We have heard much hullabaloo about adoptive T cell therapy approaches with tumour infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cell therapies, but what about T cell receptor (TCR) therapy?
Over the last couple of years, various experts we have interviewed have alluded to TCR approaches in the pipeline that they have been involved in or come across, but this is not a topic we have covered in-depth as we, like many other observers, have been on the sidelines waiting for solid clinical data to mature.
That time finally came around at ASCO last month, where we had the opportunity to discuss an NY-ESO–1 based TCR with one of the companies in this space, namely Adaptimmune.
We also covered several other constructs they have in their pipeline.
Inevitably there have been quite a few R&D setbacks with some of the TCR approaches evaluated, going back to Dr Steven Rosenberg and the NIH experiments back in the 1990’s with MART–1 as a target.
I was therefore really intrigued to find out more about how are Adaptimmune faring, what technical and clinical challenges remain, where are the programs going, and what have we learned so far?
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We know that not every patient responds to checkpoint therapy and some may respond but then stop responding, so what can we learn about the tumour microenvironment in order to fix it?
To do this may well require retrospective analyses of the existing trials in order to learn what happened and figure out an improved design of the next wave of clinical trials with rationally based combinations (as opposed to randomly testing two molecules simply because that’s what a company has in its pipeline).
The other thing to consider is that while some people might have a high level of a particular marker or inhibitory factor up front, others may see rise on treatment as an adaptive response to immunotherapy. Those two situations may well require quite different approaches or regimens to address, making things much more complicated than originally thought.
Dr Kunle Odunsi (Roswell Park) at #AACR18
One topic that caught our attention in the run-up to AACR and subsequently during the meeting was a cytokine called transforming growth factor beta (TGF-β). We have covered IL–2, IL–6 and IL–15 developments quite extensively on BSB, but what of TGF-β?
As such, we decided to investigate this little known target further and explore the concept from different perspectives in both academia and industry.
Today, we begin this latest mini-series with a thought leader interview from an academic institution who is researching a novel approach to combination therapy based on TGF-β – here’s what he had to say about the topic…
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The Great Fire of London started 350 years ago in September 1666 following a fire in a Pudding Lane bakery. It highlights the potential of what a small fire can do once it takes hold – over the course of 3 days, 13,000 houses and 436 acres were destroyed. It forever changed the landscape of medieval London.
The Monument (pictured right) to commemorate the Great Fire was designed by Sir Christopher Wren. Constructed from 1671 – 1677, it is 202 feet in height, the distance to the bakery where the fire started. You can even walk up it, if you are in the area.
When we think about cancer immunotherapy, one of the emerging important trends is the need to “inflame” or set fire to the immune system, especially in those cancer patients who don’t have a pre-existing immune response.
We want to ignite the immune system, in the hope that it will create the equivalent of the Great Fire…
In this post we’re starting at mini-series looking at neoantigens, beginning with a primer on what they are and why they matter in cancer immunotherapy. In subsequent posts we’ll look at some of the innovative ways companies are identifying and targeting them.
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I was thinking that the reader mailbag questions this week would be full of straightforward easy to answer clinical questions, after all, they usually are post ASH and ASCO… but not this year!
T-cells attacking a cancer cell. Digital illustration.
Instead, there is a huge wall of intense focus on CAR T cell therapies and the latest round of intriguing developments in this space. While CARs have received much attention, TCR cell products have largely flown under the radar to date, although that may change.
What’s particularly interesting is that these charges could potentially be transformative or absolute duds – it’s unlikely to be an indifferent middle ground here.
Here, we answer questions on the ever-increasingly complex science that is ongoing in the TCR and CAR T cell fields.
In the next mailbag, we will cover the clinical questions arising from data at ASCO, so if you have any queries on the data in Chicago, there’s still time to send them in before next Friday!
If you are interested in the new developments in the complex world of gene editing and how they may impact the ever-changing adoptive cell therapy space, then this article is for you. Subscribers can log-in below or you can click the Blue Box to nab instant access!
Aloha! It will soon be time to pack your Hawaiian shirts for the forthcoming BMT Tandem Meeting in Hawaii (Twitter #BMTTandem16 – what a long hashtag!!)
