Biotech Strategy Blog

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

Posts tagged ‘AML’

Targeting Natural Killer Cells in AML

Cellular immunotherapy with Natural Killer (NK) cells is emerging as a potentially effective treatment option for older patients (more than 60 years of age) with Acute Myeloid Leukemia (AML).

AML remains a disease with high unmet medical need, particular for those patients who relapse and are ineligible for a stem cell transplant (SCT).

There’s considerable buzz around adoptive cellular therapy and, in particular, chimeric antigen receptor modified T cells (CAR T cells). It is important, however, to note that there are other approaches worthy of consideration. See post: Could a Novel Cell Therapy replace CAR T cell therapy?

Cancer immunotherapy targeting NK cells has already shown some early promising results in AML. We await the read out of the EFFIKIR trial data for lirilumab (Innate Pharma/BMS), an anti KIR (killer inhibitory receptor monoclonal antibody (See post: Innate Pharma at an Inflexion Point, an interview with Hervé Brailly).

357-cover-sourceRizwan Romee, Maximilian Rosario, Melissa Berrien-Elliott and colleagues at the Washington University School of Medicine in St Louis (@WUSTLmed) recently published the results of a clinical trial with a novel NK cell therapy: “Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.”

The paper was published on 21 September, 2016 in Science Translational Medicine (link).

Melissa Berrien-Elliott, PhD. Photo Credit: Fehniger Laboratory, Washington University

To better understand the trial results and what they tell us about NK cell therapy in AML, BSB spoke with one of the joint first authors, Melissa Berrien-Elliot, PhD (pictured right) and senior author, Todd A Fehniger MD PhD, Associate Professor of Medicine at Washington University.

This post is part of our series on the innate immune system.

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What next for Bcl2 inhibitors after venetoclax’s approval in CLL?

This week certainly turned out to be a defining tale of two drugs with a chequered history…

Lion DancersFirst off, the FDA approved AbbVie/Genentech’s venetoclax, now known as Venclexta, in a subset of CLL patients with 17p deletions. These patients have a historically poor prognosis and the approval goes some way to addressing the high unmet medical need.

Secondly, another biotech company, Clovis Oncology, got slammed by ODAC with a 12-1 vote to wait for phase 3 data from the TIGER-3 trial for rociletinib to better determine the efficacy:safety benefit profile.

For a long while it seemed that AbbVie had nothing but toil and trouble over the tumour lysis syndrome (TLS) issues giving them some significant challenges to overcome, while Clovis were one of the new darlings of Wall Street.

In the final dash to the market, the tables were turned almost at the 11th hour and fortunes stunningly reversed.  Yet a mere eighteen months ago, few industry watchers would have predicted the difference in outcomes.

In our latest AACR Preview series, we take a look at Bcl2 inhibition and where some of the emerging opportunities might lie based on new preclinical research that is being presented here in New Orleans this weekend.  It makes for interesting reading.

While one tiger is licking its wounds, another is smacking it chops at what the future might hold for new combination approaches; how the tails have literally turned.

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Could a Novel Cell Therapy replace CAR T Cell Therapy?

King Kamehameha Statue Honolulu HI

King Kamehameha Statue, Honolulu HI

Honolulu: we’re continuing our coverage of the 2016 BMT Tandem meeting with a thought leader interview about a novel cancer immunotherapy approach that we’re excited about.

The cancer cell therapy landscape is still vastly uncharted territory in many respects.

The first CD19 targeted CAR T cell therapies expected to reach the market in 2017 are unlikely to be best-in-class, which leaves the commercial door open for other approaches that may be better, cheaper or more accessible.

If you are in the CAR T cell therapy space, there are plenty of competitive threats on the horizon, and the novel approach discussed in this post is one of them!

We’d heard a little about it, but hadn’t explored the concept in any detail, so were delighted to talk with a leading expert at the BMT Tandem meeting in Honolulu.

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Midostaurin in AML – Better Late than Never!

Acute Myeloid Leukemia (AML) is challenging disease to treat and quite distinctly different from its cousin, acute lymphoblastic leukemia (ALL).  The first is more common in adults, while the second is more prevalent in children.  Success rates with pediatric ALL have far outstripped what we have achieved with adults in AML to date, partly due to the elderly nature of the disease making for poorer outcomes with stem cell transplants (SCT), as well as increased clonal heterogeneity and cytogenetic complexity with age.

