Engineered T cells recognize and kill leukemia

[Ronja]

GenesForLife, any comments on this?

Two weeks after receiving an experimental treatment for his cancer, David Porter's 65-year-old leukaemia patient seemed to take a turn for the worse.
...
"I was sure the war was on," the patient, who has asked to remain anonymous, wrote in a statement released to reporters. "It was another week later that I got the news that my bone marrow was completely free of detectable disease."

“It vindicates the cancer researchers who believe that cells are very smart drugs.”
The dramatic results from this patient and two others, published this week in the New England Journal of Medicine and Science Translational Medicine, are among the first successes for a long-sought therapy based on reprogramming immune cells to attack cancers.

The approach aims to harness the lethal capabilities of T cells. Porter and his colleagues, including immunologist Carl June, engineered each patient's T cells to recognize a protein called CD19 that is displayed on the surface of cancerous cells as well as on normal immune cells called B cells.

Researchers have long sought to kill cancer with T cells containing such "chimeric antigen receptors", but early results were disappointing.
...
As for Porter's patient; he is still marvelling over his experience. "When I was a young scientist, like many I'm sure, I dreamed that I might make a discovery that would make a difference to mankind," he wrote. "I never imagined I would be part of the experiment."

More at: http://www.nature.com/news/2011/110810/ ... 1.472.html

[mistermack]

It's funny, it did occur to me that a cure for cancer could kill the patient, if it was TOO good.
All of those dead cancer cells would take some shifting in a weakened patient.
If they do find a really good one like this seems to be, they will have to find a way to slow it down a bit.

[Xamonas Chegwé]

It's funny, it did occur to me that a cure for cancer could kill the patient, if it was TOO good.
All of those dead cancer cells would take some shifting in a weakened patient.
If they do find a really good one like this seems to be, they will have to find a way to slow it down a bit.

Dead cells mightn't be that much of a problem. The body replaces cells all the time. No worse than scar tissue replacing a wound, I wouldn't have though.

[Feck]

it was mentioned in another 'cure for cancer' thread that suddenly killing all cells containing cancer could be harm full ...

reduce the dose /frequency of the treatment and be prepared for likely problems and I would have thought it would be ok ,esp in early stages

[Xamonas Chegwé]

it was mentioned in another 'cure for cancer' thread that suddenly killing all cells containing cancer could be harm full ...

reduce the dose /frequency of the treatment and be prepared for likely problems and I would have thought it would be ok ,esp in early stages

I suppose it could lead to septicæmia or something if a large mass of dead cells was left behind. Something to ask the Dawktor or GFL.

[mistermack]

I suppose it could lead to septicæmia or something if a large mass of dead cells was left behind. Something to ask the Dawktor or GFL.

I got it from the linked article :

Two weeks after receiving an experimental treatment for his cancer, David Porter's 65-year-old leukaemia patient seemed to take a turn for the worse. Fatigue and fever drove the patient back to hospital, where his temperature surged to more than 39º C and he began to shake, his body racked with nausea and diarrhoea.

But rather than being a clinical failure, the patient's return to hospital heralded the treatment's success. His symptoms were the dying scream of more than a kilogram of leukaemia cells

But it had occurred to me before that this could be a real problem, for a really effective treatment.
It should be feasible to slow it down though.

One thing about cancers is that they are unlikely to evolve resistance to effective treatments, or if they do, the resistant strain should become extinct when the patient dies. So weakening the treatment shouldn't encourage resistance to spread to others.

[Xamonas Chegwé]

I suppose it could lead to septicæmia or something if a large mass of dead cells was left behind. Something to ask the Dawktor or GFL.

I got it from the linked article :

Two weeks after receiving an experimental treatment for his cancer, David Porter's 65-year-old leukaemia patient seemed to take a turn for the worse. Fatigue and fever drove the patient back to hospital, where his temperature surged to more than 39º C and he began to shake, his body racked with nausea and diarrhoea.

But rather than being a clinical failure, the patient's return to hospital heralded the treatment's success. His symptoms were the dying scream of more than a kilogram of leukaemia cells

But it had occurred to me before that this could be a real problem, for a really effective treatment.
It should be feasible to slow it down though.

One thing about cancers is that they are unlikely to evolve resistance to effective treatments, or if they do, the resistant strain should become extinct when the patient dies. So weakening the treatment shouldn't encourage resistance to spread to others.

It was the sheer volume of cells that caused the trouble then - that makes sense. no need to water-down the treatment if you catch it early - but if the cancer has progressed, i can see this becoming an issue.

[GenesForLife]

[1] Mack is right, it should be feasible to slow it down.

The cells they used were genetically engineered using a lentiviral vector (a lentivirus is a retrovirus, similar to HIV) to express two proteins that would trigger increased proliferation of the T-cells that were used when they reacted with the target antigen on CLL Cells. The really clever thing about expression vectors is that it is eminently possible to couple the expression of a gene with an external signal, such as the presence of the antibiotic doxycycline (See http://www.nature.com/gt/journal/v10/n6 ... 1889a.html) for instance.

What that means is that you can put these cells in and trigger proliferation when required by using the antibiotic. While this is not a feature of the current vector, should a more precise degree of control be required, such a thing can be pressed into service.

[2] Regarding Xamonas' statement, which was thus...

It was the sheer volume of cells that caused the trouble then - that makes sense. no need to water-down the treatment if you catch it early - but if the cancer has progressed, i can see this becoming an issue.

One feature of CLL (for which the therapy has been developed, and that therapy is rendered particularly effective by the nature of the disease) is that it is a generally stable disease.

Extra food for thought;

Some people on RatSkep, for instance, have been asking if this approach can be applied to other tumour types, too, the answer is that it is unlikely, because the approach is based on targeting an antigen specifically found in CLL cells and not necessarily other tumour types. To quote from the relevant commentary in the NEJM (where the study appeared)

In addition to the tumor lysis syndrome, the patient had B-cell depletion and hypogammaglobulinemia. These conditions may not be major problems in patients with CLL, but in other tumor types, the persistence of activated T cells, memory T cells, or both could pose substantial problems. Both toxic effects to the target organ and also “on-target but off-organ” toxic effects have been observed because of unappreciated cross-reactive target antigens.8 Toxicity may become more of a problem as more potent second- and third-generation chimeric antigen receptors are used in patients with different tumor types.

Reference here - http://www.nejm.org/doi/full/10.1056/NEJMe1106965


If you want to read a case report - here it is

http://www.nejm.org/doi/full/10.1056/NE ... articleTop

We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×105 cells per kilogram of body weight) of autologous chimeric antigen receptor–modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.

The last line highlights one of the potential adverse reactions to use of the strategy; that is because these modified cells not only kill CLL Cells but normal B-cells too, which produce antibodies.

[mistermack]

You can end up with a difficult choice.
The treatment runs a risk of harm, but the patient is dying in front of you.
So with terminal cancer, it's valid to take risks that would be unthinkable in others.
(or should I say, to OFFER the patient a risky choice).