Biotech Strategy Blog

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

Posts tagged ‘STING’

Recently, PARP inhibitors have been back in the news for several reasons, including the publication of the olaparib (AstraZenca/Merck) advanced mCRPC data in the New England Journal of Medicine from the phase 3 PROfound trial and the announcement regarding achievement of the key secondary endpoint of overall survival. As Dr José Baselga quite rightly noted, this is very good news indeed because:

“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve.”

We’ve rather more trial misses in this disease setting than successes from various therapies over the last few years including ipilimumab, PROSTVAC, alisertib, and atezolizumab, to name a few off the top of my head.

Related to mCRPC, let’s also not forget the upcoming PDUFA date later this month for Clovis’s rucaparib in the very same indication.

Not to be outdone on the PARP front, just a few days GSK received FDA approval for niraparib as first-line monotherapy maintenance therapy for women with platinum-responsive advanced ovarian cancer – regardless of biomarker status – based on the phase 3 PRIMA study presented at ESMO last year and simultaneously published in the NEJM. Recall that the majority of women (51%) had homologous-recombination deficiency (HRD) and this subset saw the greatest benefit.

Flying high in the DDR space?

We have now seen clinical benefit in the PARP inhibitors in four tumour types driven by DNA damage repair (DDR) deficiencies, namely ovarian, breast, pancreatic, and prostate cancers.

How do we go about extending the concept of DDR in terms of the biology of other tumour types?

A number of related pathway targets have been investigated, including ATM/ATR, Chk1, Wee–1 and others, with mixed success.

It’s not the nature of oncology R&D to stand still, however; what if we could turn things on their head and think creatively about the problems still to be addressed?

One particular new company to the PARP space is doing just that… so what are they doing and what’s different about their approach?

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Time to unlock some novel IO targets?

Continuing our latest four part mini-series, this one is on novel targets and agents and we now turn our attention to immuno-oncology in the last two articles pertaining to this particular topic.

You can read the first two articles on targeted therapies here and here.

For the avoidance of any doubt, this latest review is not about T cells, far from it.

Instead we cover six different areas, most of which are related or integrated in some shape of form.

There’s a lot of promising new science now coming out to help us better understand the underlying biology and also think out of the box about ways to enhance or improve on existing research.

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We get to chat with many leading oncologists and cancer researchers on Biotech Strategy Blog – it’s truly one of the perks of the job to meet experts and hear them discuss their early research.

Like a tutorial, we have the opportunity to ask questions and improve our own understanding, but where it becomes really interesting is when they talk about promising translational opportunities, because this is what we are about.

How do you translate basic research into oncology new products and figure out where are the viable opportunities?

In this post, we spoke with one of the world’s leading immunologists – someone we’ve never spoken to before – who a few weeks ago spun-out a company to commercialize one of their early research areas and while we were doing the interview told us about another commercial opportunity they had in mind. This was very much “under the radar” and in a relatively earlier stage of commercialization. Both targets have potential for synergy in our view, particularly in combination strategies and cancer immunotherapy regimens.

With one company in stealth mode and the other only incorporated a matter of weeks ago (at time of writing they don’t yet have a website), it’s exciting to see science translation in action.

This is one of the reasons why one of the many tribes that read BSB are those in business development and licensing (BD&L) or investment roles.

In this post we interviewed the delightful Prof. Akiko Iwasaki from Yale. We’ve also put together commentary on the opportunities and the science behind them, as well as some recent anecdotes gleaned from another expert in one of the fields discussed.

If you are part of a BD&L team then do consider purchasing a group or team license. We’d be happy to have our group sales department discuss this further with you.

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Chicago: We’ve heard a lot of people say how they think this year’s annual meeting ASCO19 is not as good for data as previous years, and we’re going to have to respectfully disagree.

On Sunday at ASCO19 there was a wealth of data on display in multiple sessions with some noticeable “winners and losers” when it comes to drugs in development.

Dr Hedy Kindler presents phase III POLO trial in Plenary Session at ASCO19. Data simultaneously published in NEJM.

In this post, we’ve some top-line commentary on some of the Sunday sessions we covered, and what caught our attention. As always our detailed analysis comes after the meeting in the “post-game” show.

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We’re starting our review of the program for the forthcoming 2019 annual meeting of the American Association for Cancer Research (Twitter hashtag to follow: #AACR19) with a look at the cancer immunotherapy program.

One of the challenges of a large meeting is that it’s like a smorgasbord or buffet in a hotel that’s resplendent in choices, but you can’t possibly eat it all.

Choices!

Some choose to follow a research area, others a target or tumor type. There’s a lot of ways to segment the program depending on your specific interests.

However, it’s a good idea to have a plan in place ahead of a large conference such as AACR, even if you modify it as you go to take into account evolving needs.

Seasoned conference goers will be familiar with the maxim known as “the law of two feet” – if a session you are in doesn’t live up to expectations or meet your needs and something else looks more to your taste from the tweets, then simply dash off to another!

In our latest conference preview, we’ve taken a careful look at the cancer immunotherapy track.

What are some of the key sessions to put on your calendar if you’re following this track or have an interest in this area?

In Part 1, we review the IO sessions from Friday to Sunday then tomorrow in Part 2, we’ll review the schedule from Monday to Wednesday.  Yes, it’s that intense this year! Just think, five years ago you had to search the program really quite hard indeed to even find much on immuno-oncology, as it was very much in its infancy then.