Quite a few FLT3 inhibitors have come and gone over the years – many keen observers will remember Cephalon’s (now Teva) TKI called CEP-701, which was tested in relapsed/refractory disease and Elderly AML, for example, and slid off largely unnoticed to dog drug heaven.

How much does clinical trial design impact a drug’s success or failure?

Sometimes quite a bit, as this story with midostaurin demonstrates; limited activity in advanced disease but much more dramatic results in the upfront setting.  Clearly, sometimes testing drugs in later disease does not predict their future performance elsewhere!

To put more colour on the data presented at ASH, we interviewed a thought leader in adult AML for his perspective on the FLT3 R&D developments.

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Targeting MYC – the undruggable protein – or is it?

Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.

Reading Terminal Clock

Reading Terminal Clock, Philadelphia

Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC.  MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers.  These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.

For cancer patients with advanced disease, the clock is ticking on time they have left.

Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evan (Cambridge) noted:

“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”

Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically.  What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.

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Will venetoclax impact in hematologic malignancies

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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Top 10 AML abstracts at ASH 2014

San Francisco F line Trolley originally from MilanSan Francisco – Acute Myeloid Leukemia (AML) is largely a disease of the elderly since it is uncommon before the age of 45. It generally has a much poorer prognosis compared to other leukemias such as CML and even ALL.

There are two main treatment options – high chemotherapy (ara-C is the main bedrock) or a stem cell transplant in those patients who are considered eligible. With the average age at diagnosis being ~66yo, many patients may be elderly and frail, making a SCT not a viable option.

Ara-C (cytarabine) has been around for many years and despite numerous clinical trials, it has yet to be displaced. There’s plenty of room for improvement though, and a high unmet medical need still exists. The good news is that despite the challenge of finding a highly effective yet well tolerated therapy, there’s a lot of R&D activity in this space.

In this preview of the data to be presented at the American Society of Hematology (ASH) annual meeting in San Francisco, I highlight my top 10 AML abstracts that are worth checking out.

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Can Agios score a winner with their anti-cancer metabolism molecules?

Biotech IPOs were a pretty hot topic in 2013, with some of the young stars in oncology seeing very good uptake and prices. Two companies that come to mind are Foundation Medicine and Agios Pharmaceuticals.  Last week, we covered Foundation Medicine (FMI) and their progress with genomic testing, which is used by a number of Pharma companies including Novartis, in their clinical trial program. Interestingly, another company using their platform is Agios (AGIO), a start up biotechnology company focusing on metabolism and its errant mechanisms in cancer related areas. Both Foundation Medicine and Agios are based in Cambridge, MA.

Agios have an impressive Founder list in Lew Cantley, Tak Mak, Craig Thompson, all strong scientists with an interest in biochemistry and metabolism. The Scientific Advisory Board is equally impressive and includes Charles Sawyers, Jeff Engelman, Pier Paolo Pandolfi and David Sabatini, to name a few luminaries. The last two are well known metabolism researchers who have published extensively on the PI3K pathway, as has Lew Cantley. Craig Thompson has published significant research on IDH metabolism and his lectures on the topic are always fascinating and educational.

You can imagine that board meetings at Agios could well be rather different from the average biotech if the founders or the advisory board decided to brainstorm or riff on the science… Whoa, who wouldn’t want to be a fly on the wall and learn from the experts?  For a CEO, though, it might be akin to herding cats!  That said, I’m impressed that the company has such a clear, focused approach.

The company have a number of industry partnerships, including a recent extension last month to their existing agreement with Celgene.

With my background in biochemistry, I’m naturally drawn to follow metabolism-based approaches including the PI3K-AKT-mTOR pathway and anything that involves the TCA cycle.  It’s a highly complex area, not least because most cancers have a high demand for metabolic inputs such as glucose and glutamine in order to constantly drive tumour proliferation and survival.

David SchenkeinAt the recent ASH meeting, they presented interesting preclinical data for AG-221 using IDH2 mutant AML xenografts. While in New Orleans,  I had the opportunity to sit down with the Agios CEO, Dr David Schenkein, and discuss their approach, challenges and direction in some detail. He is also presenting at the JP Morgan Healthcare Conference today and giving a business update on the company’s progress.

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