Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Colorectal’ category

We have a two part mini-series this week exploring an approach on how to boost T cells in cold tumours. There are a number of different ways to do this, including adding them ex vivo such as via CAR T cell therapies, although this technique has yet to yield durable benefit in solid tumours.

So how else can it be done?

We’ve discussed immune agonists, oncolytic viruses and cancer vaccines in the past so now it’s time for something different…

In Part 1 of the series today, we explore the science behind the technology and some of the early clinical data that was recently presented at medical meetings.

In Part 2 tomorrow, we have not one but three, different voices exploring some researchers thoughts on where the approach might go.

It should make for interesting reading!

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San Francisco: In the final post of the week, it’s time to focus on some of the interesting concepts and early ideas being explored in GI tumours such as pancreatic and colorectal carcinomas.

Gems from the Poster Hall or what Dog Drug Heaven really looks like?

Despite the image implied by the used poster bins (right), there were actually several encouraging signs from emerging IO approaches as well as some surprising results that lead to some compounds – or at least some indications – going off to dog drug heaven.

There were also some salutory lessons to be learned in terms of understanding biomarkers and useful these can be.

After years of incremental improvements with targeted therapies, it’s time to look at whether some immunotherapy combinations can make an impact in what is known as cold tumours.

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San Francisco: ASCO Gastrointestinal symposium 2017 – Update on metastatic colorectal cancer

It might surprise quite a few people that colorectal cancer (CRC) is the third most commonly diagnosed cancer globally, especially in the western hemisphere where hereditary, dietary and lifestyle factors can be important.

The bedrock of therapeutic approaches in this disease have largely centred around chemotherapy (FOLFOX or FOLFIRI) along with targeted therapies against EGFR (cetuximab, panitumumab) or VEGF (bevacizumab, ziv-aflibercept, regorafenib etc).

In our second report from #GI17, we take a look at some of the emerging monotherapy and combination approaches that are showing early signs of moving the needle in advanced CRC, an area that has been relatively dormant of late.  This is partly because it’s a cold tumour and with the focus on cancer immunotherapies, it’s not the first tumour type that companies will necessarily rush to evaluate.

Things are changing though, even in colorectal cancer so it’s time to look at some key studies that may teach us more about this disease.

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This week in our colorectal cancer mini-series we have covered the validation of Immunoscore as a tool for determining which patients have high T cells in their tuours and are therefore candidates for single agent immunotherapy (Link), as well as microsatellite instability (MSI) and mismatch-repair deficient tumours and how they can respond immunotherapy (Link).

What happens in the majority (95%) of patients, the microsatellite stable (MSS) disease who are mismatch-repair proficient though?  They don’t respond well to checkpoint blockade so how can we help them?

Dr Johanna Bendell ASCO 2016In Chicago, BSB interviewed Dr Johanna Bendell from the Sarah Cannon Research Institute in Nashville, Tennessee to find out more about what she and her colleagues have been doing and where they plan to go next.

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ASCO 2016 Collective WisdomContinuing 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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We’ve been following the work of Dr Jérôme Galon, a French immunologist, on Immunoscore for a while now, and many readers will remember the last interview he kindly gave BSB from the European Cancer Conference in September [Link].

IMG_6454In 2015 the large global trial to validate Immunoscore as a biomarker was still ongoing, so if you want some background to this important concept, do check out Dr Galon’s interview as it’s well worth reading as a primer on immunosurveillance, the importance of immune cells – the type, density and location, as well as background on the Immunoscore test as a marker of outcome.

Since then, the group have also published some related data that both moves the field forward and offers a way to unify some important concepts in colorectal cancer.

In Chicago, the really good news was that the final results of a large global study involving nearly 4,000 patients were presented to a packed audience in the main hall where the plenary is held. It’s not often you see the gastrointestinal oral session allocated the prime time room over lung or breast cancers – the atmosphere was certainly electric with anticipation!

