Biotech Strategy Blog

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

Posts tagged ‘TGF-beta’

Remember the good old days at ESMO17 in Madrid? Sadly there’s no face to face networking at this year’s ESMO20 virtual meeting!

In this third ESMO 2020 Preview the focus is on early stage immunotherapies – we’ll cover targeted therapies in a separate review article.

As new regimens evolve involving multiple immune targets, this complexity brings with it a greater need to understand cell-cell interactions – not just immune cell relationships, but also oncogenic, metabolic, and even epigenetic ones. How do they all fit together and what happens when we interfere with those relationships therapeutically?

Often the simple answer is we don’t know until we head into the clinic, I’m afraid.

Beyond the obvious phase 3 IO readouts in the various Presidential symposia and Proffered oral sessions there are quite a few emerging ideas – old ones with a twist as well as entirely new ones – which we can consider and discuss.

Here, we highlight five key IO areas related to cancer immunotherapy and explore the various concepts as preparation for the upcoming meeting…

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Yesterday, we started the first of a multi-part mini series on STING agonism with a quick look at the broad landscape and some of the competitors in this space, which has definitely grown over the last four years since we first wrote about the STING/cGAS pathway.

In the latest part of the STING series, we talk to a small, privately held biotech who are developing a slightly different approach to the first generation agonists currently in early phase clinical trials.

One goal that many are looking at with STING agonism is to try and take less inflamed tumours and turn them into inflamed ones (or cold to hot in layman’s parlance).

We also need strategies for adding those middling tumours that are neither purely inflamed nor non-inflamed i.e. immune excluded and may have other factors influencing their tumour microenvironment, which is something else we also discuss in the interview.

No one would ever describe the trials and tribulations of oncology R&D as a cakewalk, there are certainly plenty of challenges to address on the discovery, preclinical, and even clinical front before we even get to consider the financial need to raise money, pharma collaborations and (hopefully), eventual commercialisation post approval. It can be a wild roller coaster ride at the best of times.

We have an agnostic approach to cancer drug development and cover small and large companies in equal measure.

So what can we learn from the first of the next generation STING agonist companies?

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The #ASCO18 poster hall scrum

Wrapping up our cytokine mini-series, we have our latest expert in the BSB hotseat discussing concepts and future developments, as well as strategically drawing things together in a way that makes sense.

It has become increasingly clear that a hostile tumour microenvironment may account for one of the reasons why many patients don’t respond to cancer immunotherapy.

How do we go about figuring out the whys and wherefores in order to significantly improve on the results seen to date with monotherapy treatment?

There are quite a few angles to look at this conundrum, so we decided to explore some concepts and analogies, as well as look at what’s going on under the hood of IO clinical trials to address the thorny issue of tumour heterogeneity.  We also discuss some of the top-line data in the cytokine niche presented at ASCO and look at the outcomes in the context of what we learn and where we going next.

There’s a lot to take in and process here, but that’s part of the fun!  As often is the case, some of the best gems are in the poster halls or poster discussion sessions…

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The potential of cytokines in cancer immunotherapy is now attracting a lot of attention with many in industry assessing whether they need a cytokine in their pipeline and if so which one may make the optimal combination partner.

We’ve been writing about cytokines for several years now and have been following several cytokine molecules, including Nektar’s novel pegylated IL–2 (NKTR–214) approach and Armo’s pegylated IL–10 (AM0010). Other technologies in early development include an IL–8 agonist from BMS and an IL–15 superagonist fusion protein from Altor Bioesciences.

#ASCO18 Blisterwalk to Developmental Therapeutic sessions

What does the future hold for cytokines – are they really the “best thing since sliced bread,” as we say in England or will they fizzle out and not prove to induce additive effects over and above monotherapy with checkpoint blockade?

For a view of where the field is at and where it might be going, while in Chicago at ASCO 2018 we spoke with Dr Mario Sznol, who is a medical oncologist at Yale Cancer Center in New Haven, where he treats melanoma and kidney cancer patients.

He’s one of the leading translational researchers in cytokine drug development and is also the in-coming president of the Society for Immunotherapy of Cancer (SITC).

Readers of Biotech Strategy will recall that we last spoke with Dr Sznol at the 2015 SITC annual meeting where he talked about his renewed interest in cytokines, and in particular, interleukin–2 (IL–2) (See post: Novel immunotherapies and combinations). Since then, much has happened and there are now even more targets being investigated, as well as a wider cadre of researchers actively involved in this field.

Being president of a medical or scientific association takes up a lot of time, so it was a privilege to talk with Dr Sznol again, before he takes up his new honorary position in 2019.

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A short, but quite important, post today highlighting an early target we are keen to follow in terms of combination trials in both GI and GU cancers, as well as others.

There’s been a lot of focus this year on the so-called inflamed (hot) and non-inflamed (cold) tumours, but what about the intermediate ones that many refer to as the immune excluded phenotype?

View of Geneva from Cathedral St Pierre, Switzerland

Clearly it makes sense to consider different combination approaches in each category, but what would be appropriate? Before we can set about doing that, we first have to uncover the mechanisms causing the inhibition on the tumour microenvironment and then figure out how best to identify those patients most likely to benefit.

Over the last couple of years, we’ve seen and written a lot about various potential candidates (not all will be useful), including myeloid derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumour associated macrophages (TAMs), chemokines, cytokines, adenosine fog and many others.

There is one target that has started gathering a little bit steam over the last year that we have mentioned a couple of times on BSB and now there is something new to discuss here, at least from a big picture perspective.

