Biotech Strategy Blog

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

Posts tagged ‘hematologic malignancies’

“Find a bit of beauty in the world today. Share it. If you can’t find it, create it. Some days this may be hard to do. Persevere.”  ~ Lisa B. Adams

In the first part of the review on novel targets in hematologic malignancies, we covered five key areas in detail relating to emerging new agents around BTK, BRD, BET, and E3 ligase modulators (CELMoDs).

Continuing our look at some additional novel targets and agents in early development in hematologic malignancies, in part two of this series we explore four additional areas that piqued our interest.

These mostly involve either small molecules or monoclonal antibodies.

In the next series, we shall look at emerging immunotherapy related targets, but for now there’s plenty of targeted therapies to focus on!

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This is an extended update that I’ve been planning to write for some time, however, there was always some shiny new clinical data to highlight and discuss so it sadly stayed on the backburner!

Is the sun rising on CAR-T cell threats from the East?

Over the next few weeks, we will post some meaty reviews on various topics pertinent to cancer research R&D. They might involve a particular tumour type that is seeing extensive developments, an important or difficult target, or even a particular category approach, for example.

In the first of this new mini-series, we take a look at the CAR-T cell therapy niche and highlight some important new developments that are well worth watching out for.

Things are a-changin’ very rapidly here, including numerous R&D threats from the east (China) so it’s a good opportunity to take stock and look forward.

Here we go – hold on to your hats…

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Continuing our NK cell series, we turn to a different area of work within this niche, namely how cytokines can help boost effectiveness of the clinical responses in hematologic malignancies through their impact on memory-like cells.

Spring is in the air!

This is an important aspect to consider bearing in mind that while NK cells can be useful in attacking cancer cells, they are also notoriously more fickle and less durable than their T cell cousins in sustaining cytlotic effects.

How can this be fixed? What therapeutic approaches might be potentially useful in addressing the problem?

To find out more, we spoke to a learned clinician-scientist involved in research in this arena to learn more about what he had to say and also discover why a molecule they are working on in early clinical development is starting to look quite promising.

The good news is that it may also have utility in solid tumours as well, through the effects that it induces.

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After extensive – and at times, intensive – preclinical and clinical research on the adaptive immune system and how best to activate the cytolytic T cells in both hematological malignancies and solid tumours, attention is beginning to increase on the innate immune system. In particular, researchers are investigating how approaches in this realm can be incorporated into rational combinations with adaptive therapies, such that outcomes might be improved more than with either alone.

Human Natural Killer cell  Source: NIH

There are a number of ways to activate the innate immune system and direct dendritic or NK cells, for example. Some therapeutics seek to boost the responses via different innate sensing pathways such as cGAS/STING or CD47/SIRPα, for example, while others involve targeting stimulatory cytokines, chemokines, toll-like receptors (TLRs), etc through various agonist molecules.

There are also a myriad of vaccination strategies to consider involving neoantigens or neoepitopes, not to forget NK cell infusions, various NK CARs, bi/trispecifics and even checkpoint blockade of NK related targets.

These development have typically not received the same amount of attention as their T cell cousins, but it’s certainly an active and fertile area of research and one that we are likely to hear more about going forward as new developments start to make their mark.

In a world of ‘T cell chauvinists’ – to quote Dr Adi Diab (MD Anderson) – let’s not forget or ignore the humble NK cells, which also have cancer killing abilities.

Over the next three weeks, we have an extended mini-series focusing on NK cells rolling out with interviews and commentary from academia and biotechs alike across both sides of the pond. It promises to be an interesting and provocative ride with plenty of critical questions to pose and resolve along the journey.

So, hang onto your hats for the first part of the journey…

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One of my favourite areas to follow in oncology research is Developmental Therapeutics, whether they be targeted, genomic, epigenetic or immune therapies. At some point, even currently approved products started off life in this category, either in preclinical research or in early phase 1 trials.

It’s almost like a primordial soup from which future pipelines spring.

