Biotech Strategy Blog

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

In the first post in our mini-series about the potential for gamma delta (γδ) T cells in cancer immunotherapy, Prof Adrian Hayday took us on a voyage of discovery through the pioneering research he and colleagues did at MIT, Yale, King’s College London (KCL) and The Francis Crick Institute in London.

Prof Adrian Hayday FRS

Prof Adrian Hayday FRS

Along the way he highlighted how our current understanding of γδ T cells has developed over the last thirty years.

“All truths are easy to understand once they are discovered, the point is to discover them.”

This maxim attributed to Galileo Galilei in a 1632 publication, is very pertinent to Prof Hayday’s research which was a fascinating journey of discovery.

For the second post in our mini-series we have a Q&A with Prof Hayday that takes the story forward and looks at how our understanding of the science behind γδ T cells has opened the door to translational and clinical opportunities such as adoptive cellular therapy.

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This is the first part of our latest mini-series, which takes a closer look at the potential of gamma delta (γδ) T cells for cancer immunotherapy.

Prof Adrian Hayday FRS

Prof Adrian Hayday FRS

In this post, we’re focusing at the voyage of discovery made by one of the pioneers in the field, Professor Adrian Hayday, FRS.

We’re living in a golden age of immunology. Basic research conducted over the past thirty years is beginning to pay dividends as it is translated into new cancer treatments that leverage the power of the immune system.

As things stand today, however, the majority of cancer patients do not respond to approved immunotherapies such as checkpoint blockade, either as single agents or in combination with chemotherapy. This means that we still have a long way to go to make these therapies an effective and widely available modality for the majority of cancer patients.

Despite the “hype and hope” surrounding the approval of two cell therapies based on CD19 directed CAR T cell therapies for certain types of blood cancers, there remain many challenges before more widespread use is likely. These include long term durability and persistence, overcoming antigen loss/immune escape, developing safe and effective allogeneic (off-the-shelf) treatments, as well as finding suitable targets for solid tumours.

The cellular therapy landscape is undoubtedly still emerging. While many companies have jumped on the CAR T cell bandwagon, others are looking at new and novel opportunities, one of which is the potential of unconventional lymphocytes, such as γδ T cells.

The Francis Crick Institute viewed from The British Library

The Francis Crick Institute viewed from The British Library

Someone who is a pioneer and leading researcher in the γδ T field is Professor Adrian Hayday. He’s a Senior Group Leader and Assistant Research Director at The Francis Crick Institute and has been the Kay Glendinning Professor of Immunobiology at King’s College London since 1998. He was elected a Fellow of the Royal Society (FRS) in 2016.

Prof Hayday kindly spoke to BSB about his γδ T cell research and the voyage of discovery that have taken him from basic biology to translation into a novel cancer immunotherapy.

What is the potential of γδ T cells for cancer immunotherapy?

BSB readers will, hopefully, have a clearer idea after reading our latest four part mini-series.

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Continuing our STING mini series, the third part looks at a company with a next generation agonist that is heading into the clinic soon.

What sort of challenges have the overcome, what can we expect to learn more about? Are they thinking narrowly or broadly?

One of the most exciting times for me in new product development is not when they move from phase 2 to approval, launch, and subsequent commercialisation, but that window between preclinical studies and first-in-man trials. The IND-enabling phase is an intense period with much to get done that can make or break subsequent advanced solid tumour dose finding trials.

Get your various key predictions wrong and you could be looking at a spate of unwanted severe side effects that will rapidly grind your trial to a halt. Sometimes they are a predicted risk at a much higher dose, for example, other times the PK/PD predictions don’t turn out as expected at all (oops). Then there’s scheduling and timing issues to think about on top of dosing and therapeutic window for combination trials.

Despite a lot of research, it’s still a very imperfect science. As one of my mentors used to say, “Better to be lucky than pedantically dotting all the i’s and t’s!”

So imagine a young up and coming IO biotech in that window between preclinical and clinical development – what are they going to do and where do they see themselves fitting in the broader landscape?

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Yesterday, we started the first of a multi-part mini series on STING agonism with a quick look at the broad landscape and some of the competitors in this space, which has definitely grown over the last four years since we first wrote about the STING/cGAS pathway.

In the latest part of the STING series, we talk to a small, privately held biotech who are developing a slightly different approach to the first generation agonists currently in early phase clinical trials.

One goal that many are looking at with STING agonism is to try and take less inflamed tumours and turn them into inflamed ones (or cold to hot in layman’s parlance).

We also need strategies for adding those middling tumours that are neither purely inflamed nor non-inflamed i.e. immune excluded and may have other factors influencing their tumour microenvironment, which is something else we also discuss in the interview.

