick and why?
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One of the unintended consequences of the rise of cancer immunotherapy has been the fall in interest from patients who might be candidates for entry into clinical trials for other therapies, such as chemotherapy and targeted agents, for example.
A number of industry friends have uniformally expressed concern over how difficult it has been enroll such trials and bemoaned the broader – and often not anticipated – effect to the extent that some trials have even been terminated.
This situation often occurs, not because of lack of efficacy or severe side effects, but simply a lack of enthusiasm and low accrual rates. Quite a few patients consider chemo to be nothing short of ‘poison’ and don’t want anything to do with it as a result, unless it can be avoided.
Here’s my advice to those in this situation – stop moaning, start re-thinking, and re-positioning your agent in a different light to the investigators who enroll these studies. If they lack heart, in a highly competitive world, you have to stand out and thus, everything flows from the basic rationale of what you’re trying to accomplish.
What exactly do we mean by that?
Yesterday, we discussed one of the rate limiting steps in the cancer immunity cycle – getting more T cells into the tumours so that that subsequent immunotherapy can be even more effective.
One way to do that?
At AACR recently, we came across some intriguing ideas and approaches that are being discussed and explored, which may open many people’s eyes and minds. It rapidly became clear during discussions with several experts that all is not what it seems, and smart companies are already taking advantage of the new science that is emerging as well as a deeper understanding of the underlying biology of how the immune system behaves in cancer patients.
Here, we offer insights from our latest interview with a thought leader in the field for his perspective on how we can improve response rates and outcomes with cancer immunotherapy.
Fair warning: I must confess that it opened my own mind to fresh ideas and different approaches in an unexpected way – you may experience the same sentiments.
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In our post AACR analysis, I noticed some consistent observations across multiple talks and informal discussions with thought leaders.
Some of these ideas are pretty important and help us see the big picture for the near and medium term future in the cancer immunotherapy space.
The “Claws” sign we saw at the University of New Orleans sums things up!
Without much ado, it seems a good point to capture and summarise these ideas so that readers can compare notes and debate their thoughts too.
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Spring has arrived in many parts of the world, and with it I am always reminded of William Wordsworth’s classic poem, “I Wandered Lonely as a Cloud:”
I wandered lonely as a cloud
That floats on high o’er vales and hills,
When all at once I saw a crowd,
A host, of golden daffodils;
Beside the lake, beneath the trees,
Fluttering and dancing in the breeze.
So what does the future hold for cancer immunotherapy?
Inspired by Wordsworth, I’ve sat on my cloud and have looked at some of the recent review papers and thought pieces published by experts in the field. Do they offer a Jerry Maguire – like mission statement: “The Things We Think and Do Not Say: The Future of Our Business” or will we have to wait till AACR 2016 in New Orleans to learn more?
This is the latest in our pre-AACR 2016 annual meeting series. Subscribers can login to read more or you can purchase access below.
Updated data are often presented at conferences and therefore the results can differ from the submitted abstracts, which are sometimes submitted as placeholders based on immature data cutoffs. That was certainly the case in several examples at the ASCO GI conference in San Francisco last weekend.
After Monday’s look at new developments in the lower GI tract, we now turn our attention today to the upper GI tract with a focus on oesophageal, gastric (stomach), and gastro-esophageal junction (GEJ) cancers.
Over the last five years we have seen new approvals for targeted therapies such as HER2+ gastric cancer and relapsed refarctory gastric cancers with a VEGF inhibitor. Will that trend continue over the next five years or will we see new approaches such as immunotherapy enter the market and dominate?
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