Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Late last week saw an incredible amount of noise in the media over the startling news that three patients with chronic lymphocytic leukemia (CLL) had responded well to an experimental gene therapy that aimed to boost T cells to fight a particular type of leukemia, some of it, unfortunately, bordering on near hysterical hype, such as MSNBC’s article entitled:

“New leukemia treatment exceeds ‘wildest expectations'”

Ugh.  There were others in similar vein, mostly derived from the AP and Reuters press releases.  Quite frankly, with a headline like that I was expecting something more substantial and robust than three patients.

The most measured story I saw came from NPR Shots, who took a more rational and thoughtful approach to the publications in New England Journal of Medicine and Science and Translational Medicine.

Gary Schwitzer also did a nice review of some of the commentary that emanated from the health media outlets as well as a well thought out longer piece.

It was clear though, that some of my medical and science friends were rather disappointed by the rather breathless nature of the general media reporting.  There is something really icky about raising peoples hopes based on very minimal data.  Part of this is due to journalists and editors with attention grabbing headlines, presumably because that’s what drives traffic, but also a noticeable lack of rigour or critical thinking in reviewing the situation in depth.

Let’s take a look at the disease in more detail first.

CLL is well known to be a disease of the elderly, with a median age around 63-65 years. It’s an indolent immune-sensitive cancer and treatment is largely based on a series of immunotherapies, either alone or in combination, such as fludarabine, rituximab, bendamustine, pentostatin and alemtuzumab, for example.  Not one of the media reports I read looked at how refractory these patients (only a small sample of n=3) really were or what their prognosis was.  It is well known that patients can live normal lives between treatments until relapse, when another treatment is initiated.  This process can go on for several years but eventually, they run out of options as these patients did.

What do we know about the patients?

Looking at the actual data reported from the two journals, we find some interesting nuggets about their prior immunotherapy treatment and karyotypes:

  1. The NEJM article is a single case report on one patient who had previously received FR (twice, for 2 and 4 cycles), BR (1 cycle), B (3 cycles) and alemtuzumab. He was found to have a 17p del with TP53 involvement, which has a known poor prognosis.
  2. All three patients had received both bendamustine and alemtuzumab (in different lines of treatment).
  3. Not all of the patients appear to have received prior fludarabine, which is surprising given that it is largely considered to be the standard of care, either as fludarabine-cytoxan-ritiximab (FCR) or fludarabine-rituximab (FR).  (Note: The patient who achieved a PR rather than CR did not apear to receive prior fludarabine).
  4. Two of the patients had a 17p deletion (with p53 involvement), the other had a normal karyotype.  The latter generally has a better prognosis.
  5. No indication of what might be expected without treatment in terms of the time elapsed after the last therapy is feasible without a comparative trial, so evaluating the effects of the gene therapy versus a control group will be needed going forward.
  6. None of the patients appear to have received a prior bone marrow transplant, which while potentially curative in about half of patients, is not without its complications such as a 20% chance of mortality from the procedure itself.
  7. All of the patients experienced some degree of tumour lysis with fevers, chills, nausea and fever, which occurs when many cancer cells die at once.

The tumour lysis reported in the patients is the most encouraging signal that the gene therapy was working effectively.

What did the researchers do?

Porter et al., (2011) described the idea behind the gene therapy in the NEJM article:

“In most cancers, tumor-specific antigens for targeting are not well defined, but in B-cell neoplasms, CD19 is an attractive target. Expression of CD19 is restricted to normal and malignant B cells and B-cell precursors”

This knowledge provided an opportunity to create a targeted gene therapy and test it in a pilot proof of concept study in a small sample size (n=3).  Patients cells were removed and then a personalised gene therapy was created:

“We designed a self-inactivating lentiviral vector (GeMCRIS 0607-793), which was subjected to preclinical safety testing, as reported previously.”

In plain English, the lentivirus vector encodes an antibody-like protein known as a chimeric antigen receptor (CAR), which is expressed on the surface of T cells and was designed to bind to the CD19 protein used as the target.

The U. Penn press release described the rationale behind the targeted therapy further:

“Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL tumor cells and normal B cells.

All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits side effects typically experienced during standard therapies.” 

What results were seen?

Two patients (one normal karyotype, one with a 17p TP53 del) were seen to have a complete response (CR) of 10 and 11 months each.

A third patient with a 17p TP53 del was adjudged to have a partial response (PR) of 7 months.

These results were fairly encouraging and offer a good proof of concept that the gene therapy is viable in CLL patients.  They also justify pursuing the gene therapy approach in larger scale clinical trials.

What do these data really mean?

Very little, other than an initial proof of concept, based on such a small sample size, but it does give some encouragement to move forward with a broader program to validate the findings.  At present, there is no doubt that people who have CLL with 17p and TP53 deletions tend to experience shorter remissions after standard therapies, so a new option that can be evaluated in clinical trials is an encouraging and welcome sign of some progress in this area.

Overall, while encouraging, these results are best described as ‘promising, but very early indeed’ – a lot more data will need to collected from randomised controlled trials before we see whether we really have a viable new therapy for people with CLL.  To suggest anything else is hype over hope at this stage and that does a great disservice to people with the disease.

Far too many agents fail between initial proof of concept to actually filing for Health Authority approval based on phase II or III data to raise hopes unnecessarily.  In fact, given more therapies fail in R&D than make it market, we would best remember that before we call anything the new ‘breakthrough’ or ‘killer therapy.’

I’m looking forward to seeing the gene therapy program develop further in larger randomised clinical trials, hopefully without excessive hype.

