Biotech Strategy Blog

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

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Posts by Pieter Droppert

Can STING agonists promote cancer metastasis?

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/nature25432) who 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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The science behind the venetoclax clinical trial strategy

Buried amongst the intense hurly burly of a major medical meeting such as the American Society of Hematology (ASH) are the unsung preclinical researchers whose work largely makes clinical development possible. After all, few sensible companies would bet on an expensive clinical trial program, especially in combination, without first knowing whether such an approach is rational or not and has a decent shot of working efficaciously.

At stake here is the potential for building a blockbuster cancer drug niche by niche.

Venetoclax (BCL-2 inhibitor) got off to a somewhat slow start compared to say, ibrutinib (BTK inhibitor), which had a much broader initial indication and a lower risk of tumour lysis syndrome (TLS), yet it may actually have a wider application across multiple hematologic malignancies. This could well end up as one of those classic tortoise versus hare stories in the long run.

Back in 2013, we posted five interviews conducted with a range of experts including:

  • Dr Oliver Sartor (prostate cancer)
  • Dr Susan O’Brien (CLL)
  • Dr Deepak Sampath (BCL-2 and ABT-199)
  • Dr John Jenkins (then deputy director at the FDA)
  • Dr Renier Brentjens (CAR-T cell therapy)

To put this in context, consider that we just recorded 15 interviews at ASH this year alone!

As regular readers know, we like to follow people and R&D stories over time, so while in Atlanta at ASH17 we took the opportunity to move a particular story forward – we wanted to learn where Dr Sampath and his colleagues are now and also where they are headed next. This gives readers a head start on anticipating what future clinical developments might be mentioned at JPM18 by either Genentech/Roche or AbbVie.

In our latest expert interview, we pick up and continue the discussion with Deepak Sampath to find out what’s happening with venetoclax four years on… it turns out quite a lot and makes for very interesting reading indeed.

Dr Deepak Sampath (Genentech)

Curious to now more about what this scientist and his work in BCL-2 targeting is all about?  Check out this short excerpt:

 

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ASH17 masterclass with Dr John Leonard on lymphomas

In our latest thought leader interview from the annual meeting of the American Society of Hematology (ASH) Dr John Leonard (Weill Cornell) provides a lesson on how to interpret key lymphoma data such as ECHELON–1, CAR T cells, and other topics at ASH, as well as what he’d like to see more of in lymphoma clinical trials.

In this hard-hitting interview, Dr Leonard reminds us that the media should not be a mere extension of the PR of companies. Instead he offers his real world insights into what may or may not be practice changing, and how we should interpret CAR T cell therapy data.

Dr John Leonard (Weill Cornell)

It’s a must read for anyone with an interest in lymphoma… here’s an excerpt to give you a flavour of the wide ranging discussion:

 

 

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Targeting Natural Killer Cells in Cancer Immunotherapy

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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The Future of Cancer Vaccines Part 5 – An Interview with Prof George Coukos

Mainz – At the recent CRI-CIMT-EATI-AACR international cancer immunotherapy conference in Germany, one of the underlying themes of the conference that attracted considerable attention from speakers and poster presenters was neoantigens, and how to generate cancer vaccines directed against them.

One of the European leaders in the field is Professor George Coukos who is Director of the Department of Oncology at the University of Lausanne Hospital and Director of the Lausanne branch of the Ludwig Institute for Cancer Research.

Lausanne is an exciting place for innovative translational oncology work with the Swiss Cancer Center, that Coukos also directs, creating synergy between partner institutions co-located in the Lausanne University Hospital (CHUV).

Mainz, Germany

We last spoke to Prof Coukos 18 months ago and much has happened since then. In Mainz, he kindly agreed to speak to BSB again and provide an update on progress.

This time we talked about the cancer vaccine research that he and collaborators such as Dr Lana Kandalaft are pioneering in Lausanne, and how this could best be applied in ovarian cancer.  It was exciting to hear him discuss his vision and some of the ambitious goals he hopes will be possible within the field.

Here’s a short excerpt from the interview – he has an interesting story to tell:

This expert interview is part 5 of our onging mini-series on the Future of Cancer Vaccines.

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The Future of Cancer Vaccines Part 4 – An Interview with Prof Kees Melief

Mainz: At the third CRI-CIMT-EATI-AACR international cancer immunotherapy conference held in Mainz recently, one of the emerging themes from an exciting and interesting meeting was novel cancer vaccines.

