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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Good News in Oncology: Oncolytic Virus Therapy | Main | Trouble for a Whole Class of Diabetes Drugs? »

March 22, 2013

Good News in Oncology: More Immune Therapy for Leukemia

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Posted by Derek

I've written a couple of times about the work at the University of Pennsylvania on modified T-cell therapy for leukemia (CLL). Now comes word that a different version of this approach seems to be working at Sloan-Kettering. Recurrent B-cell acute lymphoblastic leukemia (B-ALL) has been targeted there, and it's generally a more aggressive disease than CLL.

As with the Penn CLL studies, when this technique works, it can be dramatic:

One of the sickest patients in the study was David Aponte, 58, who works on a sound crew for ABC News. In November 2011, what he thought was a bad case of tennis elbow turned out to be leukemia. He braced himself for a long, grueling regimen of chemotherapy.

Brentjens suggested that before starting the drugs, Aponte might want to have some of his T-cells stored (chemotherapy would deplete them). That way, if he relapsed, he might be able to enter a study using the cells. Aponte agreed.

At first, the chemo worked, but by summer 2012, while he was still being treated, tests showed the disease was back.

“After everything I had gone through, the chemo, losing hair, the sickness, it was absolutely devastating,’’ Aponte recalled.

He joined the T-cell study. For a few days, nothing seemed to be happening. But then his temperature began to rise. He has no memory of what happened for the next week or so, but the journal article — where he is patient 5 — reports that his fever spiked to 105 degrees.

He was in the throes of a ‘‘cytokine storm,’’ meaning that the T-cells, in a furious battle with the cancer, were churning out enormous amounts of hormones called cytokines. Besides fever, the hormonal rush can make a patient’s blood pressure plummet and his heart rate shoot up. Aponte was taken to intensive care and treated with steroids to quell the reaction.

Eight days later, his leukemia was gone

He and the other patients in the study all received bone marrow transplantations after the treatment, and are considered cured - which is remarkable, since they were all relapsed/refractory, and thus basically at death's door. These stories sound like the ones from the early days of antibiotics, with the important difference that resistance to drug therapy doesn't spread through the world's population of cancer cells. The modified T-cell approach has already gotten a lot of attention, and this is surely going to speed things up even more. I look forward to the first use of it for a non-blood-cell tumor (which appears to be in the works) and to further refinements in generating the cells themselves.

Comments (11) + TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials


COMMENTS

1. ptm on March 22, 2013 9:13 AM writes...

These stories sound like science fiction.

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2. David Borhani on March 22, 2013 9:25 AM writes...

Not science fiction. More like William Coley and his toxins.

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3. Anon on March 22, 2013 9:35 AM writes...

"He was in the throes of a "cytokine storm," meaning that the T-cells, in a furious battle with the cancer, were churning out enormous amounts of hormones called cytokines."

Real dangerous stuff here. This type of therapy will never be FDA approved. There are already good therapies on the horizon with much less risk involved.

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4. anon on March 22, 2013 9:46 AM writes...

Here is what can happen when you mess with T-cells that could result in a cytokine storm.

The TeGenero AG story, a mAB that targets CD28 a T-cell receptor.

http://en.wikipedia.org/wiki/TGN1412

In its first human clinical trials , it caused catastrophic systemic organ failure in the subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg; some 500 times lower than the dose found safe in animals. Six volunteers were hospitalized on 13 March 2006, at least four of these suffering from multiple organ dysfunction. Tentative opinions from an as-yet uncompleted inquiry suggest that the problems resulted from "unforeseen biological action in humans", rather than breach of trial protocols, and the case therefore has had important ramifications for future trials of potentially powerful clinical agents.

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5. Dogbertd on March 22, 2013 10:43 AM writes...

But wasn't the problem with the Tegenero study that they hadn't done the right safety tasting in appropriate animal species? And as I recall, they dosed all the first cohort at the same time - and so ended up with a roomful of patients all going downhill fast.

One hopes that MSK has learnt from these lessons. But I have to say I find these reports hugely encouraging. Yes, the risk of T-cell mediated AEs is there, but we do many things on a daily basis that are dangerous if done in the wrong way (crossing the road, driving a car): seems to me that once we learn how to handle this type of therapy it's going to make a huge difference to patient outcomes.

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6. Hap on March 22, 2013 11:10 AM writes...

Dosing all of your patents at the same time with immune-modulating antibodies doesn't seem like a very good idea when you have little idea what they will do.

Cytokine storm is not very good, but the current chemotherapies (as the patient noted) do not have insignificant side effects. If better treatments show up, doctors would probably revise their treatment options, but in the absence of actual treatments (and assuming this works, which is a big if), something that works would probably not be discarded.

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7. PPedroso on March 22, 2013 11:48 AM writes...

I think that in the Tegenero, the problem was that the primates that they tested on did not suffer the same reaction due to inter-species differences.

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8. Helen on March 22, 2013 3:01 PM writes...

Sorry to be a medical bore, but just a small correction: leukaemias are actually haematological rather than oncological malignancies. (I know, chemists don't care, as my med chem husband frequently informs me, but as a medic I couldn't let that one slide...)

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9. barry on March 25, 2013 11:39 AM writes...

Given a robust cell-surface marker and knowing that you can delete the entire population of B-cells without killing the patient, you don't need these gimmicked T-cells. This is a set-up case where an antibody conjugate with a small-molecule warhead can work. But that antibody conjugate will be a clinically-tested drug. And this gimmicked T-cell will always be a experimental protocol, new for each patient.
Un-re-imbursible.

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10. Larry on March 25, 2013 4:25 PM writes...

This is great news. In the oncology field, 2013 will be remembered as the year when immunotherapy finally emerges as a real therapeutic option. There is still a lot of work ahead of us but this is such an exciting time for immunologists.

A cytokine storm is controllable and will likely happen if this kind of treatment works. BTW, The Tegenero case told us more about poor science and bad clinical practices than about cytokine storms.

The thing about T-cell based immunotherapy is that it has memory. Once T-cells get primed against a tumor antigen, they can survive and patrol the body. Memory T cells are capable of recognizing and killing tumor cells that might survive even if they reemerge years after treatment.

In some cases memory T-cells can also lead to what we call "epitope spreading". Basically, they can induce recruitment of other T-cells that recognize different tumor antigens. This means that tumor cells might not escape even if they no longer express the epitope that triggered the initial response.

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11. ken on March 27, 2013 10:10 AM writes...

T cells? Cytokine storm? Are we making assumptions where no evidence exists? Remember, all they were doing is injecting an oncolytic virus directly into the tumor. Until you perform mechanistic studies in animals its anyones guess as to what is actually happening. Until then, its just spin and talk.

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