Biotech Strategy Blog

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

Posts from the ‘CAR-T’ category

CAR-T and Gene Therapy excite BMT Tandem Meeting

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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CAR-T Cell Therapies from China are a Competitive Threat

PLA General HospitalThe announcement earlier this week that Cellular Biomedicine Group (NASDAQ: CBMG) has acquired rights to the Chimeric Antigen Receptor T cell (CAR-T) therapy of the PLA General Hospital in Beijing (pictured right) should come as no surprise to industry watchers. (Link to Press Release).

The share price in $CBMG has risen from $16.31 on February 4 to $23.60 as of close of business on Feb 10, 2015 in what looks like a poorly kept secret!  It looks like most of the rise in share price took place immediately prior to the company’s formal Feb 9, 2015 announcement of the Chinese deal.

CBMG Share Price

 

Those following the cancer immunotherapy space have known for some time that several Chinese groups are working on CAR-T cell therapies that could be a threat if licensed or acquired.

Given the significant investor interest in this space, which is almost bordering on “tulip mania,” it’s entirely foreseeable that companies looking to share in this opportunity would go looking towards China.

One investor on Twitter in response to this news asked should Chinese data be trusted?

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The application of TILs, CARs and TCRs in cancer research

Photo: National Institutes of Health

After last week’s post on therapeutic tumor infiltrating lymphocytes (TILs), we received a bunch of questions from readers.

I don’t have time to answer them all in detail individually (sorry!), but it does provide an opportunity to review the evolving landscape and address some of them within the latest article.

It seems to be a good time to take a broader look at T cell manipulation, especially as it pertains to the application of TILs, chimeric antigen receptors (CAR), and T cell receptors (TCR).

We’ve certainly come along way since the historic lecture in 1991 pictured right (photo: National Institutes of Health), but there’s still some way to go before the full potential of cancer immunotherapy is reached.

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Bellicum moves BPX-501 T Cell Therapy forward $BLCM

Bellicum logoSeveral subscribers have written to ask what we think of Houston based Bellicum Pharmaceuticals?

Bellicum is a company that along with Novartis, Kite, Juno and Cellectis has a Chimeric Antigen Receptor (CAR) T cell therapy in development, amongst other things.

Readers already know the company had a successful IPO in December (NASDAQ: BLCM) and were reported to have raised $140M to fund future development.

This morning, the company announced enrollment of the first cohort of pediatric patients in a phase 1/2 dose escalation trial of BPX-501 (link to press release). This T cell therapy aims to mitigate the risk of graft versus host disease (GvHD) after an allogeneic haploid hematopoietic stem cell transplant.

BSB spoke with Bellicum CEO Tom Farrell and COO Dr Annemarie Moseley to answer some of the questions we think subscribers would like to know more about such as:

  • Market opportunity for BPX-501
  • Mechanism of action of BPX-501
  • Strategic direction the company is taking
  • Vision with regards to its CAR-T development
  • Milestones expected in 2015

We’ve provided some additional commentary on the challenges and opportunities Bellicum may face in the GvHD market and how we think the company stacks up against the competition in the CAR-T space. Be warned this piece is a long read: 6,000+ words!

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Cellectis ramps up CAR-T development in 2015

Readers don’t need Biotech Strategy Blog to tell them that Chimeric Antigen Receptor (CAR) T cell therapy (CAR-T), along with Checkpoint blockade, is one of the hottest areas of cancer drug development.

The last two days have seen pre #JPM15 deal activity with Kite Pharmaceuticals ($KITE) announcing a commercial collaboration with Amgen ($AMGN), which is not surprising given several of the Kite senior management team previously worked at the company.

Meanwhile, both Seattle based Juno Therapeutics ($JUNO) and Houston based Bellicum Pharmaceuticals ($BLCM) had successful IPO’s at the end of 2014. Interestingly, Bellicum are initially focusing most of their IPO funds, not on bringing their CAR-T to market, but on a novel cell therapy post stem cell transplant that aims to lower graft versus host disease (GvHD). GvHD is something we’ve been writing about regularly here!

Just this morning we’ve seen yet more CAR-T activity, with European Cardio3Biosciences (Euronext Brussels and Paris: CARD) acquiring the CAR-T technology of Oncyte (the oncology division of privately-held U.S. biotechnology company Celdara Medical).

