Biotech Strategy Blog

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

Posts tagged ‘immune agonists’

It’s time to launch a new mini-series where we explore some of the issues and concepts surronding a given topic and then look at how they are being tackled through the lens of different biotech companies.

Storm clouds gathering over immune agonists and bispecific antibodies?

The latest topic is bispecific antibodies, a development we have often covered since 2014/2015 here on BSB. Much has happened in that time and many compounds have fallen by the wayside. In my view, this is a normal part of oncology R&D attrition – it’s not that we encounter problems, it’s how companies handle the road blocks along the way that matters.

What can we learn from the first two waves of immuno-oncology that can be applied to bispecific developments?  There is no doubt that while some have been successful in making it to market, quite a few have encountered various challenges along the journey.  Why is that and how to we address the emerging or thorny issues?

Change is inevitable in the cancer immunotherapy revolution, we can hardly expect to get things right first time, every time. Some approaches will work well, some won’t, others will need tweaking and turn out to be useful tools down the road in future iterations. Learning from past experience to make the next wave better and more effective is an important part of this process rather than putting everything in one basket and then abandoning it if it doesn’t work first time.

One man who has experienced the first and second waves and is ideally placed to candidly discuss the learnings and future changes needed is Dr Dan Chen. He was global head of cancer immunotherapy while at Genentech/Roche and is now spearheading clinical development at IGM Biosciences, a biotech focused on next generation antibodies and bispecifics.

In order to think about what’s needed in the future rather than rush headlong into a different modality, we first have to take stock and then reflect on the learnings of the past clinical trial experiences in order to figure out how to fix them…

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T lymphocyte    Source: Dr Triche, NCI

It’s time for an update on cytokines as there is a lot going on here across both academia and industry.

While the clinical proof of concept has been demonstrated for IL-2 with FDA approval going back to 1992, there’s still much that we don’t know when it comes to the telephone directory containing many of the others.

There’s quite a few questions that can be asked:

  • Which ones might be best in which tumour types?
  • What about timing, dosing, and sequencing?
  • Which early combinations look promising in terms of unleashing the T lymphocytes?

After all, let’s not forget that some cytokines will induce negative immunosuppression, while others might induce variable effects depending on what they encounter in the tumour microenvironment.  It’s certainly a lot more complicated than many people truly realise.

There’s also the much under-rated potential to combine cytokines with other approaches such as immune agonists in order to jumpstart the colder tumours.

In this latest update, we take a look at five very different approaches and see how much progress is being made with alternative forms of immune modulation – the resulting conclusions might well surprise quite a few readers!

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The keynote address at the 2018 CRI CIMT EATI AACR International Cancer Immunotherapy Conference in New York last month was given by Ignacio Melero (Pamplona). Professor Melero gave an engaging and informative presentation entitled, “The immunotherapy faces of Interleukin–8 and CD137.” He also had a related talk on “4–1BB and Metabolism” at the Society for Immunotherapy of Cancer (SITC) meeting this weekend.

Pinning down new opportunities in IL-8 and 4-1BB

The late and sadly missed, Dr Holbrook Kohrt (Stanford), worked closely with Prof Melero on targeting CD137 or 4–1BB, as it’s more commonly known.

Regular readers may recall our interview wth Dr Kohrt back at Immunology 2015 in New Orleans (Link).

If you missed it, we also shared some excerpts from this discussion on Episode 6 of the Novel Targets Podcast, “Stepping on the Gas” (Link). There was also a tribute to Dr Kohrt from Dr Ron Levy (Stanford) at the start of Episode 11 of the podcast (Link).

Professor Melero kindly spoke to BSB at SITC 2018 and shared his thoughts on where we are three years on and where his research is currently focused in relation to cytokines, and in particular, IL–8.

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We’ve come a long way over the last two years in the oncology market, with several novel approaches approved, numerous major phase 3 trials evolving and a huge turnaround for many companies in terms of early pipeline activity.

ASCO 2016 Posters 3

The melée at the ASCO 2016 Poster Hall

Unfortunately, this also means that the tendency of lemming activity also increases in the rush to copy everyone else and not be left behind.  Just a couple of years ago, some industry friends grumbled that there were over 20 checkpoint inhibitors chasing them in development; they may be surprised to know that now there are nearly 70!  This is both unprecedented and unsustainable, and yet it’s also a function of the perceived success these agents have had on the cancer R&D landscape to date.  Everyone wants one for fear of being left behind… except that many are indeed way behind already.

You can imagine the tall guy on the left of the picture looking at his watch and wondering, “Ah so many new posters, so little time!”

Meanwhile, as the rate of approved cancer therapies increases, so does the inexorable march in terms of hyper-aggressive basket pricing.  I would argue that at some point, it no longer acceptable or even conscionable to change a premium or even market rate for drugs that give an incremental improvement of a mere 2 months of extra life.

Equally, one thing that many industry observers and the media love to do, and wrongly in my view, is to compare the individual drug prices on an annualized basis.  This is silly for several reasons:

  1. So far, not all patients are treated for a full year
  2. If patients are treated until progression and that happens early, then therapy is stopped
  3. What people should be looking at is the average treatment cost based on the length of therapy – some people will receive a few months and some much more than that
  4. What’s the true cost of a cure or remission to a patient and their family?
  5. How do we quantify the impact of the long lasting durable remissions?

These questions will become increasingly important as we see a more aggregated therapy approach emerge over the next few years.

By this, I mean that we are now going beyond monotherapy and even combinations; those trials have already long started and are the low hanging fruit that has been rapidly snapped up by the early players, as we eagerly wait for their data readouts.

