Holbrook Kohrt MD PhD (pictured right) is a Stanford medical oncologist and clinical researcher who is leading the way in cancer immunotherapy combination strategies targeting CD137 (4-1BB).
He’s a speaker I greatly enjoy listening to at meetings. Earlier this year at The American Association of Immunologists (AAI) annual meeting (Immunology 2015) in New Orleans, he gave a noteworthy presentation on combination monoclonal antibody therapy.
The potential of a combination of an anti-CD137 monoclonal antibody such as urelumab plus an anti-CD20 such as rituximab, was one that he appeared to be particularly excited about.
Dr Kohrt kindly spoke with BSB and shared his thoughts on the potential of immune modulators, which instead of acting as inhibitors to “release the brake,” like checkpoint inhibitors, act as agonists to “step on the gas” and rev up the immune system. This is a concept that many Pharma companies are currently looking to explore for new drug development opportunities, for example:
Source: Roche Media Briefing at ESMO 2014 in Madrid
When it comes to combination strategies, the big unanswered questions are which ones will produce big gains in response rates and survival outcomes, and which ones will be duds?
After all, much like targeted therapies, not all targets will be relevant in all tumour types – it will depend on the underlying immune system.
In New Orleans, Dr Kohrt talked about the potential advantages and concerns around combination strategies and why he’s particularly interested in CD137 as a novel target for immunotherapy.
In-Memorium Holbrook Kohrt
It is with great sadness that we must report that Holbrook Kohrt is no longer with us. He died, aged 38, on February 24, 2016.
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Much has been written about the success of checkpoint blockade in solid tumours over the last couple of years with the advent of anti-CTLA4 therapy (ipilimumab/Yervoy) for metastatic melanoma followed by the more recent approval of the anti-PD-1 antibodies in advanced melanoma (pembrolizumab/Keytruda and nivolumab/Opdivo) and lung cancer (nivolumab).
What about hematologic malignancies though?
At the recent American Society of Hematology (ASH) conference, we heard about the first clinical data for anti-PD1 antibodies in patients with refractory classic Hodgkins Lymphomas (cHL) and saw some impressive results. Interestingly, though, the early preclinical work was conducted in mice looking at CTLA4 blockade in a variety of tumours, both solid and liquid.
Is there a rationale for targeting CTLA4 in leukemias, lymphomas and even myeloma? New data presented at a medical meeting in patients with heavily pre-treated and relapsed disease post stem cell transplantation suggests that this might be feasible.
Check out to today’s article to learn more about this clinical opportunity in more detail – you can log in or subscribe in the box below.
The 2015 Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2015) was held in Istanbul from March 22-25, where it offered a European perspective on some of the latest developments in cancer immunotherapy.
We’ve heard a lot in the United States about the early CAR T cell therapy clinical trial results from institutions such as UPenn, CHOP, MSKCC, Fred Hutchinson, Seattle Children’s, the NCI, and MD Anderson to name but a few, so it was good to see a leading a European center join the club: University College London (UCL).
While completing a Masters degree in Human and Applied Physiology at King’s College London, I spent several weeks training at UCL and particularly enjoyed the intercollegiality of the University of London.
At EBMT15, Dr Sara Ghorashian Clinical Training Fellow at the Insitute of Child Health at UCL, presented data on a phase 1 trial of Epstein Barr virus (EBV) specific T cells transduced with a first generation CD19 Chimeric Antigen Receptor (CAR). The trial data was first reported by Dr Ghorashian (pictured below) in an oral presentation at #ASH14 (Abstract 383).
Dr Ghorashian stated at EBMT that UCL have several CAR T cell therapy trials planned.
Readers will be aware that earlier this year that UCL spun-off a series A funded company, Autolus, to commercialize their CAR T cell therapy research.
Although £30m from Syncona (a subsidiary of the Wellcome Trust) is not a lot of money by US investment standards, UCL is nonetheless a European center to watch if you have an interest in the CAR-T competitive landscape.
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After last week’s post on therapeutic tumor infiltrating lymphocytes (TILs), we received a bunch of questions from readers.
I don’t have time to answer them all in detail individually (sorry!), but it does provide an opportunity to review the evolving landscape and address some of them within the latest article.
It seems to be a good time to take a broader look at T cell manipulation, especially as it pertains to the application of TILs, chimeric antigen receptors (CAR), and T cell receptors (TCR).
We’ve certainly come along way since the historic lecture in 1991 pictured right (photo: National Institutes of Health), but there’s still some way to go before the full potential of cancer immunotherapy is reached.
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Over the last two years we’ve written extensively about chimeric antigen receptor (CAR) T cell therapies, checkpoint inhibitors and immune agonists (stimulants), yet these aren’t the only novel immunotherapies that are being developed to target cancer cells.
One area that hasn’t received a lot of attention is adoptive cell transfer (ACT) and therapeutic tumour infiltrating lymphocytes (TILs).
- What exactly are these approaches and what progress has taken place so far?
- Where is this field going in the near future?
To answer these questions, we put together a primer based on the groundbreaking research of Dr Steven Rosenberg (NCI Surgical Branch), and his invited talk at the recent American Society of Hematology (ASH) meeting.
As Rosenberg himself noted, what they’re doing is pretty daunting and yet, results so far have shown some impressive responses in some patients, especially those with metastatic melanoma, but other cancers have also responded well to this novel approach.