Following these initial approaches over time can be useful in many ways – you can pick up new trends and emerging drugs earlier than most, and can also step back to see a broader picture of the landscape as it evolves.

While there are no formal developmental therapeutics sessions at the American Society for Hematology (ASH) annual meeting per se, that doesn’t stop the intrepid scientist from creating their own selection, in fact it’s a lot more fun this way!

That’s exactly what I’ve attempted here…

Be warned though, this year, the mix is much more complex and intriguing with a lot of interesting and, in some cases, novel targets to explore and consider, including the deeper and tricky protein-protein ones to hit, which are now receiving more attention as researchers find more creative and indirect ways to tackle the problem.

Our second ASH 2017 Preview goes deep into what for many BSB readers will be intriguing, yet for others… completely unknown.

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It’s been quite a roller coaster week so far for CAR T cell therapies, with Gilead announcing its intended acquisition of Kite Pharma on Monday.  If that wasn’t enough, Wednesday brought another surprise – the FDA approved a rare double header – for Novartis’s CTL019, now known as tisagenlecleucel (Kymriah) for pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL), as well as a new indication for Genentech’s tocilizumab (Actemra) for the treatment of CAR T cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients two years of age and older.

Inevitably there has been much hullabaloo and much anticipation over the expected price tag that might accompany the first cell therapy product approved in the US. Whatever your view on this, many of us were no doubt relieved it came in under $500K ($475K, with no charge for the product in the first month if there was a manufacturing failure or no response).  While undoubtedly pricey, frankly it could have been a lot worse given the relatively small patient population.

Of course, the approved therapy isn’t the only expected high ticket item – there’s also hospital costs (including highly trained physicians and nurses), ICU costs (for very sick patients), supportive care costs (including tocilizumab if CRS occurs), not to mention any lab, diagnostic or monitoring tests required. All of these will no doubt push the total bill nearer to $1M.  In children though, the lifetime value of curative intent and many additional years of life is a much easier to grasp concept for payers than adding a few extra months at a high cost in adults.

These issues do raise the stakes for Kite and what they plan to do strategically in aggressive lymphomas, where there is a larger pool of eligible people for therapy, which must be offset by lower response rates (vs. pALL) and likely lower durability based on the data we’ve seen to date.  If we are truly moving into a world of value based pricing in the US, then efficacy and tolerability will ultimately have an impact on the perceived cost and value of treatment.

As Warren Buffett, the famous value investor has been want to say, “Price is what you pay, value is what you get.”

Whoa that’s a lot to think about – who knows what Friday may bring at this rate – and we still have the Kite Axi-Cel approval in aggressive lymphomas to go yet…

Meanwhile, there’s also a high unmet medical need for new effective treatment options in Acute Myeloid Leukemia (AML), especially in the relapsed/refractory setting, which is why we’re firm supporters of the Beat AML trial that the Leukemia and Lymphoma Society are pioneering. (See: Interview with Dr Brian Druker).

There’s also interest from several companies in a variety of novel targets, including CD123.

Notre Dame, Paris

Cellectis recently announced the enrollment of the first AML patient into their trial of an allogeneic CAR T cell therapy (UCART123) targeting CD123.

Quite aside from the issue of addressing whether such a product can be administered safely and effectively, one major why there is notable interest in Cellectis is because an allogeneic CAR T cell therapy offers the potential of a much cheaper off-the-shelf product as well as enhanced performance from an abundance of fit immune cells from healthy donors rather than tired or exhausted ones from people who are sick, thereby reducing the risk of manufacturing failure.

While in Paris, I spoke with Cellectis Chief Medical Officer, Loan Hoang-Sayag, MD about the trial design and CD123 as a target in AML.

This is the third and final post in our summer mini-series on gene editing and allogeneic CAR T cell therapy.

The first in the series featured an interview with Professor Waseem Qasim (Link), and the second with Cellectis CSO, Dr Philippe Duchateau (Link).

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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.

YervoyIs 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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