Biotech Strategy Blog

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

Over the last few years we’ve heard a lot about the evaluation of predictive biomarkers for checkpoint inhibitors, in particular the value of using PD-L1, whether on immune or tumour cells, as a way of separating responders and non-responders to therapy with anti-PD1 or anti-PDL1 blockers. The results to date have been mixed, with some KOLs concluding that smoking history or number of mutations was more useful in lung cancer and others believing that their assay has better utility.

Some cynical observers I’ve come across have even asserted that companies don’t want to see biomarkers emerge because that then limits their opportunity for patients being treated. Ouch! I don’t believe this to be true, it’s highly complex science and there is much about the healthy immune system that we still don’t know, never mind under more complex situations such as cancer. This is an ever-evolving field about which we still have much learn.

Eventually, we may see further refinement of these approaches, at least in some tumour types and I’m particularly looking forward to hearing more about those advances at ASCO and ASH later this year when the clinical and translational work is more mature.

Next month heralds the annual meeting of the American Association for Cancer Research (AACR). As we noted in our first AACR Preview on Immunotherapy last week, it’s the first time immunotherapy has literally dominated a largely preclinical and scientific program of this nature.

Over the next week or two, will be be highlighting and explaining some of the emerging trends in more detail.

On the important topic of biomarkers, one new approach particularly caught my eye in the abstracts that were released yesterday is worthy of further discussion since it could have important implications to future clinical approaches.

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One of my favourite meetings of the year in our conference calendar is the American Association for Cancer Research (AACR) annual meeting, which is held in the spring. In years past, the agenda at this event has set the scene for the rest of the year in terms of emerging new trends, particularly with regards to targeted therapies. In the last two years though, this hasn’t been the case, as adjusting to the brave new world of immunotherapies has taken some time.

The good news is that AACR has come roaring back in 2015 with a star-studded line-up that includes some of the big hitters and sluggers in the cancer immunology space.

What’s in store for this year, you may well be wondering, and where are we likely to see the new trends evolve?

We took an in-depth look at what’s hot in immunotherapies and where the new directions are going in this latest conference preview, the first one in series relating to the AACR annual meeting being held in Philadelphia from April 18–22nd (Twitter #AACR15).

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It’s time to answer some more subscriber questions. Several readers wrote in and asked about the anti-PD1 checkpoint data that was presented at the recent American Society of Hematology (ASH) meeting in classic Hodgkin’s lymphoma (cHL):

What did we think of it?

Well, for starters it was one of our highlights of the ASH 2014 conference (see quick write-up, open access), with an impressive 87% response rate for nivolumab in refractory cHL. Many of these patients had failed both autologous stem cell transplant and brentuximab (Adcetris), for which FDA granted breakthrough therapy designation.

ASH14 CHECKPOINTSOverall, I agreed with Ron Levy (Stanford) when he noted in the packed Special Session on Checkpoint inhibitors in Hematology that there were only 4 or 5 abstracts to actually discuss (he didn’t spend much time on the preliminary data) and that the results are still very early without seeing how good the durability will be.

As he observed in the session, which was standing room only, figuring out how best to integrate these new agents into clinical practice with other successful approaches will be most interesting.

That said, there are some new data that have emerged since ASH that are worthy of discussion in terms of potential future directions and how they could impact the checkpoint landscape in both hematologic malignancies and even solid tumours.

This is part of our ongoing immuno-oncology series on how we can manipulate T cells in creative ways to kill the cancer cells.  The findings discussed in this article are completely new and have not been discussed here before.

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We have been following the results of the checkpoint inhibitors for several years now, first with ipilimumab (Yervoy) and lately with anti-PD1 and PD-L1 inhibitors such as nivolumab, pembrolizumab and MPDL3280A. Irrespective of the antibody used, the best results we’ve seen have in melanoma, lung and bladder, but some tumour types such as colon and prostate cancers have barely been responsive at all.

Why is that?

Can we find ways to make non-responsive solid tumours responsive to immune therapies, and if so, what strategies could we employ to enable improved responses and outcomes?

At the ASCO Genitourinary (GU) meeting in Orlando this weekend there were some interesting hints of what might be possible in the not too distant future.

To learn more about this phenomenon, we conducted an interview with a leading cancer immunologist to find out what they are doing to make a difference in the GU space.

Interested?  Check out the interview by clicking on the link in the box below.

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It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.

There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!

We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.

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It remains exciting times in cancer immunotherapy with breakthrough new cell therapies and checkpoint inhibitors that enhance the effectiveness of T cells.

Cellectis LogoLast Friday, Paris based Cellectis filed their IPO registration statement with the Securities and Exchange Commission (Link to F-1).

They plan to raise $115M through an offering of American Depository Shares. You can read more about their allogeneic Chimeric Antigen Receptor (CAR) T cell approach in the two interviews we did with senior management last year.

