Biotech Strategy Blog

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

Posts tagged ‘CAR T cells’

One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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Dr Michel Sadelain AACR 2016

Dr Michel Sadelain at AACR 2016

Dr Michel Sadelain, Director of Cell Engineering at Memorial Sloan Kettering Cancer Center in New York is a pioneer in the field of adoptive cell therapy.

Without his contribution, it is unlikely CAR T cell therapy would be where it is today.

He’s also President of the American Society of Gene and Cell Therapy (ASGCT), whose annual meeting is currently underway in Washington DC from May 4 to 7 (Twitter #ASGCT16).

Recently at the annual meeting of the American Association for Cancer Research (AACR), Dr Sadelain gave an outstanding presentation on turbo-charged CAR T cells, and shared some of his ideas on how to move the field forward.

In New Orleans, he also kindly spoke to BSB, and discussed how he thinks cell therapy researchers may obtain the “holy grail” of getting CAR T cell therapies to work effectively in solid tumors.

Dr Sadelin is someone who wants to break the immunology rules!

Not surprisingly, Dr Sadelain is optimistic and doesn’t share the view expressed by Dr Steven Rosenberg on CAR T cell therapies being limited to mostly hematologic malignancies when we interviewed him a year ago at last year’s ASGCT meeting.  There’s nothing like a friendly controversy to spice the field up!

If you haven’t already done so, do listen to Dr Rosenberg on Episode 5 of the Novel Targets Podcast (@TargetsPodcast).

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The immuno-oncology space continues to get both interesting and also very crowded with over 20 chimeric antigen receptor (CAR) T cell therapies now in development. Originally, the excitement began with the University of Pennsylvania’s dramatic announcement regarding the first two advanced CLL patients they successfully treated, leading to a collaboration with Novartis and spurring a new ‘arms race’ development in this niche.

While most of the CAR T cell therapy data since has largely focused on acute lymphoblastic leukemia (ALL) and to a lesser extent, non-Hodgkins lymphoma (NHL), many have been wondering what was happening on the CLL front?  Has hope been abandoned there or will we see a renaissance occur?  It is of particular relevance with the Abbvie/Genentech announcement that venetoclax has positive data in CLL patients who have the Del17p mutation and filing is likely here in this subset soon.  Therapies such as ibrutinib and idelalisib are already approved in refractory CLL and may also have a future role to play here.

Do we need suicide switches for CAR T cell therapies such as Bellicum and Cellectis are developing or not?

Meanwhile, other hematologic malignancies are also being explored, including multiple myeloma. Why would a CD19 CAR work in a disease long considered to be CD19-negative in advanced, refractory disease?

Carl June UPenn

Dr Carl June, U Penn

What about progress with solid tumours? Many commentators and investors have been highly sceptical of the chances of success here following the advent of positive checkpoint data beyond metastatic melanoma and early CAR data in mesothelin cancers.

To answer these questions and also get a flavour for where things are headed with CAR T cell therapies, we recently interviewed one of the leading experts in this field, Dr Carl June (U Penn).

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We have followed the roller coaster development of the Bcl2 inhibitor, venetoclax (ABT–199/GDC–0199), for several years now.  There have been some lowlights along the way, but lately, things have been much rosier for AbbVie and Genentech as a more sensible dosing and patient management approach has been paying off.

Recently at ASCO and ASH, we have seen encouraging new data emerge in leukemia (AML and CLL), lymhomas (NHL), and even multiple myeloma.

New data has now emerged that looks quite interesting in another blood disorder. Today, we took a look at the data and also the potential implications for venetoclax’s development program.

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A regular reader of BSB wrote in asking for an update on Amgen’s blinatumomab, an anti CD3/CD19 bispecific antibody being investigated in B cell adult acute lymphoblastic leukemia (B-ALL) and Non Hodgkins Lymphoma (NHL). It has orphan designation for both indications.

Amgen acquired Micromet and their BiTE program way back in January 2012. At the time, the R&D head, Roger Perlmutter, referred to the exploratory phase II results as being a key driver for their interest in the technology. Like many, I too, was initially enthusiastic about the bispecific antibody when it was with Micromet, since those were very encouraging results in refractory adult ALL, a particularly hard to treat malignancy with a generally poor prognosis.

Unfortunately, since then we’ve heard very little about the program, which seems to have languished in the Amgen portfolio, a not uncommon occurrence when big Pharma/Biotech take over small biotech programs. In the meantime, chimeric antigen receptor (CAR) T cell therapies have arrived to much fanfare, and with it, even more dramatic results that have caught people’s attention.

Is there still a future for blinatumomab and BiTE technology?

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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.

 

 

During the recent American Society of Hematology meeting, much of the focus in immuno-oncology was squarely on the pediatric and adult data using the chimerica antigen receptor T cell product being developed by Novartis, CTL019, in acute lymphoblastic leukemia (ALL) from Children’s Hospital of Philadelphia (CHOP, not to be confused with the chemotherapy regimen!) and U Penn, respectively. We wrote about that data earlier this year.

There are, hovever, other interesting CAR T cell therapies in clinical development, including those from Juno (based on the MSK and Fred Hutchinson partnership), Bluebird in partnership with Celgene and one that actually had data at ASH, which didn’t receive much attention from the NCI and Kite Pharma. This therapy was evaluated in a trial of non Hodgkin’s Lymphoma (NHL) patients.

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Cancer immunotherapy was described in the December 20, 2013 issue of Science magazine as their Breakthrough of the Year, but really, we are just scratching the surface of what can be achieved.

We are at beginning of a REVOLUTION in immunotherapy,” said Elizabeth M. Jaffee, MD at the start of American Society of Clinical Oncology GastroIntestinal (ASCO GI) symposium keynote lecture on Immunologic Treatments for GI Cancers.

Elizabeth M Jaffee MD ASCO GI Keynote

Elizabeth M Jaffee, MD

Jaffee likened the revolution in immunotherapy to the same excitement the Beatles brought to music, or the same magnitude of technology advances made by Apple.

Dr Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology at Johns Hopkins, and has developed a number of vaccines including GVAX, which is currently licensed to Aduro Biotech.

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Now that the last of the 2013 cancer conference season is finally over, we’re going to run a couple of post meeting summaries this week from ASH as a few subscribers have asked for the Cliff Notes version of what was hot – or not in the context of the market.

New treatments for Chronic Lymphocytic Leukemia (CLL) was one of the hot topics at the recent annual meeting of the American Society of Hematology in New Orleans.

Hot on the heels of Roche’s recent FDA approval for Gazyva (obinutuzumab/GA101) in CLL, other companies in the race to market including:

  • Pharmacyclics and Johnson & Johnson (ibrutinib)
  • Gilead (idelalisib, GS-9973)
  • Infinity (IPI-145)
  • AbbVie and Roche (ABT-199/GDC-0199)
  • Novartis (CTL019).

Here’s my subjective and personal assessment of the winners and losers based on the data presented:

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