Biotech Strategy Blog

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

Posts tagged ‘PD-L1’

We have written about a huge variety of different approaches to cancer research since 2006 but few are as intriguing as using pathogen-based approaches involving viruses or bacteria to stimulate or re-activate the immune system. After all, when such foreign bodies break through the physical barriers and enter the bloodstream, the immune system instantly springs into action to tackle them.

Can this knowledge be used effectively in the design of anti-cancer therapeutics?

We have seen some promising initial results with oncolytic viruses, but what about bacterial based approaches?  Can a different approach to drug scaffolds yield improved results?

Here, we look through the window at a novel platform using immunotoxins in early development that may well pique a few people’s interest and offer our latest thought leader interview discussing the approach…

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Autumn leaves in Munich

We have increasingly seen how oncologists like the efficacy associated with the immune checkpoint combination of ipilimumab plus nivolumab, but are leery of the increase in side effects, including immune related events.

Are there practical ways to reduce this phenomenon, other than dose reductions?

CytomX are one company who are focused on engineering a different concept with their monoclonal antibodies, bispecifics and ADCs to try and mask the effects, thereby reducing the treatment emergent toxicities.  Their main idea is that the therapeutic window can be widened, thereby improving the tolerability profile.

It’s a nice idea, but what happens in practice?

To find out, we took a look at the recent early clinical data and interviewed executives from the company…

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The hurly burly in Chicago between sessions

We have written about the positive and negative effects of various inhibitory checkpoints such as PD-L1, PD-L2, ICOS, and even B7-H3, but there are also other targets within the B7 family that might be worthwhile exploring in the clinic.

Beyond the hullabaloo surrounding the phase 3 anti-PD(L)1 data in 1L NSCLC, there were actually a lot of interesting new and emerging molecules that caught our attention from small biotechs that we plan to highlight throughout the rest of this week. They all have different targets, approaches and rationales, but offer a window into the world of oncology R&D and where things might be headed in the next couple of years.

Today we take a look at one of the long forgotten checkpoint targets and explore a number of aspects that can be considered, given that several companies have preclinical or clinical molecules in early development.

Is this an IO target to watch out for – or not?  What are the challenges and opportunities to consider?

It turns out that there could be more than one way to unleash T cells on cancer… as this interview with a company scientist and researcher demonstrates.

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With the advent of single agent checkpoint blockade and success in melanoma, lung and urothelial carcinomas has come the realisation that the majority of patients do not respond and even some that do have a response of short duration. Immune escape and adaptive resistance are not an uncommon occurrence.

There has been much focus of late in looking at ways to address this by uncovering the relevant mechanisms underlying the biology of the disease and this is an avenue we can expect to see more research evolve. We already know that JAK1/2 upregulation and PTEN loss have lead to resistance with checkpoint blockade – what about other possible mechanisms?

Indeed, at the ASCO-SITC meeting in Orlando last week, another such target emerged and clinical evaluation is already underway, making it a worthwhile area to explore.

Here we take a look at the science and biology, as well as the emerging clinical landscape to see which companies are involved and may get a jumpstart on the combination niche.

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One of the frequently cited conceptual frameworks in Cancer Immunotherapy is the Cancer Immunity Cycle developed by Drs Dan Chen and Ira Mellman from Genentech.

Ira Mellman Dan Chen Authors of Cancer Immunity Cycle

Ira Mellman and Dan Chen

As we heard Dan and Ira tell us on the Novel Targets Podcast recorded last year at #AACR16, the cancer immunity cycle doesn’t include all the elements that we now know impact the immune system and whether someone will have an immune response. The microbiome is one example that readily comes to mind.

To address this, Chen and Mellman have now published the next installment in the series in Nature:

“Elements of Cancer Immunity and the cancer-immune setpoint.”

The review paper published last month incorporates the latest research into a different framework that looks at the factors that influence what they call the ‘cancer-immune setpoint.’

Anyone involved with cancer immunotherapy knows how fast moving and dynamic the field is, something they draw attention to:

“The pace of cancer immunotherapy clinical studies is such that they have outstripped our progress in understanding the underlying science. However, this situation has created the opportunity to combine emerging scientific and clinical insights in a synergistic fashion that… will also provide guidance for the identification of new targets… and the crafting of a framework for making decisions on a personalized basis.”

Conceptual frameworks such as those proposed by Chen and Mellman will be of increasing importance as we try to make sense of the tsunami of cancer immunotherapy clinical trial data, including combinations, that is coming our way over the next 18 months.

During my recent visit to San Francisco for ASCO GI, I had the great pleasure to catch up with Daniel S. Chen, MD PhD, (Global Head of Cancer Immunotherapy Development, Genentech/Roche) and talk about his latest thoughts on how we should think about cancer immunotherapy.

In writing these review papers he told me:

“We look at this as an opportunity to really think about the field, and try to conceptualize what is happening.”

We also discussed their collaboration with Kite Pharma, something of relevance to conferences this week as we head off to BMT Tandem and the ASCO-SITC meeting.

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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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One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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It’s the end of April and just in time for two important things here on BSB…

Dan Chen and Ira Mellman on Novel Targets PodcastA) Season 2 of our Novel Targets podcast has now kicked off!

The first show (sponsored by Genentech) explores the cancer immunity cycle (CIC), how it can help see the bigger picture and how this framework can be used to help figure out what areas are missing when patients don’t respond to immunotherapy.

There are also predictions about what we will see coming up in the next year – will the crystal ball be accurate – or not?

Crank up the Sonos, grab a coffee, pen and paper – you’ll find the latest podcast show here (Link), which is open access for anyone who wants to listen.

B) Reader Q&A Mailbag: we tackle your latest tough questions that are top of mind and offer insights on the hot topics people want to know about.

We have a broad range of topics to cover today including:

  • The battle for PD-1 sales
  • What are the IO bottlenecks where we can expect to see new research focus
  • Sanofi-Medivation bid
  • AbbVie snapping up StemcentRx

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Port Sunglight SpringSpring has arrived in many parts of the world, and with it I am always reminded of William Wordsworth’s classic poem, “I Wandered Lonely as a Cloud:”

I wandered lonely as a cloud 
That floats on high o’er vales and hills, 
When all at once I saw a crowd, 
A host, of golden daffodils; 
Beside the lake, beneath the trees, 
Fluttering and dancing in the breeze.

 

So what does the future hold for cancer immunotherapy?

Inspired by Wordsworth, I’ve sat on my cloud and have looked at some of the recent review papers and thought pieces published by experts in the field. Do they offer a Jerry Maguire – like mission statement: “The Things We Think and Do Not Say: The Future of Our Business” or will we have to wait till AACR 2016 in New Orleans to learn more?

 

This is the latest in our pre-AACR 2016 annual meeting series. Subscribers can login to read more or you can purchase access.

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Lindt Gold BunnyWhat questions are BSB readers sending in to us this month?

I wanted to take a moment out of AACR Previews and catch up on some recent news that is intriguing or perplexing subscribers. All questions are anonymous and in many cases, the same questions were actually sent in by multiple people, a testament to what’s top of mind in oncology lately.

Today, we cover a Q&A on a variety of topics on Kite Pharma (the Genentech collaboration and their TCR in solid tumours), a discussion about EGVRvIII in glioblastoma, and Gilead’s woes with idelalisib and an IO pipeline.

So let’s get started – subscribers can sign-in…

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