No one would ever describe the trials and tribulations of oncology R&D as a cakewalk, there are certainly plenty of challenges to address on the discovery, preclinical, and even clinical front before we even get to consider the financial need to raise money, pharma collaborations and (hopefully), eventual commercialisation post approval. It can be a wild roller coaster ride at the best of times.

We have an agnostic approach to cancer drug development and cover small and large companies in equal measure.

So what can we learn from the first of the next generation STING agonist companies?

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We first wrote about this innate pathway back in early 2015 – before it became famous and controversial – when things seemed much simpler then.

Imagine the basic concept… add an immune agonist – this targets the innate immune system to jumpstart or wake up the immune system in colder tumours – to an established adaptive immune therapy such as checkpoint blockade and see whether any magic happens. In practice, this turned out to be much easier said than done, because in reality mouse and man have quite different immune systems and do not react in the exactly same way, which makes extrapolation from one to the other challenging at the best of times.

Still, back in 2015 there were barely a handful of STING agonists that anyone could really put a name too, now there’s 18 compounds in early pipelines and counting.

Not all the players are small biotechs either, as big Pharma is certainly paying attention to the smaller biotechs (both private and public) generating molecules, especially now that early clinical data (alone and in combination) is beginning to dribble out.

Aside from collaborations and licensing deals, there’s also an increase in patents in this niche, which is often a sign of competitive activity.

Four years on, how has the landscape changed, what does the data look like and what sort of issues need to be addressed?

In the first of our latest three-part mini series, we look at the competitive landscape and how it has changed (quite drastically since 2015, I can assure you!). In parts two and three, we look at two different up and coming players in the STING space with very different approaches.

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In the third part of our ASCO GU coverage from San Francisco, which includes previews and post-match commentary, it’s time to turn our attention to renal cancer. This isn’t one disease, but a broad tumour type with multiple subtypes, some based on histology, with perhaps others to emerge down the road as we learn more about the disease and immune profiling.

There’s quite a bit to discuss this year, some of it quite complex and nuanced.

In the old days, much of the focus was on sequencing single agent TKIs in clear cell carcinoma, now it’s getting much more complex as scientists and researchers figure out combinations and regimen approaches, never mind what to do with the various histologies.

We walk readers through the latest information as we await the data presentations coming out tomorrow…

 

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Genito-urinary (GU) cancers are a diverse population of tumour types that run the gamut from prostate, bladder, penile, and renal cell carcinomas in the main, along with a variety of rare cancers thrown into the mix.

While much attention has tended to be focused on advanced and metastatic disease, for obvious reasons, there are plenty of new developments emerging in earlier stage disease.

This year things are looking up on several fronts, which is a great time to take a look at what to watch out for in GU malignancies…

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At one point not too distant in the past, all the big news seemed to flow out of advanced prostate cancer with abiraterone and enzalutamide vying for attention, followed by occasional news on ARN–509, ODM–201, galeterone (remember that one from Tokai with all the AR-V7 kerfuffle?), radium Ra–223 dichloride, cabazitaxel, denosumab, ipilumumab, PROSTVAC, brachyury, and a few others. Predictably, not all were successful, and the count is still out on some.

San Francisco

In our latest conference coverage, we take a look at what we can learn from riding the prostate cancer train at ASCO GU ahead of the presentations in San Francisco tomorrow.

We will be updating this review as more data become available with the presentations, so do grab a cup of joe and settle down for some interesting reading ahead of time… this should get you all up to speed on the journey there!

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We have been following the progress of various classes of molecules in the myeloma space here on BSB since 2010. These include traditional approaches (e.g. HSCT and proteasome inhibitors/IMiDs and various antibodies or ADCs), as well as immunotherapy (checkpoint blockade, CAR T cell therapy, oncolytic viruses etc).

Brick Lane Grafitti

There’s much going on in this space and it’s not only becoming extremely crowded and competitive (akin to 1L NSCLC), but there is a gradual trend towards convergence on many fronts, be they targets or modalities.

In our latest look at the myeloma space, we focus on several key areas of development – antibodies, CARs, and also highlight a new target that may be of interest…

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The Francis Crick Institute in London has an admirable program of engagement with the public and external researchers.

Attending a Crick Lecture recently presented by Cancer Research UK (CRUK) Chief Scientific Officer, Prof Karen Vousden CBE FRS, reminded me of my days as a PhD student at nearby King’s College London.

Regular BSB readers will recall that Prof Charles Swanton FRS is the Chief Clinician of CRUK.

In her Crick lecture, Prof Vousden elegantly explained to the audience why p53 mattered and how it might be targeted by small molecules.

What is the potential of this research for translational drug development? In this post, we take a look at new developments in the basic understanding of what p53 does, the current state of targeting p53 and Prof Vousden’s latest approaches.

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