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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 7, 2014

Cancer Immunotherapy's Growing Pains

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Posted by Derek

Cancer immunotherapy, which I've written about several times here (and which has claimed the constant attention of biopharma investors for some time now) has run into an inevitable difficulty: its patients are very sick, and its effects are very strong. Sloan-Kettering announced over the weekend that it's having to halt recruitment in a chimeric antigen receptor (CAR) T-cell trial against non-Hodgkin's lymphoma:

Six patients died of either disease relapse or progression, said MSK, while two patients died in remission from complications related to allogeneic bone marrow transplantation. An additional two patients died within two weeks of receiving a CAR-T cell infusion.

"The first of these two patients had a prior history of cardiac disease and the second patient died due to complications related to persistent seizure activity," noted MSK's presentation. "As a matter of routine review of adverse events on study, our center made a decision to pause enrollment and review these two patients in detail."

This study is associated with Juno Therapeutics, and the company says that it expects to continue once the review is finished. There's a huge amount of activity in this area, with Juno as one of the main players, and Novartis (who are working with the team at Penn) as another. Unfortunately, that activity is both legal and scientific; the patent situation in this area has yet to be clarified. This is an extremely promising approach, but it has a long way to go.

Comments (8) + TrackBacks (0) | Category: Cancer | Clinical Trials


1. Barry on April 7, 2014 8:23 AM writes...

these are (mostly) problems not of CAR but of the field of oncology. Because we define "cancer" as the disease and we don't treat "pre-cancerous conditions" (except in dermatology and the colon), the patients are necessarily very sick. Even worse for a clinical trial in which we can only enroll patients who have already failed the approved standard of care.
But look instead at skin and colon lesions. Because the standard of treatment (usually cut it out or freeze it off) is known to be safe, doctors don't hesitate to treat pre-cancerous lesions. And the treatment success rate is better than for other solid cancers.

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2. Anonymous on April 7, 2014 8:43 AM writes...

there will be bumps in the road for all new approaches. but, make no mistake, the results in early trials such as metastatic melanoma are jaw dropping. years not weeks, folks. immunotherapy makes current 'targeted therapies' like BRAF inhibitors look arcane.

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3. Anon on April 7, 2014 9:33 AM writes...

Of course it's better than dying of cancer but I always wonder what will be the long term health effects of having completely and permanently wiping out the CD-19 cell population, as is the case in patients who have received CAR-T therapy in the NHL trial.

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4. Anonymous on April 7, 2014 9:54 PM writes...

So in place of side effects due to small molecule treatments, we are now replacing them with massive cytokine response, organ failure, and death. I thought side effects were supposed to be the exact thing immunotherapies were supposed to avoid? And not only are there still side effects, patients keep dying because of relapse or continued progression. It's going to be hard to justify huge costs for immunotherapy if chemotherapies will produce the same results and similar burden with side effects. I mean I supposed this will be worht it if immunotherapy eventually does reach the point where it can completely prevent relapse due to immune memory, but I'm wondering if they can get there first before CAR-T is abandoned all together because of too many clinical deaths and lack of efficacy.

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5. bradpalm1 on April 7, 2014 10:49 PM writes...

Adoptive cell transfer technologies are vastly inferior to recent breakthroughs to harness adaptive immunity. These complications are not unexpected and simply illustrate that the proximal end of immunotherapeutics still needs to be worked out.

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6. sepisp on April 8, 2014 5:01 AM writes...

#4: You can control the dosing of a chemotherapy drug, and you have to, since the drug is toxic to healthy cells as well. But, in an immunotherapy, the same control is exercised by the immune system itself; the "drug" there is not toxic to healthy cells. This is more of a "technical" problem, on how to control the attack and mitigate its effects, rather than an inherent problem with immunotherapy. (It would be, if it would cause autoimmune responses, for instance, which it doesn't.) You're thinking too much like a practicing clinician, whose job is to see problems, rather than a researcher, whose job is to see opportunities. I bet the first complaint against the new invention called fire was that it's hot.

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7. barry on April 8, 2014 10:41 AM writes...

Cancer immunotherapies is a broad rubric, with vast potential for efficacy for profit and for problems. Chimaeric Antigen Therapies--once you get past the tissue markers (wipe out all the B-cells) quickly becomes an individualized medicine, in which every new patient is a new clinical study and there's never a remunerable "product".
Blockade of PD-1 is a hot topic, but by disinhibiting all T-cells, you can provoke an auto-immune firestorm, potentially destroying more than just the tumor. You would want such a therapeutic to have very short half-life so that you could back off if needed.

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8. Anonymous on April 8, 2014 11:46 AM writes...

Carl June's comment:
All we can say at this point, is that if it occurs, it is rare with our CAR design, and less severe. Statistics are that we have treated 62 patients and not had a single seizure, while the seizure/aphasia frequency is ~25% of patients using the 28:z CAR (NIH and MSKCC data).

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