There’s certainly a lot of activity in the CAR-T space and I expect we will hear more at next week’s JP Morgan Healthcare conference in San Francisco (#JPM15). One player in the CAR-T space who has not been gaining as much attention, and one that I think should not be dismissed, is Paris based Cellectis (Alternext: ALCLS.PA), who struck deals with both Servier and Pfizer last year. In June, BSB went to Paris and interviewed Chairman and CEO André Choulika, PhD and CSO Philippe Duchateau, PhD.

At the recent American Society of Hematology (ASH) annual meeting in San Francisco, Julianne Smith, PhD (pictured below), Vice President CART Development at Cellectis, gave an in-depth interview to BSB. Dr Julianne Smith Cellectis ASH 2014 Interview

Some key questions to address here are what are some of the important milestones for Cellectis in 2015 and and what makes the Cellectis CAR-T approach different from other companies in this space?

Update Nov 7: This post now has two updates relating to the important news that came out after this post was published concerning the issuance by the USPTO of a gene editing patent that covers Cellectis’ intellectual property. 

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Targeting the unmet medical need in GvHD

T cell activation has been very much to the fore over the last couple of years with many companies looking at different ways to use them against cancer cells, with chimeric antigen receptor (CAR) T cell therapy, vaccines or monoclonal antibodies. There are situations though, where T cells are not necessarily a good thing.

Graft versus Host disease (GvHD) is an area of tremendous unmet medical need that is triggering the interest of a number of biotech and rare disease companies such as Alexion Pharmaceuticals (ALXN).

Houston based Bellicum Pharmaceuticals (BLCM), whose IPO raised around $140M last month, have said they plan to spend most of the funds on bringing to market a new cell therapy that could make stem cell transplants more effective and reduce GvHD. They also have a CAR-T therapy in early development.

Indeed, at last month’s ASH 2014 annual meeting in San Francisco, GvHD was very much a hot topic, with data presented in the plenary session by Dr Wei Li (pictured below) on a novel biomarker for GI GvHD.

Dr Wei Li ASH 2014 GvHD Plenary

This post discusses one of the GvHD oral sessions at ASH 2014, and includes post-presentation commentary from Dr Marcel van den Brink, who is an expert in the area. The related interview Dr Brink kindly gave BSB at the SITC annual meeting is well worth reading if you missed it.

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Challenge of Cytokine Release Syndrome in CD19 CAR-T Cell Therapy

Juno Therapeutics LogoThis morning we heard that Juno Therapeutics have registered their plans with the SEC for an Initial Public Offering (IPO), highlighting the desire of the VC investors to generate a fast turnaround on their money before a multi-center trial of their CAR-T cell therapy has even started!

One of the challenges with CAR-T cell therapy is despite some stunning results, particularly in pediatric ALL, it remains an experimental one with toxicities that have to been managed. Adult patients, who are extremely sick, have died on trials. If I was at the end of the line faced with certain death, I’d probably roll the dice and take an experimental therapy, but CAR-T cell therapy does have challenges that need to be addressed.

Indeed at the Society for Immunotherapy of Cancer (SITC) meeting last week, one of the Hot Topic sessions that took place after the conference formally ended was in managing the toxicities associated with chimeric antigen receptor T cell (CAR-T) therapy.

Of particular concern for all CAR-T cell therapies in development is severe cytokine release syndrome (sCRS), which requires treatment in hospital intensive care.

Cytokine release syndrome (CRS) involves fevers, hypotension, hypoxia and even neurological toxicities. It’s been known for some time to be a challenging side effect of CAR-T therapy. We first wrote about it at ASH 2012.

As Novartis, Juno and Kite all look towards multi-center registration trials, the identification of patients at risk of severe CRS (sCRS) and the management of this in very sick, often end stage patients remains a real challenge, especially given that we don’t fully know what causes it to occur in some patients, but not others. Patient deaths due to sCRS are not good news on any clinical trial, and even less so when it’s a novel therapy in development.

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Can Cellectis Revolutionize CAR-T cell immunotherapy?