Here’s an excerpt of the interview Cellectis CEO André Choulika, PhD gave Biotech Strategy Blog last year – it was the No1 post in 2014: Can Cellectis Revolutionize CAR-T cell Immunotherapy?

As multiple companies seek to move CAR-T cell therapies forward in clinical trials, what will be interesting to see is how this novel treatment fits in with existing therapies such as bone marrow transplants. Will it replace them, or be a bridge to a transplant that enables relapsed or refractory patients to have a second chance?

In addition, where are the potential opportunities beyond B-cell malignancies such as acute lymphoid leukemia (ALL) where there’s been dramatic success, particularly in children?

Dr Krishna KomanduriLast week Biotech Strategy Blog had the privilege to interview Dr Krishna Komanduri who is Director of the Adult Stem Cell Transplant Program at the University of Miami Sylvester Cancer Center and holds the Kalish Family Chair in Stem Cell Transplantation.

A physician scientist, he exudes a sense of calm professionalism – I am sure this must reassure many of his patients. Having a bone marrow transplant has been likened to jumping off a cliff in terms of what it does to one’s immune system.

In the last 2-3 years, he has dramatically increased the number of transplants at the University of Miami Sylvester Cancer Center.

Dr Komanduri (@DrKomanduri) was co-chair of the 2015 BMT Tandem meeting that took place earlier this month in San Diego. It’s the combined annual meeting of the American Society of Blood and Marrow Transplantation (ASMBT) and the Center for International Blood and Marrow Transplant Research (CIBMTR).

In a half hour interview he shared his thoughts on what was exciting at Tandem, where the field is going and some of the best abstracts at the meeting which included data on CAR-T cell therapy, GVHD and gene therapy.

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After the intensity of gastrointestinal cancer, we now turn our attention to genitourinary (GU) cancers with the upcoming ASCO GU meeting later this week in Orlando.

Two of the big topics here will be prostate and renal cell (RCC) cancers.

Unfortunately, the long awaited data in adjuvant RCC demonstrated that early treatment with sorafenib or sunitinib did not improve outcomes in locally advanced kidney cancer after resection. According to the ASCO press release, the trial conducted by Dr Haas and colleagues at U Penn discovered that:

“The average period to disease recurrence was similar between those who received sorafenib or sunitinib after surgery (5.6 years) and those treated with placebo (5.7 years).”

We will therefore turn our attention to castration resistant prostate cancer (CRPC).

One of the recent and ongoing controversies is splice variants, especially AR-V7, which is thought by some research groups to confer resistance to the hormonal therapies, enzalutamide and abiraterone. The big question though, is does it, and how useful is an assay in helping to determine appropriate therapy? Are there other factors at play?

We looked at the latest data and put the findings in context with what we know from other published research.

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Continuing our series on the ASCO GI meeting, today marks the end of the conference coverage with an interesting look at overcoming resistance to EGFR therapies such as Erbitux and Vectibix.

One of the hallmarks of EGFR monotherapy in colorectal cancer is stable disease with eventual relapse, but few dramatic responses. This suggests that other factors may play a role in driving oncogenic activity.

Dr Tejpar, Leuven

Dr Tejpar, Leuven

Recently, patient derived xenografts (PDX) have begun to play an increasingly important role in helping to understand the biology of the disease and facilitate improved trial design.

Earlier this week, we discussed the molecular characterisation of the disease based on the keynote talk by Dr Sabine Tejpar. Her group in Belgium as well as others in Italy and Spain have been very active in European translational work in this area to identify and map the pathways influencing EGFR therapy in GI cancers.

What can we learn from the latest findings in this space?

The answer may well surprise you.

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Over the last decade or so, we’ve seen a lot of new targeted agents approved in a variety of different tumour types. Of the big five cancers (breast, lung, melanoma, prostate, and colorectal) one clearly stands out as missing out on exciting new developments in the last 5 years.

In fact, we haven’t really seen anything startlingly new in the colorectal cancer (CRC) space since 2004, when the FDA approved cetuximab (Erbitux) and bevacizumab (Avastin) to much fanfare a few weeks apart at the beginning of that year. Sure, there have been other EGFR and VEGF inhibitors approved since, including panitumumab (Vectibix), z-aflibercept (Zaltrap) and regorafenib (Stivarga) in various lines of therapy, but you could argue that they’re all more of the same (type of inhibitors) and incremental in their improvements, rather truly game changing or disruptive.

Why is this? Why the discrepancy?

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After the recent raft of posts on immunotherapy, it’s time to turn our attention back to oncogenic addiction.  A couple of key topics have dominated colorectal cancer over the years, namely what causes EGFR resistance and why don’t patients with the BRAF V600 mutation do as well with RAF monotherapy compared to melanoma patients?

In today’s post, we take a more detailed look at BRAF mutant colon cancer in terms of what we’ve learned so far and what the potential therapeutic solutions are, which could influence patient outcomes in a positive way.

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