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A couple of years ago we had a lot of fun here on BSB following the progress of ibrutinib (Imbruvica), obinutuzumab (Gazyva), and idelalisib (Zydelig) in CLL and indolent NHL. It seemed back then that the stunning trio were the hot topics for some time at ASCO and ASH meetings. Exciting times! All three target different entities (BTK, anti-CD20 and PI3K-delta) and made it past the tape to market, with Gazyva leading, Imbruvica a close second and Zydelig a slightly more distant third. I was reminded of the race again over the last week or so as the 4Q earnings were announced, with Pharmacyclics reporting almost $500M for Imbruvica last year and estimating sales to hit $1B in 2015. In contrast, Zydelig revenues for 2014 were $23M, reflective of their much later market entry in the US.
Still, that was a pretty impressive set of drugs all in development at the same time.
Two other agents we also reported on regularly were Infinity’s IPI-145, a PI3K delta-gamma inhibitor, and ABT-199/GDC-0199 (now known as venetoclax). I haven’t heard much about the former of late, but after a few missteps, the next big question to consider is whether venetoclax is coming back strongly or destined for dog drug heaven?
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San Francisco – “Manic Monday” is what I call Monday at the annual meeting of the American Society of Hematology. It’s when the majority of oral presentations take place in multiple parallel sessions that require you to run between meeting rooms if you want to follow a particular drug across different blood cancers.
It’s even more challenging this year by the fact the conference is in three buildings at the Moscone Center in San Francisco. While Moscone North and South are interconnected thanks to an underground atrium, to get to sessions in Moscone West from North/South you have to go out of the building, cross one or two main roads, then go up elevators to the second or third floors. Not ideal! I think ASH is now too big for the venue.
Looking back on yesterday, it was a privilege to be in the audience when Dr Kanti Rai received a well-deserved lifetime achievement award for his work in chronic lymphocytic leukemia (CLL). A visibily moved Dr Rai was given a standing ovation by the thousands present in the plenary hall.
Expect the #ASH14 Twitter stream today to be like opening the tap to run a bath. I congratulate all the hematology experts who have shared data and commentary from sessions via social media. #ASH14 stands out in terms of expert engagement and a high signal to noise ratio.
If there was an award for best conference coverage of #ASH14 on Twitter I would nominate @drmiguelperales.
Not only does Dr Perales from Sloan-Kettering share tweets from the sessions that he is in that are accurate and informative, but he frequently offers links to relevant papers for those that want to learn more. In addition to showcasing his expertise, this is a really good way to use social media to educate and inform. I look forward to his commentary, particularly if I am in another session at ASH. A must follow on Twitter!
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San Francisco – do you want to know the difference between Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma? Do you want to know what my top 10 abstracts are in Hodgkin’s Lymphoma and aggressive lymphomas that discuss promising new agents in development? Which of these abstracts should have been a plenary at the meeting?
If the answer is “Yes” to the above, then this blog post is for you!
When I consider what is worthy of a plenary presentation at a meeting like ASH, I think back to the Gleevec phase 1 data presented at ASH in 1999 when I was in Novartis Oncology New Products. It’s data that makes you go WOW!, is transformative or has the potential to change the field. That’s what Gleevec did in CML.
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This morning we heard that Juno Therapeutics have registered their plans with the SEC for an Initial Public Offering (IPO), highlighting the desire of the VC investors to generate a fast turnaround on their money before a multi-center trial of their CAR-T cell therapy has even started!
One of the challenges with CAR-T cell therapy is despite some stunning results, particularly in pediatric ALL, it remains an experimental one with toxicities that have to been managed. Adult patients, who are extremely sick, have died on trials. If I was at the end of the line faced with certain death, I’d probably roll the dice and take an experimental therapy, but CAR-T cell therapy does have challenges that need to be addressed.
Indeed at the Society for Immunotherapy of Cancer (SITC) meeting last week, one of the Hot Topic sessions that took place after the conference formally ended was in managing the toxicities associated with chimeric antigen receptor T cell (CAR-T) therapy.
Of particular concern for all CAR-T cell therapies in development is severe cytokine release syndrome (sCRS), which requires treatment in hospital intensive care.
Cytokine release syndrome (CRS) involves fevers, hypotension, hypoxia and even neurological toxicities. It’s been known for some time to be a challenging side effect of CAR-T therapy. We first wrote about it at ASH 2012.
As Novartis, Juno and Kite all look towards multi-center registration trials, the identification of patients at risk of severe CRS (sCRS) and the management of this in very sick, often end stage patients remains a real challenge, especially given that we don’t fully know what causes it to occur in some patients, but not others. Patient deaths due to sCRS are not good news on any clinical trial, and even less so when it’s a novel therapy in development.
One of the things I most enjoy in cancer research is hearing wonderful patient stories from oncologists who are at the coal face of clinical trials. They get to deal with death and dying every day and like those in Pharma R&D, also live for the successes, the drugs that make it through pipeline despite great odds against them and make a meaningful impact on the daily lives of ordinary people.
We’ve all heard topline data presented at medical conferences around the world, but what the summary data can’t tell you is how a drug can impact people in ways that are clinically meaningful yet are more obtuse to capture in the aggregate. This is why case studies at CME sessions are increasingly popular, because they add value and context to common issues in a way that a Kaplan-Meier curve can never do.
With the flurry of recent US and EU approvals for obinutuzumab (Gazyva), ibrutinib (Imbruvica) and the newest kid on the block, idelalisib (Zydelig), in CLL and indolent lymphomas, I wanted to take a look at these drugs from a different perspective.
A reader wrote in asking which of these new agents would emerge the winner and why?
Today’s post therefore offers some thoughts on the emerging CLL landscape now that we are shifting from new product development to the marketplace.
Drugs mentioned: Gazyva, Imbruvica, Zydelig, ABT–199/GDC–0199, Arzerra, IPI–145, CTL–019
Companies: Roche/Genentech, J&J/Pharmacyclics, Gilead, GSK, Infinity, Novartis
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