Biotech Strategy Blog

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

Posts from the ‘Immunotherapy’ category

Like the Battle of Britain, the cancer immunotherapy landscape is a dynamic one where tactical decisions can make the difference between “winning” and “losing.”

As Bristol Myers recently found out in first-line NSCLC, if you choose the wrong trial design or adopt an overly-aggressive strategy, you can end up losing badly (see post: Detailed thoughts on BMS CheckMate 026 1L trial in NSCLC)

A recent trip to the operations bunker at former RAF Uxbridge, from where the fighters of 11 Group were directed, shows how close we came to losing the Battle of Britain.  Had the German Luftwaffe continued to target RAF airfields instead of diverting their efforts on London, the outcome of the war is likely to have been quite different.

History provides a valuable lesson that strategy and tactics can and do matter; in R&D the targets you choose and how effectively you execute on a plan can make a big difference to outcome.

Battle of Britain Bunker Plot

Pictured: the RAF 11 Group Operations plot as it looked on September 15, 1940.

In Part 2 of the BSB interview with PsiOxus Therapeutics CEO Dr John Beadle, we discuss corporate strategy, and some of the challenges faced by an emerging Biotech company, many of which are likely to be shared by other small companies in the field.

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HMS VictoryThe dog days of summer are usually quiet on the Pharmaland front, although this year has been a bit of an exception, being notable for a batch of deals being completed and announced already.

The cell therapy space is one area that has courted both controversy and new collaborations, for example. Nary a week seems to pass without something appearing in the news! This has proven pretty interesting for a number of subscribers, who write in asking plenty of astute questions.

Today’s questions from BSB readers therefore encompass allogeneic cell therapies and what’s going on in that fast moving dynamic space.  Not all of the announcements may be what they seem though, and some are much more riskier than others.

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The Shard from River ThamesMuch has been written about the impact of cancer immunotherapies, particularly the twin pillars of checkpoint blockade and CAR T cell therapies, but beyond that lies a huge wealth of alternative approaches that may come in very useful indeed.

Just as we have seen oncogenic escape witth targeted therapies, there is also a related phenomenon called immune escape. Likewise, this can occur as either primary or secondary resistance.

It’s very important to consider this issue, because, after all, the vast majority of cancer patients with solid tumours do NOT see durable clinical benefit with immunotherapies when given as single agents. Some don’t respond at all (primary resistance), while others may see an initial response, then relapse (secondary resistance).

Understanding the mechanisms involved in resistance may help us design better combination trials to address the underlying biology as well as develop biomarkers to help select appropriate patients for each regimen. Clearly resistance can vary, not only by tumour type, but also by lesion and patient, making it a very complex situation to research.

Some interesting new information has recently come to light that is worthy of futher discussion and analysis, particularly in the context of other published data in this niche.

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At the recent annual meeting of the American Association for Cancer Research (AACR), one controversial area that arose was centred around targeting OX40, a stimulatory checkpoint. We’ve written extensively about anti-OX40 checkpoint agonists on the blog in the past.

Targeting OX40 is an area of interest to several companies looking to improve the effectiveness of checkpoint inhibitors. As a result, several companies have OX40 agonists in development, including AstraZeneca/MedImmune, Roche/Genentech, Pfizer, GSK and Incyte/Agenus, for example, making it a competitive target and interesting race to market.

Meanwhile, in their recent 1Q earnings call, Roche announced that they expect to present clinical data on their PD-L1/OX40 combination at the forthcoming American Society of Clinical Oncology (ASCO) annual meeting in Chicago from June 4th to 7th. This therefore makes it a timely moment to reflect on the data generated so far and what we can expect next month.

In New Orleans, we spoke to several researchers who are active in the OX40 field, since there were both mouse and human data presented at this year’s conference.

The interviews conducted were wide-ranging and informative, so in our latest mini-series we explore Part 1 today with Part 2 tomorrow.  They are relaxed fireside chats with different experts included in each to discuss their data (and other relevant topics) presented in New Orleans.

This way, you’ll be able to follow along and find out where the common areas are, as well as the differences in perspectives, and even where we could be headed in the near future.

This latest series on OX40 agonists raises many intriguing questions that we hope may be answered at ASCO and other clinical meetings going forward. We also discuss the challenges and opportunities associated with research into cancer immunotherapy combinations.

