Biotech Strategy Blog

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

Posts tagged ‘Innate immune system’

Sometimes research topics that we’ve researched and covered for several years, including interviews with thought leaders, suddenly become ‘hot’ or are seen as the latest shiny silver lures by sceptics when a new bandwagon starts rolling. They don’t always end well, but some do and take off and become embedded in new standards.

Checkpoint blockade and CAR T cell therapies are two such approaches, which we wrote about in 2010 and 2012, respectively.

When I included what was then known as MDX–1106 and MK–3475 in an ASCO 2010 or 2011 preview video, folks scoffed at highlighting phase 1 data in advanced solid tumours with obscure compounds – “too early to tell” apparently. They subsequently went on to become nivolumab (Opdivo) and pembrolizumab (Keytruda) and are indisputely multi-billion blockbusters. Now it’s hard to imagine a discussion about cancer immunotherapies without them mentioned as a bedrock therapy to build on.

I mention this story because it’s easy to follow the herd and dismiss early promising developments as ‘too early’ – fortune favours the brave, even if it means that many approaches need to be tested and evaluated along the way before finding the best solution.

Pathway to success

There is no doubt that the path to success in oncology R&D is paved with many challenges and hurdles – it is rarely a straight road.  Some drug classes will inevitably fail and fall by the wayside, others will need tweaking, incorporated into more optimal trial designs or even evaluated with other combination partners. And let’s not forget those twin issues of dosing and scheduling, which are no slouches when it comes to providing tricky or even exasperating hurdles for hitting an optimal therapeutic window, as many early phase PIs will no doubt be all too familiar with.

We currently live in a very T cell centric world despite the fact that they aren’t the most numerous of the various killing machines available to the immune system. They do happen to be extremely potent and highly effective fire power though, much as a machine gun is over, say, a combat knife or Samurai’s sword. That doesn’t mean that knives or other approaches aren’t effective, far from it, they’re just different and can even be more useful in appropriate situations.

Our heads were first turned by the potential for NK cell engagers a couple of years ago at ASH and we’ve keenly followed their progress since then, documenting the challenges and successes as we went.

With the Affimed-Genentech collaboration announced last night, it’s time to consider where we are with this approach and what this all means…

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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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Every year for our annual AACR Preview coverage we like to mix things up and explore what’s happening with different targets, pathways, and even companies.

In this latest post for #AACR18, we take a look at a company that has historically been involved in R&D associated with the innate immune system. As new molecules have evolved against different targets, researchers have begun to realise that we can actually target both the innate and adaptive immune systems together rather than one or the other.

We have covered several clinical developments from Innate Pharma on lirilimumab, but they are actually more than a one compound biotech and have a growing pipeline of antibodies against several novel targets, some of which are unique to the company.

This isn’t just about the science behind the pipeline as we also explore facets of corporate strategy and where the company is headed in the near to medium term future.  While in London earlier this month, we caught up with Dr Mondher Mahjoubi (CEO) and Prof Eric Vivier (CSO) for a candid and detailed fire side chat.

There was plenty to discuss and some interesting new developments to highlight…

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ciml40-marseille-luminyThere is a lot of interest in manipulating the microbiota to improve clinical outcomes – there was a whole session dedicated to it earlier this week at the CRI-CIMT-EATI-AACR international cancer immunotherapy conference in New York.

At the recent scientific meeting to celebrate the 40th anniversary of the Centre d’Immunologie de Marseille-Luminy (CIML40) in the South of France, Dr Eric Pamer spoke about his research into microbiota-mediated defense against intestinal infection.

Dr Eric Pamer presenting at CIML40

Photo Credit: ATGC Partners

Dr Pamer is an infectious diseases expert at Memorial Sloan Kettering Cancer in New York, where he runs a laboratory (The Eric Pamer Lab) focused on the role of the microbiota in immune system development and in defense against antibiotic resistant pathogens.

The gazillions of bugs in our gut, collectively the microbiota, interact with the innate immune system.

