Biotech Strategy Blog

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

Posts tagged ‘TGF-ß’

It occurred to me after several such events this year that virtual meetings create a very different pattern for spectators from live events where we all dash from one hall to another trying to optimise the viewing experience and catch as many key talks as we can.

Gems from the ASCO Poster Halls

Instead of the annual rugby scrum in the ASCO poster halls, we can imagine ourselves in an entirely different world with social distancing virtually

Many people will no doubt be eager to listen to the various oral presentations of phase 3 data come Friday morning, while the poor posters may well languish until some undetermined time later, so why not take a step back and highlight some of the early work in developmental therapeutics ahead of time?

In the final part of our ASCO Preview series, we offer our independent take and candid commentary on ten abstracts in developmental therapeutics to watch out for.

A word of warning – we don’t take a particular perspective through the lens of rose tinted glasses, so not all the analyses are positive and there are some firm words against some of the selections regarding continued development or the researchers conclusions/recommendations.

Some of these are agents in early development, some are biomarkers or even emerging trends, but all are intriguing in their own unique fashion.

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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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We know that not every patient responds to checkpoint therapy and some may respond but then stop responding, so what can we learn about the tumour microenvironment in order to fix it?

To do this may well require retrospective analyses of the existing trials in order to learn what happened and figure out an improved design of the next wave of clinical trials with rationally based combinations (as opposed to randomly testing two molecules simply because that’s what a company has in its pipeline).

The other thing to consider is that while some people might have a high level of a particular marker or inhibitory factor up front, others may see rise on treatment as an adaptive response to immunotherapy. Those two situations may well require quite different approaches or regimens to address, making things much more complicated than originally thought.

Dr Kunle Odunsi (Roswell Park) at #AACR18

One topic that caught our attention in the run-up to AACR and subsequently during the meeting was a cytokine called transforming growth factor beta (TGF-β). We have covered IL–2, IL–6 and IL–15 developments quite extensively on BSB, but what of TGF-β?

As such, we decided to investigate this little known target further and explore the concept from different perspectives in both academia and industry.

Today, we begin this latest mini-series with a thought leader interview from an academic institution who is researching a novel approach to combination therapy based on TGF-β – here’s what he had to say about the topic…

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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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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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