Dr Bernard Fox at #AACR16

Dr Bernard Fox at #AACR16

Intriguing preclinical data in mice models were presented by Dr David Messenheimer (Portland). We spoke with the senior author of that abstract, Dr Bernard Fox.

He is the Harder Family Chair for Cancer Research and Chief of the Laboratory of Molecular and Tumour Immunology at the Earle A. Chiles Research Institute in Portland, Oregon, and a leading cancer immunotherapy expert. He’s also the CEO of UbiVac, a biotech spin-off from Chiles in 2005 to develop therapeutic vaccines for cancer and infectious diseases.

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Dawlish TrainspottingIt’s Day 7 of our 12 day Countdown to AACR 2016 in New Orleans.  After exploring GITR and OX40, we’re now looking at another stimulatory target for cancer immunotherapy: CD40.

We’ve been writing about CD40 as a cancer immunotherapy target for some time. See posts: “CD40 as a Cancer Immunotherapy Target” and “Targeting CD40 in Cancer Immunotherapy.

Anti-CD40 antibodies are agonists that act on stimulatory signalling receptors on T cells and antigen presenting cells (APCs). Targeting CD40 effectively acts to “put the foot on the gas” and may help generate a better immune response. This could be important in cancers that have fewer natural T cells present.

CD40 is an attractive target because it’s expressed in more than 50% of carcinomas and melanomas and almost all hematological B cell malignancies.  Of particular interest is the potential to combine a CD40 agonist with a PD-1/PD-L1 checkpoint inhibitor.

Multiple companies have CD40 agonists in clinical development including Roche, Apexigen, Alligator Biosciences and Seattle Genetics.  There are others coming too.

In this preview of AACR 2016, we’re looking at the CD40 landscape. New products and companies have entered the scene, so we’re highlighting them and some of the CD40 presentations to look out for at AACR 2016 (and why they matter).

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British Javelin TrainIt’s Day 6 of our Countdown to the AACR 2016 annual meeting in New Orleans. We’re at the halfway, 6 posts written and 6 more to go!  Then it will be daily Live blogs from the meeting.

There’s a lot of cancer immunotherapy at AACR this year, so after yesterday’s post on GITR we’re continuing our mini-series with a look at another immune agonist.

Today, we’re moving onto OX40 (CD134) as a novel immuno-target. Regular readers will know that we’ve been following this target for some time.

Immune agonists such as GITR, OX40, CD40, CD27 and 4-1BB help to rev up T cells. As Dr Tom Gajewski (Chicago) told us last year, in an interview published on the blog and excerpted in Episode 6 of the Novel Targets Podcast: Stepping on the Gas:

…there are inhibitory receptors on activated T cells that are involved with shutting immune responses down. There are also activating receptors that help to rev up those T cells. You might question whether you can push an activator and block an inhibitor, and maybe get a good anti-tumor response going as well.

When we drive a car, we both lift our foot off the break and we step on the accelerator. We have really beautiful data in animals that that this is exactly the case, that if you hit one of those strong positive regulators, and block just one of the negative regulators, you can have complete disappearance of the tumors in mice.

Several of those positive agonistic antibodies against costimulatory receptors are in the clinic. One of them is anti-OX40 that a couple of groups have in the clinic. We’re working with Genentech, that has one of those agents in phase I.

What does the OX40 competitive landscape look like?

In those post we’ve provided commentary on some of the new products in development from companies and highlighted a surprising number of abstracts that you’ll want to watch out for at AACR 2016 if you’re on the cancer immunotherapy track.

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Macarons in shop windowWe’re all familiar by now with the idea of checkpoints that can be inhibitory (release the brake) or stimulatory (put the foot on the gas) on the immune system.

There are multiple checkpoint modulators in development, it’s becoming a bit like buying a macaron – which flavour do you want?

As the late Holbrook Kohrt said on the Novel Targets Podcast last year:

There are two types of checkpoint inhibitors, one checkpoint inhibitor are these series of markers that each of them when you target them, they will slow down the function of that cell. Now that’s a good thing if that cell is a suppressor cell, such as a regulatory T cell. Anti-CTLA-4, ipilimumab, the first approved immunotherapeutic monoclonal antibody targets these regulatory T cells. Essentially is this concept as you said of taking off the brake .

Now if you want to press on the gas pedal, you want to find a target that is essentially that actually increases the function of a cell you want to make work better…….

…. these ideas of the different checkpoint inhibitors, essentially we should really call them, checkpoint modulation, because the checkpoints can either be gas pedals or they can be brakes.