This week’s post ASCO mini series focuses on colorectal cancer, with a look at several important aspects of this disease as we learn more about the underlying biology, as well as how the immune system functions and how we can use that scientific knowledge to improve outcomes for patients, sometimes in a dramatic way.

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Driving St Charles StreetcarAfter exploring the science behind chemotherapy improving T cell trafficking into the tumour yesterday – which is one of the key rate limiting issues that need to be addressed with immunotherapies such as checkpoint blockade – some obvious follow-up questions comes to mind:

  1. Does the compelling data in mice translate to humans?
  2. Can chemotherapy turn a cold tumour into a hot one?
  3. Will patients have improved outcomes as a result – or not?

It’s easy to dismiss traditional therapies in favour of appealing new developments, but what happens when we combine them?  Do we get additive effects, synergies or a negative impact?

As part of our ongoing AACR coverage, we explored this conundrum in the context of new data readouts, as well as the broader competitive landscape.

What we found was really interesting!

BMS, Merck and Genentech/Roche all have trials ongoing in the metastatic colorectal cancer space, with very different approaches being taken.  Does it matter?  Which one’s driving the bus?  We summarise these trials and offer some strategic insights on this niche.

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One thing has become very clear in the oncology space over the last year… checkpoint inhibitors are insufficient on their own for the vast majority of tumour types and patients that they have been explored in to date.  There are a number of reasons for this, but the main one is lack of T cells in the tumour, which enable an effective immune response to be mounted.

This begs the question – how can we address that issue and manipulate the tumour microenvironment in our favour, thereby making subsequent checkpoint blockade more effective?

There are a number of different ways to do this.

In the past, we’ve discussed several methods including innate immunotherapies such as Aduro’s STING or Biothera’s immunotherapeutic, Imprime PGG.  Other approaches include vaccines, which we have discussed in detail, t-cell receptors (TCR) or even monoclonal antibodies, such as AdaptImmune’s approach with their ImmTac technology.

There are other novel strategies currently being investigated by numerous companies too.

In this article – and also the second part of the latest miniseries – which will post tomorrow, we straddle our final reviews of interesting data from the European Cancer Conference (ECC) in Vienna with the upcoming one from the Society of Immunotherapy for Cancer (SITC) being held in National Harbor, Maryland.

Today’s post explores the concept of immunocytokines, engineered antibodies that are designed to boost the immune system, so that subsequent therapies will be more effective.

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For some time now there has been much debate about finding a predictive biomarker of response for EGFR monoclonal antibodies used in the treatment of advanced colorectal cancer.  These include cetuximab (Erbitux) and panitumumab (Vectibix).

After all, we know that they tend to work in wild type disease (as shown in the US label below) and that KRAS and NRAS mutations on codon 12 and 13 on exon 2, as well as others on exon 3 and 4 tend to portend resistance to therapy, but beyond that not much is known.

Cetuximab v2

At the European Cancer Conference in Vienna last month I was intrigued to see some new data emerge that may help researchers better understand and predict which people with metastatic colon cancer are more likely to respond in the future.

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Continuing our series on the ASCO GI meeting, today marks the end of the conference coverage with an interesting look at overcoming resistance to EGFR therapies such as Erbitux and Vectibix.

One of the hallmarks of EGFR monotherapy in colorectal cancer is stable disease with eventual relapse, but few dramatic responses. This suggests that other factors may play a role in driving oncogenic activity.

Dr Tejpar, Leuven

Dr Tejpar, Leuven

Recently, patient derived xenografts (PDX) have begun to play an increasingly important role in helping to understand the biology of the disease and facilitate improved trial design.

Earlier this week, we discussed the molecular characterisation of the disease based on the keynote talk by Dr Sabine Tejpar. Her group in Belgium as well as others in Italy and Spain have been very active in European translational work in this area to identify and map the pathways influencing EGFR therapy in GI cancers.

What can we learn from the latest findings in this space?

The answer may well surprise you.

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