Biotech Strategy Blog

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

We now turn our sights to targeted therapies and DNA Damage Repair (DDR). This is an important topic that has seen much focus in ovarian cancer of late and will likely see renewed interest in breast cancer at the forthcoming ASCO meeting next month. As we segue from one set of conference coverage to the next, there is inevitably going to be overlap, which is a good thing here as it helps with background and preparation in getting up to speed.

There is no doubt that DDR has had a bit of chequered history over the last decade, whether it be the spectacular (and sadly predictable) flop of Sanofi’s iniparib in triple negative breast cancer (TNBC), the negative ODAC incurred by AstraZeneca’s olaparib in ovarian cancer, or AbbVie’s more recent veliparib failures, to the much more positive events such as three PARP drugs now approved in different lines of therapy in ovarian cancer (olaparib, rucaparib and niraparib).

If ever there was a niche for the roller coaster ride that is oncology R&D, it has to be PARP inhibitors.  There’s much more to DDR than just PARP though.

Indeed, there are multiple intriguing targets to explore and also the potential for combinations with cancer immunotherapy approaches that may yield encouraging results in the future.

Can we go beyond ovarian cancer into other tumour types and if so, which ones look encouraging and how woluld we go about exploring those idesa? What makes one approach more successful than another?

Here we explore the world of DDR through the lens one company’s approach and look at what they’ve done, where are they now and where they hope to be. It certainly makes for an intriguing and candid fireside chat.

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Gritstone Oncology hit the ground running with a $102M Series A financing round back in October 2015. Any company that raises that amount of initial funding is on the radar as a company to watch, especially one in the cancer immunotherapy space.

Since the AACR meeting in DC, Gritstone have also hired Genentech’s Dr Raphael Rousseau as CMO (Link) and appear to be an exciting young company going places.

As attention on neoantigens increases, what is Gritstone’s strategy and where could they fit into the cancer immunotherapy landcaspe?

At AACR17 in DC last month, Dr Andrew Allen, President and CEO of Gritstone Oncology kindly spoke to BSB about his vision for the company.

This post is part of expert interview series (Link) and also forms part of our ongoing series on neonatigen based immuno-oncology.

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At AACR17 one of the fascinating topics that came up in several presentations was exosomes, what they are, and how the information they contain can be used to best effect.

One of the evangelists of exosomes, and their potential in cancer research is Theresa Whiteside, PhD who is a Professor of Pathology, Immunology and Otolaryngology at the University of Pittsburgh.

At the recent 2017 American Association for Cancer Research (AACR) annual meeting, Dr Whiteside gave two fascinating talks in education symposia.  Afterwards, she kindly spoke to BSB about her research.

Love them or hate them, exosomes were a hot topic in Washington DC and something you should be aware of, if you aren’t already.

This post continues our volley of expert interviews from AACR17 and is the ninth in the series.

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Dr James Gulley is Chief of the Genito-Urinary malignancies branch and Director of the Medical Oncology service at the National Cancer Institute (NCI) in the National Institutes of Health. He’s a world-leading GU cancer expert and at the forefront of pioneering research to make cancer immunotherapy work in prostate cancer.

We last spoke to him at ASCO 2015 (See post: The future of prostate cancer immunotherapy). You can listen to excerpts from this interview on Episode 4 of the Novel Targets podcast (See: The non-inflamed tumour show).

Almost two years on, and new research by Dr Gulley and colleagues from the NCI shows that the STING pathway may have an important role to play in prostate cancer immunotherapy. Activation of this pathway through a novel mechanism could turn a cold non-inflamed tumor into a more inflamed or hotter one in men with advanced prostate cancer. How cool is that?!

At the 2017 annual meeting of the American Association for Cancer Research (AACR) that was recently held in Washington DC, Dr Gulley graciously spoke to BSB about some of the novel trials that are underway at the NCI, with the aim of making cancer immunotherapy work in men with advanced prostate cancer.

Dr Jim Gulley, NCI at AACR17

This is the seventh expert interviews in our series from AACR17 where we explore the conundrum:

How does Dr Gulley plan to light the immune camp fire in prostate cancer?