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Cancer immunotherapy has been very much focused on T cells of late, but perhaps we shouldn’t ignore the importance of the innate aspect of the immune system and how that might help generate cytolytic activity to help kill cancer cells.

Regular readers will know that we’ve been following the potential of Natural Killer (NK) cell therapy and targeting NK checkpoints.

Sculpture in Mainz

At the recent CRI-CIMT-EATI-AACR international cancer immunotherapy conference in Mainz, we spoke with a scientist active in NK cancer immunotherapy research.

Dr Nicholas Huntington (@Dr_Nick_Bikes) leads a laboratory at the Walter and Eliza Hall Institute (WEHI) of Medical Research in Melbourne, Australia.  He’s also co-founder of oNKo-innate, a startup company focused on developing innate immunotherapies.

After his presentation in Mainz, he kindly spoke to BSB about his NK cell research and its potential as a novel target for cancer immunotherapy.

Here’s a short excerpt from our discussion:

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One of our popular series from conferences is Gems from the Poster Halls, where we take a look at some of the studies or research data that caught our attention and explain how they may have future significance. In the past, posters have lead to phase 2 or 3 trial designs and subsequent approval. Others have sadly missed signals in small studies that could have prevented an expensive phase 3 faiure. Hence, it is often important to pay attention to posters.

esmo16-poster-hall

The ESMO16 Poster Hall Maze

Posters can also give early warning for what’s developing in pipelines. The BTK inhibitor, ibrutinib, was originally codenamed CRA–032765 (at Celera) and later PCI–32765 (at Pharmacyclics), for example, while the PI3K-delta inhibitor, idelalisib started life as CAL–101 (at Calistoga). We previously followed the progress of these compounds while they were in preclinical and phase 1 and documented progress long before they became active drugs in a race to market in CLL.

My favourite codename is always going to be STI–571 (imatinib). We would start planning ASCO and ASH activities every January and September, so companies should be well in hand in their preparations for ASH and SABCS by now. There’s a tremendous amount of work involved behind the scenes in order to have a great event, and I’m not talking about the fripperies like exhibits and light boxes here.

Last year at ECCO, StemCentRx burst on the scene and were subsequently acquired at a significant premium by AbbVie, taking quite a few people by surprise.

So what can we learn about the data from ESMO this year? What new trends are emerging this time around?

Here, we take a fresh look at FOUR interesting new developments from small and large pharma/biotech companies alike in Part 2 of the Gems series. In the first one [Link], we interviewed an expert and discussed their approach to biomarkers in early small studies to help them better design larger follow-on trials more effectively.

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One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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Taxanes are a class of drug that are used in breast, lung and ovarian cancer chemotherapy to disrupt the function of microtubules that are essential to cell division. They include paclitaxel (Taxol®) and docetaxel (Taxotere®).

Paclitaxel is also used to prevent the narrowing (restenosis) that occurs with coronary artery stents that are used to open blocked coronary arteries. Drug coated stents (a.k.a. “drug-eluting stents) reduce scar tissue.

Research published in the February 18, 2011 edition of Science, by Farida Hellal and colleagues has now shown that treatment with paclitaxel reduces the scarring associated with spinal cord injury (SCI) and promotes nerve regeneration.

The paper in Science is well worth reading and takes the reader through a logical thought process as the researchers tested their hypothesis that paclitaxel might stabilize microtubules around the site of SCI.

One of the cellular events that occurs after SCI is the activation of transforming growth factor-ß signaling (TGF-ß).

Increased TGF-ß leads to fibrosis or scarring.  TGF-ß acts on Smad2 to bind to microtubules through kinesin-1.  Hellal and colleagues asked if treatment with paclitaxel would impair Smad-dependent TGF-ß signaling? The answer from their elegant series of experiments is that yes it does.

Not only that, but TGF-ß also regulates the axon growth inhibitor, chondroitin sulfate proteoglycans (CSPGs).  The researchers asked whether pacllitaxel decreased CSPGs after SCI?  They found that cultured meningeal cells and astrocytes treated with 10 nM paclitaxel showed a 35% and 32% decrease of glycosaminoglycan (GAG) levels.

The next logical question is whether the reduction of scar formation by paclitaxel results in any benefits for new nerve formation? The regeneration of dorsal root ganglions (DRG) were evaluated.  In what to me was a finding of great significance, the researchers found (references to figures omitted) that:

“Taxol-treated animals had regenerative fibers growing along the edge of the lesion cavity into the injury site and beyond. The longest axons per animal grew 1199 T 250 mm in the Taxol-treated group versus 176 T 225 mm in the vehicle-treated an- imals (n = 13 animals per group; P = 0.002; two- tailed t-test). The Taxol-treated lesion site thus becomes favorable for regeneration of growth-competent axons.”

The final part of this research asked whether treatment with paclitaxel led to any functional improvement after the test animals received a spinal cord injury? They found that those rats that received paclitaxel after injury, had greater improvement in their locomotor function.   The conclusion being that “Taxol-induced functional recovery correlates with its axon growth–inducing effect.”

The results from any animal study must be viewed with caution, since they don’t necessarily translate to humans.  However, this animal research, if supported by data from human clinical trials, suggests that treatment with taxanes may be of benefit to those with spinal cord injuries.

Given the debilitating effect of any spinal cord injury, this is an important finding.

 

ResearchBlogging.orgHellal, F., Hurtado, A., Ruschel, J., Flynn, K., Laskowski, C., Umlauf, M., Kapitein, L., Strikis, D., Lemmon, V., Bixby, J., Hoogenraad, C., & Bradke, F. (2011). Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury Science, 331 (6019), 928-931 DOI: 10.1126/science.1201148

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