And ultimately, it’s a question about how do you combine them in a rational way so that way you’re not either pushing the car too hard or taking the brake off at a time when the car is rolling in the wrong direction.

So essentially, you need to do checkpoint modulation in a setting where you still have the steering wheel on your car to ensure it’s directed against the right cells, otherwise you’re going to get significant toxicity.”

Which is a good introduction to Day 5 of our Road to AACR 2016 mini-series.

Over the course of 12 days in the run up to the 2016 annual meeting of the American Association for Cancer Research (AACR), we’re taking a look at some of the areas we expect to hear more about in New Orleans.

In today’s post, which continues our look at some of novel cancer immunotherapy targets, we’re look at the modulation of GITR (glucocorticoid-induced tumor necrosis factor receptor related gene) and companies that are targeting this.

GITR was named as the 12th most promising cancer immunotherapy target by the National Cancer Institute (NCI) back in 2006.  Interestingly, high GITR expression can be found on both T cells and NK cells.

There are now several agonist antibodies in development and entering the clinic that seek to activate GITR, and new data is expected at AACR 2016.

What GITR pathway data is worth looking out for at AACR 2016?

If you want to know more about why GITR matters, and where it fits into the cancer immunotherapy landscape then do read more. 

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AACR Annual Meeting 2016 BannerOne of the hot topics at the forthcoming 2016 annual meeting of the American Association for Cancer Research (AACR) in New Orleans is likely to be CAR T cell therapy (Twitter: #AACR16).

Several research groups have shown impressive results in acute lymphoblastic leukaemia (ALL), but challenges remain in using adoptive cell therapy to treat other leukemias such as CLL, as we heard from Dr Porter at the recent BMT Tandem meeting. See post: Challenges and Opportunities of CAR T cell therapy in CLL. Perhaps more significantly, there’s a long way to go before CAR T cell therapies hit prime time in solid tumours.

What is fascinating is the pace of scientific research in the field. By the time the first CAR-T cell therapy is FDA approved, the second generation constructs used in them will most likely be obsolete.

This post reviews completely new research, which we’ve not written about before, that I expect we’ll hear more about at AACR, and discusses novel concepts about how to make CAR T cell therapy more effective in both leukemia and solid tumours.  It’s a good pre-AACR preparation for those interested in cancer immunotherapy and the emerging CAR T cell therapy landscape.

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One of the most important challenges in cancer immunotherapy is overcoming immune resistance. For example, even with the high response rates seen in acute lymphoblastic leukemia (ALL) with CAR – T cell therapy, a significant number of patients relapse after an initial response.

Chinatown Honolulu

Chinatown, Honolulu 2016

Could immune resistance be reversed or prevented by the addition of appropriate checkpoint blockade? Which ones matter though, that is the critical question?  Rather than randomly picking ones to try, we need scientific evidence regarding these choices.

This post explores some of the latest data presented at the BMT Tandem meeting on the role of T cell immunoglobulin mucin–3 (TIM–3) and PD–1 upregulation in causing resistance.

If you’re not already a sub and want to read our coverage of ASH, BMT Tandem and the forthcoming AACR 2016 annual meeting, you can purchase individual access below. This week only – inspired by the story of Eddie Aikau in Hawaii – we have a special offer that we’ve never done before (and may never do again) of $75 off a quarterly subscription. The deal ends tomorrow Friday March 4th at 12 noon HST. Check it out!

Subscribers can login to read more about the latest data on how alternative checkpoint inhibitors may have a role to play in cancer treatment.  Welcome to the new folks who signed up this week, good to see y’all!

Cell therapy is one of the hottest topics in cancer immunotherapy; however, it remains a field still in it’s infancy as companies and researchers work on strategies and concepts to increase efficacy and overcome resistance. The strategic landscape is still being defined. In cell therapy the ultimate winner may not be the company that is first to market.

Unum C suite

Drs Seth Ettenberg and Michael Vasconcelles, Unum at #ASH15

In this post, we’re continuing this week’s theme of posts around novel cell therapies. Unum Therapeutics is a company that is no doubt already on your radar if you are into CAR-T cells.

Back at ASH 2015, I had the pleasure of interviewing Dr Seth Ettenberg (CSO) on the left and Dr Michael Vasconcelles (CMO) on the right.

We talked about what differentiates their approach from others in the CAR T cell space.

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