As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.
One way to do this is to better understand the tumour microenvironment.
Wall of people at ASH16 in San Diego
If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.
If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.
At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?
Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.
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One of the interesting and exciting parts of major medical meetings such as the ASH annual meeting, held last month in San Diego, is hearing about new compounds in development.
When it comes to the treatment of aggressive lymphomas, there remains a high unmet medical need to improve the response rate to first line treatment, as well as offer better outcomes post relapse.
At #ASH16, we heard more about a novel ADC called polatuzumab vedotin (Genentech/Roche).
Preliminary safety and clinical data for polatuzumab plus obinituzumab in relapsed or refractory Non-Hodgkin Lymphoma (NHL) was presented in an oral session by Dr Tycel Phillips (University of Michigan).
Three posters were also presented showing early data in combination trials in R/R follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), as well as in first line DLBCL.
To find out more about the potential of this novel ADC, BSB spoke with Dr Michael Wenger, Senior Group Medical Director at Roche Genentech.
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John P. Leonard, MD is the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell in New York. He’s a Lymphoma specialist.
Dr John Leonard at ASH16
Like many hematologists, he’s embraced Twitter as way to share his expertise with others in the hematology community. You can follow him at @JohnPLeonardMD.
Over the last couple of years prior to the ASH annual meeting, Dr Leonard has highlighted 10 lymphoma abstracts that caught his attention. You can tell he gets excellent social media pickup by the fact he’s even generated a hashtag to make them easy to find: #Leonardlist and other hematologists generate conversations around his eagerly awaited picks:
In case you missed them on Twitter, and in the spirit of David Letterman, Dr Leonard took me through this year’s #LeonardList and thoughtfully explained in detail why each selection made the cut… for oncology watchers, the why is often more important than the what.
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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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Seattle Genetics ASH 2015 Exhibit – photo with permission
San Francisco – Seattle Genetics are presenting later today at the JP Morgan Healthcare conference (2.30pm PST) and we’ll be covering this as part of our daily rolling blog.
As blog subscribers already know, one of the presentations that caught our attention at ASH 2015 was the updated phase 1 data for Seattle Genetics latest ADC, denintuzumab mafodotin (SGN-CD19A) in B-cell malignancies, including diffuse large B-Cell lymphoma (DLBCL).
Unlike with brentuximab vedotin, where one of the main side effects seen is peripheral neuropathy, with 19A, as it’s commonly known, there is ocular toxicity. Will this toxicity bring the house of cards down for Seattle Genetics?
I spoke to President and CEO Clay Siegall, PhD about this, the company’s corporate strategy moving forwards in 2016 and how checkpoint inhibitors may impact classical Hodgkin’s Lymphoma (cHL).
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Aggressive lymphoma… the very phrase is enough to send chills down your spine!
In the past, much of the focus at previous American Society of Hematology (ASH) meetings in this area has focused on the myriad of chemotherapy regimens and dose/schedule optimisations that followed in trying to boost patient outcomes.
This year, I’m pleased to say that things have quite a different flavour with numerous new therapeutics and promising combinations in development.
Some of these are inevitably hypothesis testing, while others will be up-levelling to large randomised controlled multi-centre trials.
As part of our ongoing preview series, we take a look at the different categories to watch out for beyond chemotherapy. These include monoclonal antibodies, antibody drug conjugates, targeted therapies and yes, even immunotherapies.
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One of the hotly debated topics at the 2014 American Society of Hematology (ASH) annual meeting was the arrival of checkpoint data in classical Hodgkin’s lymphoma (cHL), with initial data presented on 20-30 patients with relapsed or refractory cHL who received either nivolumab (BMS) or pembrolizumab (Merck) in open label, single agent trials.
Updated phase I data is expected to be presented at the 2015 ASH annual meeting in Orlando (Dec 5-8) (Twitter #ASH15)
At the recent ESMO symposium on Immuno-Oncology in Lausanne (Twitter #Immuno15) – great hashtag, there was an excellent overview of checkpoint blockade in lymphomas. What did this tell us about progress in this disease and where are things going?
The ESMO IO meeting set the scene for what we can expect at ASH this year?
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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.
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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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