Yesterday Novartis announced the initial data from the JULIET trial in relapsed/refractory aggressive lymphomas such as diffuse large cell lymphomas (DLBCL) that were presented at the upcoming International Conference on Malignant Lymphoma (iCML) meeting in Lugano.
Here at BSB, we’ve been following CAR T cell therapy developments in earnest since 2012 when Penn and Novartis first announced their collaboration to develop what is now known as CTL019.
Five years on, we now have two such cell therapy products already filed with the Health Authorities and the JULIET trial will likely be the third indication submitted by the end of the year. This niche is now well established for regular readers and not something that has been a flash in the pan over a year or so.
There are a few interesting points of note on the CAR T cell front that are also worth exploring in conjunction with this news.
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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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It’s finally time…
US Capitol Building, DC
By popular request from BSB readers, we have a CAR T cell therapy preview of the main abstracts to watch out for, including talks and posters, and what emerging themes to expect are likely to be.
If you are registered on the AACR site and signed in, then clicking on any of the abstracts highlighted in this review will enable you to add any interesting ones you fancy to your conference itinerary.
There’s a surprising amount to cover this year, especially when we consider the incredible work that’s ongoing to address a number of suboptimal aspects in the construct developments. It’s continuing to progress at warp speed, so hold onto your hats and buckle down for our latest rock around the AACR clock.
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Hans Bishop, Juno
After a rocky 2016 for Juno with JCAR015 and the trial that imploded unexpectedly and badly, the CEO Hans Bishop quietly announced that announced that ROCKET has been abandoned:
“2016 was a year of progress and learning for Juno and the cancer immunotherapy field. We continue to experience encouraging signs of clinical benefit in our trial addressing NHL, but we also recognize the unfortunate and unexpected toxicity we saw in our trial addressing ALL with JCAR015. We have decided not to move forward with the ROCKET trial or JCAR015 at this time.”
A strange year of hubris attracting nemesis might be another way of describing the events for some observers.
We covered the Juno roller coaster and events in July and December 2016 for those who want to catch up on the full history of this unfortunate and ongoing debacle:
Where does the latest Juno news leave things and what can we expect going forward?
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ASH16 in San Diego
Today we resume our coverage from the recent American Society of Hematology (ASH16) annual meeting with a look at some fascinating and highly compelling science that was presented in an obscure and hard to find tiny hall in San Diego.
This story is also about how a small biotech company that many casual observers may not even be aware of, is taking advantage of advances recent research to grab a clinical lead in a very specialised field in oncology that may yield a novel approach worthy of taking notice of..
Genomics is increasingly becoming a core element of cancer research. Think of it as the alphabet soup of molecular biology concerned with the structure, function, evolution, and mapping of genomes.
Once we understand and identify the genomic landscape in health and diseases such as cancer, it allows numerous platforms to evolve whereby those unique differences can be identified (as driver vs. passenger mutations, for example), explored in depth, and later key ones targeted with therapeutics. Inevitably, there are many ways to do this.
Much of the focus in genomics has been on DNA, but what about RNA?
RNA is important because a mistake – even a single nucleotide – can be devastating to the cell, and a reliable, repeatable method of RNA processing is necessary to ensure cell survival. Mis-splicing can thus lead to the development of new point mutations and genomic instability deep in the cell nucleus, potentially causing the evolution of certain cancers.
Paradoxically, these aberrations also offer novel therapeutic targets – but are they druggable?
What we are exploring here is a completely different approach, both in terms of how a fledgling company is funded and also the type of research that is conducted.
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Much of the focus in multiple myeloma over the last decade has focused on two key drug classes – proteasome inhibitors and IMiDs – with some recent approvals for monoclonal antibodies targeting key proteins on the surface of malignant myeloma cells such as CD38.
#ASH16 in San Diego
Combinations of these core therapies have lead to a noticeable improvement in outcomes for people living with the disease – from 3-4 years over a decade ago to now approaching 10 years post diagnosis.
If we want to continuously beat the status quo and improve on the chronicity, however, it is likely that several things will need to happen:
- Better understand mechanisms of resistance that induce relapse
- Develop predictive biomarkers of response
- Identify novel therapeutic targets
Here. we focus on the latest preclinical findings that were recently presented at the American Society of Hematology (ASH) in San Diego and explore where the future might be headed in this disease.
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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 pioneers of CAR T cell therapy in children is Dr Stephan Grupp, who is Director of the Cancer Immunotherapy Program at The Children’s Hospital of Philadelphia (CHOP).
Dr Stephan Grupp ASH16
He led the way in developing ways of treating cytokine release (CRS) syndrome through the use of tocilizumab. At the recent American Society of Hematology annual meeting, Dr Grupp presented the results of the ELIANA study, the first global, multi-center clinical trial with CTL019 (Novartis) in pediatric acute lymphoblastic leukemia (p-ALL).
What was surprising to many at ASH was that despite the fact that CAR T cell therapy is one of the hottest topics in hematology (if not the hottest), many presentations were in small (tiny) meeting rooms, which many people could not get into. Several overflow rooms were rapidly opened up, but still people were left out. Someone clearly did not get the memo!
If you didn’t make into the meeting room at ASH to hear Dr Grupp, he kindly spoke to BSB about the data he presented and also shared his perspective of what the future may hold for CAR T cell therapy in pediatric ALL.
There’s also additional commentary on some of the other key CAR T cell presentations that caught our attention at ASH.
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Over the last five years the face of the chronic lymphocytic leukemia (CLL) landscape has changed quite dramatically with the advent of new approvals in several categories. These include anti-CD20 antibodies, BTK inhibitors, PI3K inhibitors and apoptotic Bcl–2 inhibitors.
In yesterday’s wide ranging interview we explored in-depth how these therapies are impacting the broader landscape, as well as emerging trends in how these regimens might be used.
In Part 2 of the ongoing series, we spoke with another CLL expert and explored promising new and earlier agents in development for a different perspective on how outcomes might be improved further.
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Targeted therapy and Chemo-Immunotherapy in CLL
At last December’s 2016 annual meeting of the American Society of Hematology, one of the areas that attracted attention was the latest clinical data on the treatment of chronic lymphocytic leukemia (CLL).
ASH 2016 in San Diego
In recent years, we’ve seen tremendous advances in the field with several new agents approved such as obintuzumab, ibrutinib, idelalisib, and venetoclax. There are also new treatment options available for CLL patients with high risk disease such as 17p deletions (Del17p).
Other new targeted therapies such as acalabrutinib are now in clinical development, plus we have CAR T cell therapies and combination strategies also being evaluated in the clinic.
So what was the hot news from #ASH16 in CLL?
- Does chemotherapy still have a role or is it a targeted therapy world?
- Are we further forward towards a cure?
- Have we worked out how to identify those at risk of relapse?
- Will CAR T cell therapy be a game changer in CLL?
- Is financial toxicity going to be an issue with combination strategies?
BSB interviewed two experts in CLL while in San Diego who kindly shared their thoughts on which CLL data impressed them at the ASH annual meeting and discussed some of the big strategic issues facing the field right now. These interviews are being posted in a two-part series.
Part 1 today answers some of the questions highlighted above and explores the changing face of the broader CLL landscape.
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