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

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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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Sunny Day in Orlando, FL

Orlando, FL was the place to be last week thanks to two specialist meetings in town: BMT Tandem 2017 #BMTTandem17 (joint meeting of ASBMT and CIBMTR), and the inaugural ASCO-SITC Clinical Immuno-Oncology Symposium #Immunosym.  Indeed, several speakers spoke at both events!

Throughout this week we’ll be writing about the insights we gained from the two meetings into the latest data and trends in immunotherapy, immuno-oncology and adoptive cell therapy.

We’re kicking off with cell therapy insights from the BMT Tandem Meeting. It’s the joint meeting of the American Society for Blood and Marrow Transplantation and Center for International Blood & Marrow Transplant Research. If you don’t already, do follow the ASBMT President for 2017-2018 Dr Krishna Komanduri, @drkomanduri. He’s actively involved in CAR T cell therapy trials in Miami.

It’s worth remembering that bone marrow transplanters led the way in the use of immunotherapy to provide cures for cancer. Today, the BMT transplant community are pioneering adoptive cell therapy, and in particular  CAR T cell therapy in multiple hematologic malignancies including ALL, NHL, CLL and Multiple Myeloma. This makes the annual BMT Tandem meeting one to watch for some of the latest cell therapy data.

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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.

Subscribers can login to read the latest expert interview, or you can gain access below to the latest article in our Journal Club series…

After several years in the wastelands of cancer research due to lack of significant results and only one product on the market, therapeutic cancer vaccines now look to be back in fashion and are seeing a revival with their inclusion in clinical trials.

One of the reasons behind the resurgence of interest is the advent of checkpoints, and the potential of vaccines in the immuno-oncology space to boost or enhance the immune response.

Their use could not only increase the response to checkpoint inhibitors in people who might otherwise not respond, but in those who obtain some initial response such as a partial response, they could also potentially help achieve a more durable long-term response.

As we continue to ride the wave of cancer immunotherapy on BSB, the cancer vaccine field is suddenly an exciting area to watch.

I’ve long been known as a cancer vaccine sceptic, although recently several approaches in this niche have begun to look rather promising indeed.  Here, we highlight and discuss one such company in the field, including an interview with the CEO.

Subscribers can login to read more insights or if you have an interest in immuno-oncology, you can gain access to the interview via the blue box below…

At the recent Triple (EORTC-NCI-AACR) and ASH meetings, Blueprint Medicines (Cambridge, MA) presented data on some of their targeted compounds in early clinical development including data in KIT, PDGFα and FGFR4 driven cancers.

While many observers attention is currently distracted on cancer immunotherapies, let’s not take our eye off the ball and forget that when we do find driver oncogenes in rare tumours, the activity of TKIs can still be superior in these situations and offer exquisite sensitivity, leading to exceptional responses.

Here, we take stock with a look what Blueprint are doing, where they’re going and also offer some perspectives from senior company executives, whom we interviewed last month.

Which reminds me, someone recently asked why we do so many interviews, “You do a prodigious amount of interviews on BSB, why is that?”

The answer is very simple – to learn faster and share that knowledge with other like minded souls. Charlie Ambler, author of Daily Zen, sums it up well in an essay about Talk Less:

“In Zen tradition, I’d like the kill the Buddha that is Lao Tzu and revise his ancient saying. It’s not that those who talk don’t know and those who know don’t talk— it’s that talking often inhibits us from knowing.”

Thus, the corollary here is that if you undertake interviews with scientists and researchers regularly then you have the pleasure of talking less – the person in the hotseat naturally talks more – and you learn faster.

What’s not to like? We all learn different things depending on our perspective and knowledge base. Sometimes, I even find re-reading old interviews a year or so later while preparing for a new one a related topic teaches me something new I didn’t see or realise before, simply because my own understanding has improved. Hopefully that is also true for subscribers!

To learn more insights about this promising small biotech, including an interview with company executives, subscribers can log-in below or you can gain access via the blue box…

ASH16 in San Diego

Today we resume our coverage from the recent American Society of Hematology (ASH16) annual meeting with a look at some fascinating and highly compelling science that was presented in an obscure and hard to find tiny hall in San Diego.