In an editorial in the NEJM, Urba and Longo (2011) urged some caution:

“Only with the more widespread clinical use of chimeric antigen–receptor T cells will we learn whether the results reported by Porter et al. reflect an authentic advance toward a clinically applicable and effective therapy or yet another promising lead that runs into a barrier that cannot be easily overcome.”

I couldn’t agree more with those sentiments.

Still, on a much lighter note, XKCD came to the rescue with this awesome cartoon to brighten up a dull grey morning:

Source: XKCD


ResearchBlogging.orgPorter, D., Levine, B., Kalos, M., Bagg, A., & June, C. (2011). Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1103849

Kalos, M., Levine, B., Porter, D., Katz, S., Grupp, S., Bagg, A., & June, C. (2011). T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia Science Translational Medicine, 3 (95), 95-95 DOI: 10.1126/scitranslmed.3002842

Urba, W., & Longo, D. (2011). Redirecting T Cells New England Journal of Medicine DOI: 10.1056/NEJMe1106965

12 Responses to “On T cells and chronic lymphocytic leukemia”

  1. Jose

    Hey…. three out of three is not bad. Re-engineering a T-Cell is not bad either. That it will not work in 30 or 40% of the people, probably, but also are the TNF- alpha therapies and big pharma is selling them for lots of green.

  2. Jose

    Hey…. three out of three is not bad. Re-engineering a T-Cell is not bad either. That it will not work in 30 or 40% of the people, probably, but also are the TNF- alpha therapies and big pharma is selling them for lots of green.

  3. JJ

    I’m sorry but I disagree.  This is the most exciting news to come out regarding cancer treatment for decades.  I appreciate your apprehension regarding patient size, but what I find ‘icky’ is big pharma disinterest in funding trials that bring about a cure, and the FDA’s policy of denying approval of any drug not already in the hands of big pharma.  Just have a look at their treatment of Dr Burzinski over the years.  This trial was only possible because of a very generous donation from Barbara Netter, hence the small sample size.  After one treatment, two patients had over 7 pounds of tumor disappear in three weeks, and do not have any sign of leukemia in their blood after almost 1 year, and minimal side effects (at least that this stage), and the other is very much improved.  Show me any other treatment that has even 1/10th of a response without major surgery or massive amounts of chemotherapy and radiation, which have very adverse side effects.  I’m not suggesting that this will last for years, or that it will work in every patient, but even if it gives the vast majority of leukemia patient several years of healthy life back, it is surely worth investigating further.  The patients’ responses were ‘incredible’ and the more noise, the more likely people will start demanding that the medical world pay attention.  Only then will big pharma’s stonghold on what does and does not get to market be broken.

    • maverickny

      Many thanks for your comment JJ. This wasn’t a phase I trial at all, just a proof of concept pilot. Before anyone invests in clinical trials, it is not unreasonable to so show such proof of concept in animals or humans. Normally, the NIH fund this kind of early research, but in the current economic climate of budget cuts, there is less dollars to go around so they can’t fund everything. No doubt the initial results will now generate interest and the project will hopefully move forward for more rigorous testing.

      • JJ

        Thanks for your reply maverickny, Yes, it was just a proof of concept pilot.  However, they already had extremely promising animal studies and they were turned down by big pharma and denied goverment grants to take it further.  This trial with 3 patients cost over 1 million.  How are any of these trials going to progress to phase I without people jumping up and down regarding the spectacular proof of concept results.  There are only so many wealthy benefactors out there.  The governments appear to have no hesitation in bailig out the banks to the tune of trillions of dollars, at the expense of decent healthcare.  I’m sure that the many cancer patients out there would be less than happy that potential drugs that might have saved their lives (if they had gotten it quick enough that is) was abandoned for the sake of bankers bonus payments.  I see your point regarding the hype and getting current sufferers hopes up being a bad thing, but unfortunately, without the sensationalism, the research would end here.

        • maverickny

          Frankly, I don’t blame either Pharma or the NIH for not funding it – $1M for 3 patients would make for a very expensive therapy down the line at $333K a pop!  Unfortunately, a lot of animal studies look very promising on paper but few translate to clinical results. You have to remember that outside of prevention, there have been few gene therapies or vaccines that have proven successful in humans.  The last 20 years have been littered with more failures in this field than I can remember.  That said, now they do have some initial data, funding might come along to progress the trials further but many will no doubt be very sceptical indeed.

    • Doug

      Hi JJ, this approach has been in the public domain for quite a while, no intellectual property can be claimed therefore no possibility for industry to fund! It is the role of public agencies and the main issue is their relative lack of long term commitment. This exciting approach will need years to reach confirmation.

      • JJ

        Hi Doug, according to the above article the method used is covered by patents.  An extract from the article:

        ” Dr. Bruce Chabner, clinical director at Massachusetts General Hospital Cancer Center, told ABC News. However, owning the patents on the method makes Dr. June’s technique a viable procedure for any company that gets involved. “I want to make sure it gets FDA-approved…it’s at an early stage…whether we’ll work with an existing company or a new start up, I don’t know yet,” he told Bloomberg. Dr. June is currently testing his patent on other cancer types, including pancreatic, ovarian, and mesothelioma. “

        • maverickny

          Doug is correct, JJ – this concept has been going around since the 1980’s when Ron Levy first developed a way to add T-cells back into refractory patients with NHL. Some of them did very well, others less so.  It will take years a lot of trials/research to bear fruition.  I’ve seen cancer trials where the first 3 responded and the next 27 relapsed, hence my scepticism.

  4. Kate

    While I agree with your general review of what the work means, I have to point out that the MSM pretty much took the U of Penn’s press release and ran with it.  The researchers themselves should be ashamed of themselves for the spin they put on their work.  But I’m sure they’re too busy structuring an IPO to think very much about it.

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