Directions to Cellectis in ParisCellectis is a Paris based biotechnology company, (NYSE alternext: ALCLS.PA) with an aspiring “blue ocean” strategy that, if successful, could revolutionize cancer immunotherapy.

The potential of using engineered T-cells (known as chimeric antigen receptors) to fight cancer was highlighted by the impressive data presented at last year’s annual meeting of the American Society of Hematology (ASH 2013).

To many, the data for the U Penn/Novartis engineered T-Cell therapy (CTL019) in pediatric acute lymphoblastic leukemia (pALL) was worthy of presentation in the plenary session at the meeting.

Over the past year, investors have poured money into companies active in the field: we’ve written about the launch of Juno Therapeutics and their intellectual property (IP) dispute with Novartis. More recently Kite Pharma had a successful IPO.

Why was Biotech Strategy Blog keen to interview Cellectis Chief Scientific Officer (CSO) Philippe Duchateau, PhD and Chief Executive Officer (CEO) André Choulika, PhD (picture left and right respectively)?

ellectis CSO CEO

The answer is they have a completely new and innovative approach to CAR-T cell therapy that in the long run could be a “game changer.” Their lead product (UCART19) is an allogeneic CAR T cell for ALL and CLL. Allogeneic means the T cells that are modified come from a donor. This is in contrast to the autologous approaches that Kite, Novartis and Juno are developing where the engineered CAR-T cells come from the patient themselves.

All credit to Pfizer for seeing the potential in a company that has been on our radar for a while. They recently announced a major collaboration with Cellectis that could turn both Cellectis and Pfizer into major players in the cancer immunotherapy space.

In this fast moving R&D space there are already signs of where competition to Cellectis may come from, and it’s not Novartis, Juno or Kite.

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Kite Pharma Challenges and Opportunities Post-IPO $KITE

At ASCO 2014, one of the posters that attracted a lot of attention was the one from Kite Pharma ($KITE) on their rapid cell expansion (RACE) technology for the production of engineered autologous T cell therapy.

Dr Renier Brentjens at 2012 Chemotherapy Foundation Symposium

As regular blog readers will know, we’ve been following the development of CD19-targeted T cells for the treatment of B cell malignancies such as CLL, ALL and aggressive NHL for some time.

Back in Autumn 2012, at the Chemotherapy Foundation Symposium (CFS) in NYC, more commonly known as the “Greenspan” meeting after the late Dr Ezra Greenspan, we heard presentations on early CAR-T cell data from Dr Renier Brentjens (pictured right) of Memorial-Sloan Kettering Cancer Center (MSKCC) and Dr Michael Kalos from the University of Pennsylvania (Penn).

At ASH 2012, we wrote about the data presented by Dr Carl June in the Ernest Beutler Prize Lecture. Dr Blazar, who jointly received the award, gave this quote from Dr Beutler, which is a reminder of why basic science is worthy of funding, and how important it is to innovation:

“The tendency to merely elaborate on what many others are doing arises, at least in part, from the almost universal misconception that our understanding of nature is profound, that most or all of the basic concepts have already been discovered, and that success in science consists of filling in the blanks with large teams of collaborators.”

What started off as pure academic research, has within a short period of time, become a hot (if not the hottest) area of immunotherapy drug development as inspired by the potential of early data, companies and investors pour money into commercializing CAR-T cell therapy.

Novartis had obtained the exclusive rights to Penn’s CTL019 CAR-T cell therapy in August 2012 at what now seems a bargain price.

Juno Therapeutics was subsequently created with $176M in Series A private equity funding at the end of 2013 to commercialize the CAR-T cell research of Memorial Sloan Kettering in New York and Seattle’s Fred Hutchinson Cancer Research Center.

Last week brought further development with an Initial Public Offering (IPO) from Kite Pharma who have a collaboration with the National Cancer Institute (NCI). Kite said they expected to raise $106M at a share price of $17, which was at the high end of the range. The shares soared 70% in initial trading, and closed at $29 on Friday.

To throw more fuel into the competitive fire, Pfizer have announced the signing of an agreement with French company, Cellectis, to collaborate on the development of their CAR-T cell technology.

In this first of a series of blog posts on gems from the ASCO poster hall, we take a look at the data presented by Kite Pharma and some of the challenges and opportunities the company faces.