Despite the announcement last month that the Bavarian-Nordic phase 3 PROSTVAC trial in prostate cancer was futile (See post: PROSPECTing for nuggets with PROSTVAC in CRPC), therapeutic cancer vaccine research is experiencing a renaissance.

In this new mini-series, we’re featuring interviews with leading scientists and clinical researchers at the forefront of cancer vaccine research.

Mainz, Germany

It’s not meant to be an exhaustive list of the “good and great,” as not all leaders in the field were actually in Mainz, but nonetheless we hope this series, like a series of postcards, captures some of the excitement along with challenges and opportunities facing researchers at present.

Up next is Professor Cornelius “Kees” Melief, who is Emeritus Professor at Leiden University in the Netherlands and Chief Scientific Officer of ISA Pharmaceuticals – where ISA stands for Immune System Activation.

Earlier this year, Professor Melief received a lifetime achievement award from the Association for Cancer Immunotherapy (CIMT) for his work in research in this niche.

He’s a global expert on cancer vaccine research.  Ironically, back in July he published an editorial in Nature entitled, “Cancer: Precision T-Cell therapy targets tumors” that discussed some two letters on neoantigen cancer vaccine research from other thought leaders we have interviewed in this current mini-series, namely Dr Cathy Wu (Link) and Prof Ugur Sahin (Link).

While, in Mainz, Professor Melief kindly shared his thoughts on the field, where it is going, and how ISA Pharmaceuticals are looking to make a difference.  Here’s an audio postcard for those interested in hearing a sample of what he had to say…

This is the fourth interview in our mini-series on the Future of Cancer Vaccines.

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Is CD123 a good target in AML?

It’s been quite a roller coaster week so far for CAR T cell therapies, with Gilead announcing its intended acquisition of Kite Pharma on Monday.  If that wasn’t enough, Wednesday brought another surprise – the FDA approved a rare double header – for Novartis’s CTL019, now known as tisagenlecleucel (Kymriah) for pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL), as well as a new indication for Genentech’s tocilizumab (Actemra) for the treatment of CAR T cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients two years of age and older.

Inevitably there has been much hullabaloo and much anticipation over the expected price tag that might accompany the first cell therapy product approved in the US. Whatever your view on this, many of us were no doubt relieved it came in under $500K ($475K, with no charge for the product in the first month if there was a manufacturing failure or no response).  While undoubtedly pricey, frankly it could have been a lot worse given the relatively small patient population.

Of course, the approved therapy isn’t the only expected high ticket item – there’s also hospital costs (including highly trained physicians and nurses), ICU costs (for very sick patients), supportive care costs (including tocilizumab if CRS occurs), not to mention any lab, diagnostic or monitoring tests required. All of these will no doubt push the total bill nearer to $1M.  In children though, the lifetime value of curative intent and many additional years of life is a much easier to grasp concept for payers than adding a few extra months at a high cost in adults.

These issues do raise the stakes for Kite and what they plan to do strategically in aggressive lymphomas, where there is a larger pool of eligible people for therapy, which must be offset by lower response rates (vs. pALL) and likely lower durability based on the data we’ve seen to date.  If we are truly moving into a world of value based pricing in the US, then efficacy and tolerability will ultimately have an impact on the perceived cost and value of treatment.

As Warren Buffett, the famous value investor has been want to say, “Price is what you pay, value is what you get.”

Whoa that’s a lot to think about – who knows what Friday may bring at this rate – and we still have the Kite Axi-Cel approval in aggressive lymphomas to go yet…

Meanwhile, there’s also a high unmet medical need for new effective treatment options in Acute Myeloid Leukemia (AML), especially in the relapsed/refractory setting, which is why we’re firm supporters of the Beat AML trial that the Leukemia and Lymphoma Society are pioneering. (See: Interview with Dr Brian Druker).

There’s also interest from several companies in a variety of novel targets, including CD123.

Notre Dame, Paris

Cellectis recently announced the enrollment of the first AML patient into their trial of an allogeneic CAR T cell therapy (UCART123) targeting CD123.

Quite aside from the issue of addressing whether such a product can be administered safely and effectively, one major why there is notable interest in Cellectis is because an allogeneic CAR T cell therapy offers the potential of a much cheaper off-the-shelf product as well as enhanced performance from an abundance of fit immune cells from healthy donors rather than tired or exhausted ones from people who are sick, thereby reducing the risk of manufacturing failure.