Commonly known as “Tandem,” it’s the combined annual meetings of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the American Society for Blood and Marrow Transplantation (ASBMT).
Hawaii is great location for a meeting in February, and one that I’m sure will generate a lot of envy for those who can’t attend and are stuck in the winter cold and chill. Who said we don’t go the “extra mile” for BSB subs?
One of the presentations I’m looking forward to hearing at Tandem is by Ann Leen, PhD, who is an Associate Professor at Baylor College of Medicine.
Dr Leen will be talking about “Immunotherapy for Lymphoma using T cells Targeting Multiple Tumor-Associated Antigens.”
At last December’s ASH annual meeting, Dr Leen presented preliminary data with this novel approach in patients with Hodgkin’s Lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). After her ASH presentation, she kindly spoke to BSB.
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Sarcoma is something we call one disease but actually represents 50-70 different histologies, which poses challenges for drug development. Not only do you have to identify what’s the unique target, but it’s hard to accrue patients into trials, when a major center may only see a few of each sub-type.
Soft tissue sarcoma is an area of unmet medical need, and one I have been interested in since launching Gleevec in GIST (way back when) when I was fortunate to get to know many of the leading sarcoma experts.
George D. Demetri, MD. Photo Credit: DFCI
One of these is Dr George Demetri, who is Director, Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School.
At the recent European Cancer Congress in Vienna, I had the privilege to talk with Dr Demetri about some of the latest research in soft tissue sarcoma.
We spoke about cancer immunotherapy, new small molecules and monoclonal antibodies, and the potential of targeting the epigenetic machinery.
A lot of what Dr Demetri is doing is currently “under the radar” and while he didn’t give any secrets away, he did give some sense of where some breakthroughs may occur in the not too distant future. He also talked about how sarcomas with a specific target can be used for proof of concept clinical trials of novel agents.
Given the pressure that many companies are under to speed up their path to market strategies, accelerated approval in a rare tumour subset is one approach that can be considered.
It’s an exciting time in the field with the potential for several agents in development to move the needle and make a difference. I hope you enjoy this post, it was a real pleasure to talk with Dr Demetri again.
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Over the last year or two, we have covered a number of different pathways that are involved with the immune system including CD19 and 20, CTLA–4, PD–1 and PD-L1, IDO1, CD40, OX40, TIGIT, ICOS and others.
Today, it’s the turn of an oncoprotein called NY-ESO–1 that has been garnering quite a bit of attention of late and will also be highly relevant to some upcoming posts and thought leader interviews we have scheduled here on Biotech Strategy Blog. It’s always a good idea to cover the basics first, before exploring the more advanced concepts.
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Many years ago, I used to work in the sarcoma and GIST space, which is a very interesting and fascinating disease to explore from a biology perspective. There are many different subsets of sarcoma, several different histologies, as well as numerous targets such as KIT in gastrointestinal stromal tumours (GIST). Some of these subsets are sensitive to chemotherapy such as doxorubicin, while others such as GIST are sensitive to targeted therapies including imatinib, sunitinib, regorafenib etc. Imatinib (Gleevec) is particularly effective in GISTs with exon 11, while the less common exon 9 has been shown to be more sensitive to sunitinib (Sutent), for example.
Often pharma companies will work with the Sarcoma Alliance for Research through Collaboration (SARC) cooperative group to undertake a phase 1 allcomers trial to evaluate which subsets might be appropriate for a given therapy, before exploring a narrower inclusion/exclusion criteria in a larger phase 2 or 3 study. You can check out their current clinical trials in sarcomas here.
Overall, people with malignant sarcomas tend to be seen by specialist centres where there are usually clinical trials available, representing a way to determine which of the agents in development are superior to the current standard of care.
Dr Margaret von Mehren
One of my favourite moments at ASCO this year was escaping the heavily mobbed poster halls to sit down for a quiet ‘fireside chat’ and catching up with an expert in this field to learn more about the latest new developments in sarcoma.
I’m delighted to publish another thought leader discussion today on Biotech Strategy Blog (BSB), where we have an in-depth interview with Dr Margaret von Mehren, the Director of Sarcoma Oncology at Fox Chase Cancer Center. She has spent spent her career trying to identify new therapeutics for gastrointestinal stromal tumours (GIST), as well as soft tissue sarcomas (STS).
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