Researchers have shown that the effectiveness of antibiotics and the type of immune response we generate depends on the type of bacteria and their diversity in our gut.

ciml40Readers may recall the interview we did with Dr Marcel van Brink (@DrMvandenBrink) at the Society for Immunotherapy of Cancer (SITC) 2014 annual meeting, where he talked about his research into how gut bacteria can impact survival post allogeneic bone marrow transplant. See post: Can you reduce Graft Versus Host Disease GvHD by regulating gut bacteria?

Almost a year ago in November 2015, researchers and the pharmaceutical industry were both galvanized by work from Laurence Zitvogel and Tom Gajewski labs, published simultaneously in Science. See post: Gut Bacteria Impact Checkpoint Inhibitor Efficacy.

Not only could the results from mice experiments be influenced by the gut bacteria they had, but the microbiome could also impact the effectiveness of checkpoint inhibitors.

You can listen to Dr Gajewski on Novel Targets Podcast summarize the research from his lab published in Science. Link to Episode 9: Targeting the Microbiome.

ebmt17

Next year’s European Society for Blood and Marrow Transplantation Congress (#EBMT17) will be held in Marseille.

Given the impact the microbiome has on post-transplant GvHD and survival, I expect we’ll hear more about this at the Congress. Marseille is well worth a visit if the opportunity presents.

Marseille Vieux Port

In case you missed them do check out our recent posts from the Marseille Immunopôle and #CIML40:

In the meantime, our latest expert interview with Dr Pamer covers his wide ranging thoughts on a number of issues, including the impact of the microbiota on the innate and adaptive immune systems and where he sees the field going in the future.

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Aduro Biotech LogoWe’re almost at the end of our coverage of AACR 2016. Post number 30 (!!) is on Aduro Biotech ($ADRO) and their STING (Stimulator of interferon genes) agonist currently in development.

On the final day of AACR, in a packed session chaired by Tom Gajewski, MD PhD (Chicago), the meeting heard from Tom W. Dubensky, Jr, PhD Chief Scientific Officer of Aduro Biotech in a presentation (SY39-02) entitled:

“Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity.”

Dr Tom Dubensky Aduro CSO

Dr Tom Dubensky, Aduro CSO

I spoke with Dr Dubensky (pictured) afterwards. In my interview recording you can hear Vice President Biden’s cavalcade arrive at the Ernest Morial convention center in New Orleans for his plenary presentation.

Since AACR 2016, Aduro announced that the first patient has been dosed with ADU-S100 (MIW815) in a May 12 press release.  This triggered a $35M milestone payment from Novartis, who are undertaking the clinical trial (NCT02675439).

In March 2015, Aduro entered a collaboration with Novartis that, according to the Aduro press release, led to an initial payment of $200M and an additional $50M in equity investment.

After the recent failure of their pancreatic cancer vaccine, announced in a May 16 press release, there is a lot riding on ADU-S100 for both Aduro and Novartis.

I had the privilege to interview Dr Gajewski last year at Immunity 2015, where we talked about his work on STING (see post: Tom Gajewski takes the STING out of cancer). You can hear a short excerpt from the interview on Episode 2 of the Novel Targets Podcast.

So a year later it’s a good time to return to the STING pathway and take a fresh look at what Aduro/Novartis are doing.

For this post, I’ve chosen to write this up as a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis of ADU-S100 based on what I learnt at AACR from talking with Dr Dubensky and other experts.

Your SWOT analysis of ADU-S100 may be different from mine, you may have access to other sources of information, an alternative opinion, or reach an entirely different conclusion. There is no right or wrong answer. We all view the world through our own individual bias and lens.

Before you read this post, I heartily encourage you to map out on the “back of an envelope” – or as I’d say in England, on the “back of a fag packet” – what your SWOT analysis looks like. That way you can compare yours to mine.

By definition, we’re dealing with a new product in early clinical development, where many questions remain unanswered. It’s always easier to see the picture after all the cards have been dealt……

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