If you have new agents coming-out of preclinical and into phase 1 development over the next year, there are a number of important questions to consider:

  • What are you going to do and where do you start?
  • How do you gain an edge when coming from (way) behind?
  • How do you develop unique positioning that could sustain your molecule in a sea of similar competitors?
  • Is it realistic to expect the 17th and 50th checkpoint to have equivalent efficacy as what went on before and will all of these seriously make it to market?

You can see now why even the FDA’s Dr Richard Pazdur was moved to grumble about the surfeit of me-toos here and company expectations that the FDA should consider them – it’s on a massive scale that we haven’t seen before.  For once I agree and empathize with him over that dilemma, it’s madness to think they will all be as good as pembrolizumab or nivolumab.

What we are starting to see emerge now is a surprising synthesis of ideas and a merging of disparate approaches. How will this affect oncology R&D over the next 1–5 years?

A couple of smart readers wrote in asking about these emerging trends, what have we identified so far, and where do we see the oncology space going in the near to medium term future. Now that AACR and ASCO are behind us, what can we learn about the new developments and where they all fit in the oncology landscape strategically?

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UNO SignIn our post AACR analysis, I noticed some consistent observations across multiple talks and informal discussions with thought leaders.

Some of these ideas are pretty important and help us see the big picture for the near and medium term future in the cancer immunotherapy space.

The “Claws” sign we saw at the University of New Orleans sums things up!

Without much ado, it seems a good point to capture and summarise these ideas so that readers can compare notes and debate their thoughts too.

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The 30th anniversary meeting of the Society for Immunotherapy of Cancer (Twitter #SITC2015) starts today at National Harbor, MD just outside of Washington DC.

Congratulations to SITC on 30 years of Advancing Cancer Immunotherapy Worldwide!

National Harbor MD SITC

It’s an unusually packed conference season this month with the AACR-NCI-EORTC Molecular Targets (#Targets15) meeting in Boston unfortunately clashing with SITC 2015.  In previous years, the Triple meeting has been held in late October, something we hope it will return to in future.

Many of the leading cancer immunologists are at National Harbor…

In our latest conference preview post, we’ve taken a quick look at some of the late breaker and poster abstracts of note and will cover the main oral presentations at the end of each day, so do check back daily for more news and views.

As subscribers already know, we generally provide most of our commentary and analysis after a meeting when we’ve had a chance to hear the data, “kick the tyres” and talk to researchers. However, for those who can’t be at SITC, we will be writing a “top-line”post at the end of each day to give you a flavor of what’s hot at SITC 2015 and our initial impressions of the data we heard.

We typically generate a separate page for each conference we cover, so you can find the SITC 2015 coverage here; it includes some additional posts that make for background reading.

Wednesday’s program at National Harbor starts off with a Global Regulatory Summit (which we’ll miss due to travel) and an International Symposium on Cancer Immunotherapy later in the afternoon.

The weather looks like it’s going to be quite delightful at National Harbor – hopefully the meeting room won’t be as frigid as last year – and in addition to the great science, we’re look forward to meeting up with those of our subs who are here too!

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There are now several CD40 agonist antibodies in early clinical development from several different companies, including:

  • Roche – RO7009789
  • Apexigen – APX005M
  • Seattle Genetics – SEA-CD40
  • Alligator Bioscience – ADC–1013

This post is the last in our cancer immunotherapy coverage from the European Cancer Congress in Vienna. It features excerpts from an interview with Dr Christian Rommel, head of oncology discovery at Roche in Basle, Switzerland in which he talks about the development of their CD40 monoclonal antibody. Readers may recall we wrote about this from SITC 2014 last year: “Targeting CD40 in Cancer Immunotherapy.

This post is also a new primer on CD40 as we start our coverage of the Society for Immunotherapy of Cancer (SITC) 2015 annual meeting. We’re informed by SITC it’s a sell out conference with 600 more people than last year’s record breaking number. Cancer Immunotherapy is indeed the hottest topic in cancer drug development.

If you have plans to be at National Harbor this week, we hope to see you there!

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Vienna Torte

Which of these cakes will you choose?

Greetings from Vienna where we are gearing up for our coverage of the European Cancer Congress (Twitter #ECC2015).

We’ll be writing a “highlights” post for subscribers at the end of the day here on Saturday, Sunday and Monday, then will follow- up with more in-depth coverage after we have talked with experts about the data presented.

Checkpoint Inhibitors and Cancer Immunotherapy are not surprisingly hot topics at the meeting.

In case you missed it, this month’s episode of Novel Targets (are we really on show #6 already?!) takes us on a new branch of the journey looking at various aspects of cancer immunotherapy:

Boosting T cell production – Stepping on the Gas

In past shows, we’ve looked at unlocking the brakes (checkpoint inhibitors), immune biomarkers (MDSCs and STING pathway), an inflamed or immunologic tumour type (lung cancer), a non-inflamed tumour type (prostate cancer), adoptive cell therapies and now it’s time for something really different… what happens when we literally step on the gas with immune agonists?

That’s the theme of the latest show – listen to Episode 6 on SoundCloud or iTunes (open access thanks to our sponsors, Genentech).

This article focuses on more detailed background and show notes for BSB subscribers.

It’s an important topic that is both simple in concept to understand and yet highly complex in terms of optimising therapy.

It’s time to take a deeper dive…

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Several groups have banded together to produce the first CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (Twitter #cicon15) which focuses on the science underlying the immune system as it relates to cancer.  You can view the program agenda here.

These groups include the American Association for Cancer Research (AACR), Cancer Research Institute (CRI), Association for Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology (EATI).

We’ll hopefully be covering key abstracts at this event over the next few days and reporting on not only what the data is, but also the broader significance of the findings.

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