While in Paris, I spoke with Cellectis Chief Medical Officer, Loan Hoang-Sayag, MD about the trial design and CD123 as a target in AML.

This is the third and final post in our summer mini-series on gene editing and allogeneic CAR T cell therapy.

The first in the series featured an interview with Professor Waseem Qasim (Link), and the second with Cellectis CSO, Dr Philippe Duchateau (Link).

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The dawn of a new beginning for Cellectis?

Paris – amazingly it’s now 3 years since we interviewed Cellectis (NASDAQ: $CLLS) CEO André Choulika and CSO Philippe Duchateau (See post: Can Cellectis revolutionise CAR T cell therapy):

Cellectis CSO CEO

Cellectis Senior Management – Drs Duchateau and Choulika

Since then, we’ve followed the company over time, including an interview with one of their leading scientists, Dr Julianne Smith at ASH 2014, followed by the initial results of their first allogeneic CAR T cell therapy UCART19 presented at #ASH15 by Professor Qasim.

It’s hard to believe 3 years have gone by so quickly! As regular readers know what we often do on BSB is follow stories longitudinally, so while in Paris for an Immuno-Oncology Summit we thought it a rather timely opportunity to revisit Cellectis and take stock of where they’re at and ask what the future may hold for them?

With the recent news that Gilead have acquired Kite Pharma, there’s going to be a lot of interest in what companies such as Cellectis are doing to bring allogeneic “off the shelf” CAR T cell therapy to market.

This is the penultimate post in our summer mini-series on gene editing and allogeneic CAR T cell therapy and features a candid interview with Dr Philippe Duchateau, Chief Scientific Officer, at Paris based Cellectis.

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Waseem Qasim Pioneers Allogeneic CAR T Cell Therapy

When we think of pioneers in the CAR T cell therapy space, one person who comes to mind is Waseem Qasim, Professor of Cell and Gene Therapy at the Institute of Child Health at University College London, and a Consultant Immunologist and Pediatrician at Great Ormond Street Hospital (GOSH).

Institute of Child Health

As readers may recall back in 2015, he gave the first allogeneic CAR T cell therapy under compassionate use to an infant with ALL, and in the process undoubtedly saved her life.

The subsequent case report published in Blood was the talk of 2015 annual meeting of the American Society of Hematology (ASH) in Orlando.

The poster focused on the first child that Prof Qasim treated and attracted a phenomenal amount of attention:

Prof Qasim UCART19 #ASH15 Poster

Where are we now with allogeneic CAR T cell therapy?

It’s been 18 months since we spoke to Prof Qasim, so while in London over the summer BSB caught up with him in his office at the Institute of Child Health.

This interview is the first in our latest 3-part mini-series on allogeneic CAR T cell therapy, which runs throughout this week. Here’s a teaser clip:

Kite’s first autologous product, Axi-Cel (in aggressive lymphomas), heads for regulatory approval in the US (PDUFA date November 29th), offering Gilead a hematology launch product with a high unmet need and, presumably, a relatively high price tag to match. Inevitably, some critical attention will subsequently be focused on the pipeline and whether they will move towards allogeneic CAR-T cell therapy (reduces cost of goods and increases profit margin) as well as how the TCR platform in solid tumours will fare.

It’s certainly a timely point to consider allogeneic CAR T cell therapies again given that things are rapidly heating up in the cell therapy niche following the Gilead announcement yesterday that they are acquiring Kite Pharma for $11.9 Billion.

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How to revolutionize cancer immunotherapy trials

Paris: If cancer immunotherapy is a revolution in how cancer is treated, then Dr Jérôme Galon is a revolutionary.

In addition to being a Research Director at INSERM in Paris, Dr Galon is one of the co-founders of Marseille based HalioDx, an immuno-oncology diagnostics company that is commercializing the research from his laboratory.

Last month, while in Paris, I had the great pleasure to talk with him in his office at the Centre de Recherche des Cordeliers (CRC) on the left bank of Paris.

At the time of the French revolution in 1789, it was the gathering place of the “Club des Cordeliers,” for famous revolutionaries such as Danton, Marat, and Camille Desmoulins. Dr Galon told me it was where the Declaration des droits de l’homme et du citoyen de 1789 (Declaration of the Rights of Man and Citizen) was signed.

As such, it’s a very appropriate place to find a cancer immunotherapy revolutionary…

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