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This week I’ve been attending the excellent AACR Special Conference on Tumour Immunology and Immunotherapy here in Miami Beach. I must say that it’s really rather nice to have a local event literally less than 20 blocks away for once – it sure beats all the stress and hassle of long distance travel!

Were any of the early IO developments flying high in Miami Beach this week?

The meeting is designed to “integrate multidisciplinary facets of basic cancer immunology and immunotherapy to broaden the understanding of ways to harness the immune system to treat cancer.”

In this latest conference report, we cover some key highlights and insights learned, as well as review some early clinical data that was presented on several fronts including new companies and novel approaches to CAR-T cell therapy, as well as an important update on STING agonism.

We also identify some emerging trends that may teach us more about the future landscape developments in immuno-oncology.

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Early morning starts for #ESMO18

Munchen – If you haven’t checked out yesterday’s live blog post, which is packed with numerous updates and highlights from various sessions and embargoed data releases throughout the day, you can check it out here.

There’s much more in store today as the conference gets deeper into the swing of the program.

We have also been busy with expert interviews – more on those later – as well as digging out gems from the poster halls.

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ESMO18 is rapidly approaching with only a week to go before the conference kicks off in Munich this year.

Munich

So far in our Preview series we have highlighted what to watch out for in the late breakers, neoantigens, as well as the oral talks and poster discussions.

Now it’s time to turn our focus on the nuggets or gems that can be gleaned from the poster halls – there’s always a few pleasant surprises in store. There are small and large pharma/biotech companies included in this latest list on a wide range of therapeutics and tumour types.

There are also some interesting emerging trends, as well as hints of what might happen with some future phase 3 readouts that could catch a few people by surprise.

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Last week we reported on a paper published in Nature by Bakhoum et al that raised the provocative question, Can STING agonists promote metastasis? (Link to BSB post).

As Dr Bakhoum subsequently tweeted an image from the research made the front page of the print edition of Nature:

In this latest post, we continue the story with a perspective on this research from one of the world’s leading experts on the science behind the STING (stimulator of Interferon genes) pathway.

Glen N. Barber, PhD is Chairman of the Department of Cell Biology at the University of Miami Miller School of Medicine and holds the Eugenia J. Dodson Chair in Cancer Research.

He has published extensively on the biology of STING and targeting the innate immune system.

In science we often hear that the truth is what the data tells us, but what does the data by Bakhoum et al really tell us and what conclusions can we draw from it that will guide future translational and clinical research?

Dr Barber kindly spoke to BSB at his office in the Papanicolaou Cancer Research building at the UM medical school and offers a perspective that reignites the controversy over STING and Metastasis.

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Can STING (stimulator of interferon genes) agonists promote cancer metastasis in some patients?

That’s the intriguing question posed by research published recently in the journal Nature by Dr Samuel Bakhoum @Samuel_Bakhoum and colleagues. (doi:10.1038/nature25432who found that, “chromosomal unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.”

Samuel F. Bakhoum, MD PhD is a Holman research fellow at Weill Cornell Medicine and a senior resident in radiation oncology at Memorial Sloan Kettering Cancer Center in New York. The joint first author of the Nature article is Bryan Ngo, a student in the Weill Cornell Graduate School of Medical Sciences. It’s impressive work from two early career researchers.

The paper raises several important questions that drug developers – several of whom already have STING agonists in the clinic – may need to carefully think about.  It is, however, important to point out that this data is preclinical, so we don’t yet know what may or may not happen in cancer patients.

We first heard about the data published in Bakhoum, Ngo et al’s Nature article, “Chromosomal instability drives metastasis through a cytosolic DNA response,” at last October’s excellent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Philadelphia.

What we learnt at #Targets17 was that chromosomal instability is linked to tumour metastasis through the STING pathway.

Readers of BSB will know that we’ve been covering activation of innate immunity through the STING pathway for several years now (See posts:What we learnt at AACR about Aduro ADU-S100” and “Tom Gajewski takes the STING out of Cancer,” to name but a few.

So how do we reconcile the positive and encouraging data that has led to development of multiple STING agonists, several of which are now in the clinic, with the potential that there might be a harmful aspect to them?

There are some important subtleties and nuances around this critical issue and that is the essence of this post and what we sought to gain more insight into, beyond the obvious superficial answer that there could be harmful effects involved.

The Roman god Janus is depicted as having two faces – one looking to the future and the other to the past.

There are also two faces to cancer immunotherapy: It can be a force for good, we can harness our immune system in a way that results in a positive outcome – people with cancer live longer, some are even cured.  Alternatively, if we harness the immune system in a negative way it can also be a force for harm. 

We heard on the recent Novel Targets Podcast episode that while combination cancer immunotherapies can be effective in a subset of people, they can also lead to rip-roaring toxicities as well as unwanted auto-immune side effects, and in some cases, these can be fatal.  With multiple inhibitory and activating forces at place, cancer immunotherapy can tread a fine line balancing these out.

Dr Bakhoum kindly spoke to BSB about the translational and clinical implications of this latest research.

Given the potential impact of this research, we also sought additional commentary from experts active in STING research such as Jason Luke, MD FACP (@JasonLukeMD). He’s an Assistant Professor in the Department of Medicine at the University of Chicago and a Principal Investigator for early immunotherapy trials, including those with STING agonists.

BSB readers may recall we did an in-depth interview with him at AACR17 (See post: Overcoming Immunotherapy Resistance). This time around, he shared his perspective on Dr Bakhoum’s research and looked at the potential clinical implications.

Like Janus, does the STING pathway really have two faces to it?

Should companies with STING agonists be concerned or not?

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