Biotech Strategy Blog

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

Posts tagged ‘macrophages’

Sunset in Puerta del Sol, Madrid

Not in Madrido – In our latest ESMO20 Preview, we take a look at five emerging areas of cancer drug development involving early stage pipelines and highlight some important features and benefits to watch out for.

These topics won’t be on everyone’s radar, especially if the focus is on the big phase 3 trial readouts, yet they can teach us much about new combinations and future pipeline evolution.

Who’s actively moving novel approaches along and who’s sitting on their laurels?

After covering biomarkers to watch out for yesterday, we now take a dive into what’s looking interesting in terms of novel targets and the fresh new opportunities for the not faint of heart…

To learn more from our oncology analysis and get a heads up on insights and commentary pertaining to ESMO 2020, subscribers can log-in or you can click to gain access to BSB Premium Content.

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For the final postcard in our 2020 summer mini-series on the potential of immunometabolism in oncology R&D, we’re taking an in-depth look at the ways in which metabolic programming can overcome immunosuppression in the tumour microenvironment (TME), as well as looking at additional novel ways in which the fitness of T cells can be impacted.

We’ve already covered glutaminase, arginine, p38 and others, yet there are other metabolic effects to consider too, as we discover in our latest expert interview.  In the penultimate postcard, we looked at mitochondrial phenotypes and how they can impact both mitochondrial and T cell fitness, which are important aspects in making adoptive cell therapy (ACT) based approaches such as TILs and CAR-T cell therapies more effective.

Deep thoughts on immunometabolism and how it can impact antitumour response

These themes show up yet again, but in a rather different context because T cell fitness can also impact immune checkpoint blockade, oncogenic targeting, as well as transcriptional and epigenetic approaches.

As much as we have been slowing building up the evidence during this series, in the finale it’s now time to kick up things up a notch or two and draw some unifying ideas together.

We accomplish this feat with a rising young star in this particular niche, Dr Ping-Chih Ho, who is at the University of Lausanne.

He kindly spoke to BSB about his pioneering and prolific research, some of the critical questions he has sought to answer, plus what he sees are important future directions to consider in metabolism research.

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What do T cells want?

In the third post in our summer mini-series on immunometabolism, we’re continuing our journey by taking a look at glutamine as a target, and in particular, the potential of glutaminase inhibitors.

Cancer cells compete with immune cells for glucose and glutamine in the tumor microenvironment, and if the cancer cell wins then immuno-surveillance and anti-tumour immune response can be diminished. Of interest, glutamine addiction is commonly seen in cultured cancer cells.

This begs a critical question – can we target glutamine therapeutically in patients, and if so, what happens?

In this article we highlight an expert interview with Dr Jeffrey Rathmell, who is Professor of Pathology, Microbiology and Immunology at Vanderbilt, where he directs the Vanderbilt Center for Immunobiology.

Dr Rathmell is at the forefront of research into T cell fuels such as glutamine and has published preclinical work on early compounds in this niche, including Calithera’s glutaminase inhibitor, CB-839, for example.

He kindly spoke to BSB after the AACR20 virtual annual meeting where he chaired a session on Metabolism and the Tumor Microenvironment.

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When the boat comes in

Much has been written about new and emerging immuno-oncology targets where we can add new targeted agents to existing immunotherapies – after all, quite a few have already tried and failed in clinical trials to shift the survival curve upwards and to the right.

Can it be done?

I firmly believe so, but this endeavour is going to take the whole field much time and energy, as well as quite a few iterations in molecule and trial design.  No one knows what the next big target is though, but when they do it will be a bit like when the boat comes in – you know it when you see it.

In the spotlight today is a relatively obscure target we have written about perhaps once or twice before and now there is suddenly burgeoning interest in this subniche with a couple of players already active in the space.  Will there be others? Maybe, it will likely depend on how the phase 1 trials pan out.

We have attempted to cover a couple of key questions:

  • What can we learn about the science and research conducted thus far?
  • Why is a big biotech company suddenly interested in this target?
  • Which tumour types look like being important?

Most importantly, though, a long time reader wrote in and asked why on earth is there sudden interest?  Will start a new stampede?  Who are the competition?