This story is also about how a small biotech company that many casual observers may not even be aware of, is taking advantage of advances recent research to grab a clinical lead in a very specialised field in oncology that may yield a novel approach worthy of taking notice of..

Genomics is increasingly becoming a core element of cancer research. Think of it as the alphabet soup of molecular biology concerned with the structure, function, evolution, and mapping of genomes.

Once we understand and identify the genomic landscape in health and diseases such as cancer, it allows numerous platforms to evolve whereby those unique differences can be identified (as driver vs. passenger mutations, for example), explored in depth, and later key ones targeted with therapeutics. Inevitably, there are many ways to do this.

Much of the focus in genomics has been on DNA, but what about RNA?

RNA is important because a mistake – even a single nucleotide – can be devastating to the cell, and a reliable, repeatable method of RNA processing is necessary to ensure cell survival. Mis-splicing can thus lead to the development of new point mutations and genomic instability deep in the cell nucleus, potentially causing the evolution of certain cancers.

Paradoxically, these aberrations also offer novel therapeutic targets – but are they druggable?

What we are exploring here is a completely different approach, both in terms of how a fledgling company is funded and also the type of research that is conducted.

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HI Koko Crater Flowers

Over the last week or so, we’ve received a lot of questions on the following topics relating to women’s cancers in breast and ovarian carcinomas:

  • APHINITY impact – pertuzumab and neratinib
  • PARPs in ovarian cancer – niraparib, rucaparib and olaparib
  • Seattle Genetics and Immunomedics

So this is probably a good time for a February BSB Reader Q&A post on the hot topics of the moment in cancer research.

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The huge pile of interesting scientific papers yet to be read seems to breed overnight and one constantly feels like they’re 2,000 articles behind, even with spending Friday mornings attacking them with gusto.

This was as true in my PhD days as it is now. For a scientist, these represent a lifeline and an important necessity, rather than a luxury.

In the last journal club posting we covered some hot topics in cancer immunotherapy, so this one covers a very different topic, namely targeted therapies.

It’s a good time for a new journal club post, where we tackle some of the recent published literature in oncology and highlight some important new findings that could have an impact on cancer research and development.

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Today we continue the second of a two part interview with a global thought leader who is also a scientist-clinician and well versed in cancer research as well as clinical trials.

Old Town Hall, Munchen

We explore how we can do clinical trials better in order to learn via a more rigorous process what works, what doesn’t, and why. After all, we we don’t know why certain approaches didn’t work or what the mechanisms of resistance are, how can we possibly improve?

Randomness is not necessarily a good thing in clinical research, especially if you don’t know what target you’re actually trying to hit!

If you missed the first part of this latest KOL interview and want to catch up then you can find it here (Link).

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Two of the most intriguing developments in cancer research over the last 5 years have been checkpoint blockade and CAR T cell therapies. There’s no doubt that they work – in some patients – or that toxicities can be challenging to manage at times, but what has been very interesting to me has been physician reactions to the rise of immunotherapies.

There has been much noise about biomarkers, including whether they work or not in this niche, as well as how do we go about selecting patients for therapies and combinations?

Ultimately, immunotherapies will be no different from targeted therapies in that we need to better understand the underlying biology in order to move forward beyond the low hanging fruit and figure out how we can best select appropriate therapy for each individual based on their particular characteristics.

The worry that many researchers have is that we could end up making the same mistakes with immunotherapies as targeted therapies, i.e. treat them in a broad fashion akin to throwing mud at the wall. Indeed, some companies are already doing this, much to the consternation of the research community.

So how do we go about doing things better and thinking more strategically about what needs to be done?

Up next is the first in a two-part interview series with a global thought leader who is a scientist-clinician with expertise in both immunology and oncogenic pathways. What does he have to say about where we are now and importantly, what does the future hold?

This is the penultimate article in our coverage from the Triple meeting in Munich, held in November 2016.

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