Biotech Strategy Blog

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

Posts tagged ‘Chimeric Antigen Receptor CAR Technology’

It’s that time of the month where the BSB readers get their chance to put us on the hot spot!

SITC 2015 Land GrabHere, we take a look at reader questions that have been submitted and argue the toss – is there evidence preclinically or clinically that is useful or instructive?

We can’t promise to answer every question, sometimes there simply isn’t any data to help either way.

This week, the topic is CAR T cell therapies, a subject that seems to be very high on many people’s minds and many of you had similar questions, so here goes…  

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At the recent American Association of Immunology (AAI) and American Society of Gene & Cell Therapy (ASGCT) meetings in New Orleans, we had the good fortune to interview a number of leading cancer immunologists about their work. Some of these have already been published either here on Biotech Strategy Blog, or on the Novel Targets podcast.

In the meantime, the huge tsunami of data from the annual meeting of the American Society of Clinical Oncology (ASCO) hit and we have been a bit backlogged! Time to address that and focus on some more thoughtful reflections about where the cancer immunotherapy field is going.

Already, we are seeing another round of new collaborations and deals hit the newswires with AstraZeneca announcing two collaborations, one with Inovio on the INO–3112 HPV cancer vaccine and another with Heptares, where they acquired the exclusive global rights to develop, manufacture and commercialise the adenosine A2A receptor antagonist, HTL–1071. The first involves a cancer vaccine and the second immune escape mechanisms.  Not to be outdone, their rivals Clovis also announced a collaboration with Genentech to explore rociletinib (EGFR T790M) with atezoliumab (anti-PD-L1) in EGFR mutation-positive lung cancer.

Cancer vaccines have not, however, been a very successful or fertile area of R&D for Pharmaland to date, with only one such therapy approved by the FDA (sipuleucel-T or Provenge) and literally hundreds of other such compounds consigned to dog drug heaven. This illustrates the sheer enormity of the task we need to undertake in stimulating the body’s immune system to successfully attack the cancer in a sustained and robust way.

Dr Rosenberg, NCI

Dr Rosenberg, NCI

Despite this setback, there is still notable interest in exploring the innate immune system and finding effective ways to target and stimulate the T cells or T lymphocytes to attack the cancer.

One man who has accomplished an incredible body of work over the last two to three decades is Dr Steven Rosenberg from the NCI’s Surgery Branch (right).

No one who attended any of the cancer conferences where he spoke at over the last year is ever going to forget the dramatic before and after slides of remarkable transformation in his patient case history examples using Tumour Infiltrating Lymphocytes (TILs) as this example illustrates:

 

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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.

 

 

The Inquirer yesterday reported on Philly.com that start-up Juno Therapeutics (Juno) are now in control of a legal dispute between St Jude Children’s Hospital (St Jude) and the University of Pennsylvania (Penn) over chimeric antigen receptor (CAR) intellectual property that contributed to the development of CTL019, licensed by Penn to Novartis. Thanks to @lomu_j for sharing this news on Twitter.

According to the Inquirer, last month Juno entered an agreement with St Jude to commercialize their CAR T-cell technology, which gave them the right to “control, pursue and defend” the dispute between Penn and St Jude.  On December 18, Juno’s intervention was approved in Federal District Court in Philadelphia.

(Update Jan 10: Zack Seward (@ZackSeward) provides additional commentary on WHYY Philadelphia newsworks on “The high-stakes legal fight over a ‘cancer cure from Penn.’ He reports that St Jude have every confidence in their patent.

 

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For many attendees, the most exciting news at the 2012 annual meeting of the American Society of Hematology (ASH) held last December in Atlanta was the prospect of personalized T cell therapy for the treatment of patients with B cell cancers such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

The potential of this new treatment option was recognized at ASH 2012 by the award to Dr Bruce R. Blazar, MD and Carl H. June, MD of the Ernest Beutler Lecture and Prize for research that generated major translational advances in T-Cell Infusions.

ASH 2012: Carl June, MD receives Ernest Beutler Prize

ASH 2012: Carl June, MD receives Ernest Beutler Prize

Dr June, in his accompanying lecture discussed preliminary data for the trial of CTL019 (formerly CART-19), a novel chimeric antigen receptor-transduced T cell therapy against CD19. Subscribers to premium content can login to read more below:

In the 12 patients (10 adults CLL and 2 children with ALL) who have received CTL019, the responses have been extremely promising with a clinical response (CR+PR) seen in 9 out of the 12.

There have already been several reports in the media about this trial with many news outlets reporting that one of the children with ALL had been “cured.” That this treatment has tremendous potential is undisputed, but in my view it is a case of “hype over hope” at this stage to say that anyone has been cured in the absence of long-term follow up over at least five years.

In August 2012, Novartis announced they had formed an alliance with the University of Pennsylvania and had obtained a worldwide license to commercialize CART-19 (now CTL019). In December 2012, Novartis purchased a NJ manufacturing facility from Dendreon for $43M that will used for the production of personalized immunotherapy.

Novartis, through their recent acquisition of the Dendreon facility in NJ, are fortunate to gain access to the technology, state-of-the-art tracking system that matches the product to each patient, as well as the Good Manufacturing Practices (GMP) that were pioneered in the production of sipuleucel-T (Provenge).

In the immediate future, Novartis and U Penn have the challenge of showing that the dramatic results seen in some of the initial patients are reproducible in a larger trial and also at institutions other than Penn.

ASH 2012 Carl June Ernest Beutler Prize LectureIn his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.

This suggests it is unlikely this therapy will be used outside of the hospital setting.  In the United States, I would not be surprised to see it only used at hematology transplant centers, where there is the necessary expertise to deal with both the process and any complications that arise. Novartis may end up with a high priced therapy targeted at a small niche market.  It will be interesting to see the commercial strategy that Novartis decide to adopt.

I expect we will hear a lot more about chimeric antigen receptor technology in 2013. Personalized immunotherapy is a complex topic and one that will require significant investment in medical education by Novartis if a broader audience is the intended target. Dendreon failed miserably at launch in explaining how sipuleucel-T (Provenge) worked and did not convince large numbers of medical oncologists that their immunotherapy worked.  Even to this day, there remains considerable sceptism amongst that physician segment.

If you would like to know more about the science behind CAR therapy and it’s potential in hematology, Sally Church, PhD (who co-launched Gleevec in the US while at Novartis Oncology) will be offering insights in a monthly newsletter to be launched soon. Check out Pharma Strategy Blog for more information.

 

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