Please note this post offers no investment advice and makes no recommendation on whether you should buy or sell shares in $KITE.

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The real story behind Juno’s CAR T cell therapy suspensions

This weekend, a controversy erupted at the American Association for Cancer Research (AACR) relating to Juno’s chimeric antigen receptor (CAR) T cell therapy following a series of tweets by Jonah Lomu, a keen biotech investor:

This innocuous looking tweet started a maelstrom of speculation and wild rumours that spiraled a little out of control.  This was perhaps not helped by Dr Michel Sandelin being a little caught off guard after his presentation yesterday, essentially saying, ‘no comment’ and that the trials were stopped for ‘safety reasons’.  Rather than calm things down, it unfortunately added fuel to the fire.

renier-brentjensYesterday, we spoke remotely with Dr Renier Brentjens (MSKCC) off the record and ascertained that the furore, far from being a major incident that impacts the whole field negatively, was actually a tempest in a tea cup that has been blown out of all proportion.

After his invited presentation and Dr June’s discussion in the clinical trials symposium today, Dr Brentjens agreed to answer our questions on the record to provide some detail and straight facts to put things in context to address the concerns.

To learn what Dr Brentjens had to say in this exclusive interview, check out the full post – it makes for interesting reading:

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Without much further ado, you can hear what Dr Brentjens has to say about the ‘safety concerns,’ interactions with the FDA and the CAR T cell therapy class effects in the brief, unedited, yet very candid interview below.

Please note that I’m here at the conference centre without a laptop or editing to tone down the background hubbub – this is the raw recording, which is just how I heard it live:

Some thoughts:

The two adult ALL deaths reported are unfortunate but should come as no surprise when considering these patients were mostly considered ‘salvage’ and very sick indeed.  I think MSKCC and the FDA are rightly taking a sensible and cautious approach to patient safety while they consider the need for dose reductions before resuming the trials once IRB approval has been obtained.  While the deaths were seen in the adult ALL study, the institution took a conservative approach and temporarily suspended all of the studies in that protocol group. I thought this was a measured response.

Tumour lysis syndrome and cytokine release syndrome are both, in some ways, a sign of great efficacy, as we have clearly seen with AbbVie’s Bcl2 inhibitor, ABT-199 in the past.  The challenge with highly effective therapies, as always, is going to be learning how to expand the T cell production and induce tumour cell killing in a controlled way.  Not every patient is going to be able to cope with the dramatic biologic effects that ensue, nor is the response consistent in every patient.  Controlling the immune system response is not an easy task.

Interestingly, the neurotoxicity issues associated with confusion etc were also reported by Dr Kochenderfer in the Kite lymphoma trial at ASH, so it is unclear whether this is a class or dosing effect. It clearly isn’t limited to just the Juno therapy. No doubt this will be continue to be watched and monitored carefully once trials resume at a lower dose. We should remember that these are patients not only with poor performance status, but also with a very poor prognosis so the risk:benefit considerations are very different from a frontline trial in healthier patients.

Dr June brought up the issue of persistency and implied that the MSK/Juno construct had an effect for only a few weeks, while the UPenn therapy was longer (months).  This was not my perception from all the data I saw recently at ASH and Dr Brentjens was quick to address this in the interview above.

My expectation is that a dose reduction will be quickly proposed, the exclusion criteria amended for co-morbidities and a revised IRB approved to all parties satisfaction, including the FDA.

We can expect more data on CAR T cell therapy at ASCO, where we will continue to follow the progress of this exciting class of immunotherapy.  We should not expect it all to be plain sailing, there are bound to be a few periods of doldrums (challenges to be overcome) interspersed between the exhilarating and positive data that is being reported in very refractory and sick patients.

{UPDATE – April 19th, 2014}

We’ve literally just heard from Juno that the adult ALL study hold has now been lifted by the FDA and they are enrolling patients again.

This is really excellent news for patients and good work all around in getting the issue resolved so promptly, which is no mean feat.

Juno have confirmed that the clinical trials database has yet to be updated administratively (that will probably happen early next week after the Easter holiday weekend), but all five trials associated with the IND have had their hold removed and are recruiting.

 

 

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