Good questions, and now we get to set the scene to explain what’s what and why the target matters…

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We are living in exceptionally challenging times and our thoughts are very much with all those healthcare professionals at the front line in the battle against Covid–19.

For people living with cancer, particularly those who have stage IV disease, the stark reality – in the UK and even some States in the US – is an ICU bed may not be available if they come down with the severe form of the disease.

When it comes to cancer research most labs, with the exception of those working on Covid–19, are now closed, but there is still data coming out to keep us all going as we work from home. ASCO20 will be a virtual meeting this year, while AACR will likely have some virtual presentations later in April. There are also plenty of publications coming out in journals from work already completed.

In this post we’re looking at newly published research and one possible immunological link between inflammation related to cancer and certain infectious diseases.

Last week we spoke to Dr Kamal Khanna (@Kamal_M_Khanna), Associate Professor at NYU Langone about research from his lab, which has just been published in the journal Science Immunology.

Although science is important, what matters most in these exceptional times is making sure everyone comes through it safely. Dr Khanna kindly spoke to BSB under embargo on Wed 25th March, where we also spoke about the surreal experience going on around him as we asked, how are things going with you in New York?

“It’s crazy. This has become the epicenter now. It just moved so fast here from having no cases and everyone wondering what’s going on to just explosion. Lab is shutdown, unfortunately. They’re allowing one person to go in at one time, in my lab just to maintain mouse colonies and do very limited experiments.

They’re allowing us to do the Covid–19 experiments, which we started just a few days ago, but also in a limited fashion. Those are the things we’re doing right now is simply plaquing the virus, and we have a few strains and we’re just testing growing them and so. We’re getting some limited human samples, but probably that will explode now. Our hospital has the most amount of Covid patients, so much so that they just made a makeshift morgue with a tent, unfortunately, right next to where we are.

So that’s the reality of where we are right now and hoping that this will peak at some point, they’re predicting in about 2 to 3 weeks that it would reach its apex and then all the social distancing and things that we’ve been doing, hopefully that will start to bring some of the numbers down, that’s the hope.”

In this post we offer an extended interview with Dr Khanna where we explore possible immunological links between inflammation in relation to cancer and infectious diseases and how research from his lab could generate new insights into cancer, as well as some potential impacts for Covid–19.

If you’d like to read our latest in-depth expert interview on cancer-related topics, please do consider supporting independent science journalism in these challenging and exceptional times.

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Part of the next wave of early immuno-oncology agents are focused on addressing the tumour microenvironment and inhibitory factors that dampen down immune responses.

As we look at all the options available, there are a few obvious ones such as physical barriers and inhibitory cytokines or chemokines, but beyond that are a vast array of other potential targets we can aim at therapeutically.

We have covered quite a few of these already, but here’s a new one to add to the list.

One particular advantage is that because it is early in development, few competitors have cottoned on to the concept yet. First mover advantage can have quite a few benefits, after all.

Here’s an important question to consider in terms of oncology R&D – would you rather explore a blue ocean strategy or follow the lemmings off the cliff and be 14th to market in a highly competitive red ocean?

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With the Jounce-Celgene announcement that the ICOS agonist, JTX–2011, is being returned and new priorities being pursued there is much to consider. There are quite a few nuances to this story to consider beyond the obvious that BMS already have an ICOS stimulating molecule.

Here we put together a synopsis and some commentary in looking at several relevant targets of interest in the context of the broader landscapes that are evolving.

Are Jounce left high and dry with this latest development or is there still a future in ICOS agonism?

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We’ve written extensively about various cellular therapy approaches in hematologic malignancies involving T cells and natural killer (NK) cells over the last few years, but if we are to see significant lasting success in solid tumours then we may need to consider the involvement of other immune cells.

Indeed, if they can be engineered in some way to enhance the anti-tumour response then they might turn out to rather useful in combination with existing established approaches such as checkpoint blockade as a way to generate more responses.

How do we go about achieving this state?

There are some very intriguing and different approaches in early development that we plan to follow over time. Here, we explore this potential and the possibilities through our latest in-depth expert interview…

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As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.

One way to do this is to better understand the tumour microenvironment.

Wall of people at ASH16 in San Diego

If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.

If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.

At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?

Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.

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