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After yesterday’s popular update on Ignyta where we posted our recent interview with the CEO, Dr Jonathan Lim prior to the 2Q conference call, a flood of questions have come in from eager beaver BSB readers.

Rather than add to an already lengthy article, this seemed a good opportunity to start afresh and do our latest Reader Q&A mailbag on a specific topic, namely the TRK/ROS1/ALK space.

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Tropomyosin receptor kinase (TRK) inhibitors are not a name that rolls off the tongue easily and yet this niche is attracting a lot of interest from observers curious to learn more about a highly targeted approach to rare oncogenes such as TRK, ROS1 and ALK that occur in several different tumour types.

Much of the focus has been on the more commonly expressed ALK-positive lung cancers with crizotinib, ceritinib, alectinib, brigatinib, lorlatinib and others. Crizotinib also targets ROS1 and is approved by the FDA in metastatic NSCLC whose tumors are ROS1-positive.

As the next part of the development in this sphere, TRK and ROS1 mutations are now in the spotlight. Indeed, we have been reporting on the data since 2014, which has been encouraging thus far, particularly from two companies, namely Ignyta and Loxo Oncology.  These two agents differ in that entrectinib targets TRK/ROS1/ALK whereas larotrectinib is a specific pan TRK inhibitor.

There was a new raft of data at the recent AACR annual meeting and more data is expected at the forthcoming ASCO conference.

Here, we take a look under the hood through the lens of one of the small biotechs in this space via a candid interview with Ignyta CEO, Dr Jonathan Lim.

Dr Jonathan Lim, CEO Ignyta

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Over the years we’ve interviewed folks from numerous pharma and biotech companies here on BSB, including those with targeted therapies (small and large), as well as immunotherapies.

Some companies have small pipelines and may be forced by circumstances to explore what they have or seek collaborations with bigger partners.

For big pharmas with large pockets plus broad and deeper pipelines, the challenge is quite different – how do you prioritise potential combinations and tumour targets given it is impossible to evaluate them all in the clinic? How do you create differential advantage and value when you’re relatively later to market compared to your competitors?

In the BSB spotlight this week we have two researchers in clinical development and R&D from the same company, who happen to have both elements in their pipeline in areas of high competition.

Part one of our latest mini-series explores the IO side of the business as we look ‘Through the Keyhole’ at what’s going on in terms of biomarkers, monotherapy trials, combination studies (both IO-IO and IO-targeted) and what to expect in the near-term future later this year. It’s a wide ranging, candid, and fascinating discussion that highlights a lot of potential in terms of what could happen with a large pipeline.

In all, it makes for rather interesting reading and certainly changed how I perceived the company’s efforts in the IO sphere (for the better, I might add).  So what’s fascinating about their approach and what can we learn from their progress to date?

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At the AACR 2017 annual meeting, there was a surprising amount of early clinical data on offer, particularly in the field of cancer immunotherapy.

A shortage of reliable preclinical models that predict human response to cancer immunotherapy has led to a mad rush to the clinic to do trials in man – thee are now over 800 combination trials – if anyone wants to try and follow them all!

If you missed it do listen to the Of Mice and Men” episode of the Novel Targets Podcast recorded at AACR 2016 that features experts such as Dr Bernard Fox (@BernardAFox) and Professor Cornelius “Kees” Melief (Leiden) who discuss the challenges of mouse models.

Several thought leaders at this year’s AACR annual meting described it as “mini ASCO” given the focus on clinical data, with several plenary sessions devoted to the results of early trials.

Dr Julie Brahmer at AACR17 in Washington DC

At AACR17, Dr Julie Brahmer, a leading lung cancer expert and an Associate Professor of Oncology at the Johns Hopkins Bloomberg Kimmel Institute presented long-term survival data for nivolumab in second-line non-small cell lung cancer (NSCLC).

The 5-year survival rate of 16% with a single agent checkpoint inhibitor, while better than historical data with chemotherapy (~4%), is far from being a home-run, illustrating what a dismal disease this is to treat.

One of the challenges that we are starting to see with checkpoint inhibitor cancer immunotherapy is immune escape or acquired resistance in some patients. They may have an objective or partial response, and then relapse and progress (acquired resistance), or they may not respond at all (primary resistance).

From our experience with targeted therapies, it should perhaps come as no surprise that cancers may evolve, adapt and seek to evade immune detection. There are also many inhibitory factors in the tumour microenvironment to overcome in order to enable an immune response.

At AACR17, Dr Brahmer kindly spoke to BSB about what researchers at Johns Hopkins have learnt about checkpoint inhibitor resistance in lung cancer so far. Her insights are both insightful and very useful when we consider what to watch out for at the forthcoming ASCO meeting.

This post is part of our on-going series of expert interviews from AACR17.

In the additional commentary, now that the ASCO17 abstract titles are publicly available, we’ve also highlighted a few that caught our attention.  This is the first in our series of previews of ASCO17. We’ll be rolling out more hybrid posts as we segue our coverage from AACR17 to ASCO17.

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Long time attendees at the annual meeting of the American Association for Cancer Research (AACR) know that there are usually interesting posters and sessions buried on the last day of the meeting.

This year was no exception, with a major symposium on CAR T Cell Cancer Immunotherapy chaired by Michael Jensen MD (pictured right).

BSB readers will recall we interviewed him at the 2016 BMT Tandem meeting in Honolulu (See post: Optimizing CD19 CAR T cell therapy).  Excerpts from this interview also featured in Episode 14 – Cell Therapy Pioneers of the Novel Targets Podcast.

The CAR T symposium on the last day of AACR was one of my highlights of the meeting. The three speakers were:

  • Michael Jensen, MD (Seattle Children’s) Engineering Next Generation CAR T cells using Synthetic Biology-Inspired Technologies
  • Terry J. Fry, MD (National Cancer Institute) Defining and overcoming limitations of CD19 CAR immunotherapy in pediatric ALL
  • Christine E. Brown, PhD (City of Hope) Progress and Challenge in CAR T Cell Therapy for Brain Tumors

Each of these presentations would merit a full blog post in their own right, but in this particular post we’re focusing on CAR T cell therapy targeting glioblastoma multiforme (GBM).

GBM is the most common primary malignant brain tumor, and one with a dismal prognosis – the 5-year survival rate is only around 5%, so there is also a high unmet medical need for new effective treatment options. This devastating disease has proven to be a miserable graveyard for Pharma over the last decade, with many agents unfortunately ending up in dog drug heaven.

After her AACR17 presentation, Dr Brown kindly spoke to BSB.

This post is part of our series of thouight leader interviews from AACR17. It also continues our ongoing posts on the adoptive cellular therapy landscape, and in particular, CAR modified T cells.

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The majority of patients do not respond to cancer immunotherapy. That’s a fact. If you don’t have an immune response to start with, there’s no point giving a checkpoint inhibitor on its own because there are no T cells present in the tumor.

Dr Bernie Fox (@BernardAFox), a world leading cancer immunotherapy expert from Earle Chiles Research Institute in Portland, nailed this a year ago on the Novel Targets Podcast:

“What I teach the first year medical students is that if you have metastatic cancer, the only thing that makes a difference in your life is whether you’ve got your immune system turned on. If it’s not turned on, it doesn’t make a difference what you get, chemo, radiation, surgery, you aren’t going to do well.”

Lincoln Memorial, Washington DC

As we have seen with targeted therapies, drugs can also stop working as a result of acquired resistance. This is also true with cancer immunotherapy treatment.  Cancer constantly evolves and finds ways to bypass or evade detection or ways to kill it.

Faced with a complex jigsaw where we only have some of the pieces in place and an evil double sided version as a model for sneaky advanced cancers, where are we in overcoming cancer immunotherapy resistance?

At the recent AACR annual meeting we spoke with a rising star – an up and coming thought leader in the field of cancer immunotherapy who has taken all the disparate information out there and come up with a perspective on where the field is at and where it needs to go.

Jason Luke MD FACP (@jasonlukemd) is an Assistant Professor at the University of Chicago where, as a medical oncologist, he leads multiple early stage cancer immunotherapy drug development trials and treats patients with melanoma.

Dr Jason Luke AACR17

Working with colleagues such as Dr Tom Gajewski, he has a unique perspective on cancer immunotherapy resistance, and how to overcome this. Dr Luke kindly spoke to BSB in Washington DC.

This is the 3rd post in our series of expert interviews from AACR17.

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