Sunday, August 21, 2011

New Cure for Leukemia?

Leukemia is the cancer of white blood cells.
The Penn scientists targeted chroniclymphocytic leukemia (CLL) by hacking a harmless version of the HIV virus to hack T cells in order to kill cancer cells. In previous studies, the cancer-killing cells died out quickly after infusion, but in this study, the genetically engineered cells multiplied a thousand-fold and were sustained for over 4 months. 

Let's go over the study first.  Three patients with chemotherapy resistant tumors had their blood drawn, separated, modified, and cultured. These patients underwent lymphodepleting chemotherapy, and their blood was reinjected. Endpoint assays were conducted a month after reinjection.

They did the same thing in mice, and the cells of interest were sustained for over six months, although I'm not sure whether the same monthly cycle was repeated. It doesn't say. But the cells of interest reached levels of up to 95% of white blood cells, up from 2.3-4.46% (figure 2). After an initial decay with first-order kinetics, the CART19 cell numbers stabilized between three to six months after reinjection. The fact that the cell levels were sustained after four months is at least some evidence the body can remanufacture the CART19 cells on their own.

What is most remarkable, however, is that the cells of interest seem to be able to remanufacture themselves within the body. In the third patient, flow cytometry showed that there were CAR19-expressing T cells with an absence of B cells 169 days after infusion. This is remarkable, since, "previous studies have not demonstrated robust expansion, prolonged persistence, or functional expression of CARs on T cells after infusion."

Figure 2 from the study showing levels of CART18 cells after infusion. Click to enlarge.

"There were no significant toxicities observed during the 4 days after the infusion in any patient other than transient febrile reactions. However, all patients subsequently developed significant clinical and laboratory toxicities between days 7 and 21 after the first infusion...With the exception of B cell aplasia, these toxicities were short-term and reversible. Of the three patients treated to date, there are two complete responses and one partial response lasting greater than 8 months after CART19 infusion according to standard criteria." The only side effect these three patients suffered was fever. One was hospitalized for a week, and another went into remission for 10 months.

In fact, "one of the preclinical rationales for developing CAR+ T cells with 4-1BB signaling domains was a projected reduced propensity to trigger IL-2 and tumor necrosis factor–α (TNF-α) secretion compared to CAR+ T cells with CD28 signaling domains (7); indeed, elevated amounts of soluble IL-2 and TNF-α were not detected in the serum of the patients." The cells infused into the patients were designed specifically to avoid a cytokine storm and to circumvent the donor's immune system.

"In our preclinical studies, we found that large tumors could be ablated and that the infusion of 2.2 × 107 CAR T cells could eradicate tumors composed of 1 × 10^9 cells, for an in vivo effector-to-target (E/T) ratio of 1:42 in humanized mice (8), although these calculations did not take into account the expansion of T cells after injection." In mice studies, billion cell tumors were ablated.

The three human patients had trillion cell tumors weighing around 1 kg before the infusion of CART19 cells. They all showed great progress, with the third patient surpassing others by 40:1. "Using the estimate of initial total tumor burden (1.3 × 1012 CLL cells) and the observation that no CLL cells were detectable after treatment, we achieved a marked 1:93,000 E/T ratio. By similar calculations, an effective E/T ratio in vivo of 1:2200 and 1:1000 was calculated for UPN 01 and 02 (table S6). Therefore, a contribution of serial killing by CART19 cells combined with in vivo CART19 expansion of >1000-fold likely contributed to the powerful antileukemic effects mediated by CART19 cells."

The trials for the three patients were financed by Alliance for Cancer Gene Therapy.

(the study) and MSNBC.

19 scientific replies:

GMSoccerPicks said...

While i dont understand the specifics of this, any improvement or breakthrough regarding cancer is big news. So hopefuly this works out for the best, hopefuly one day cancer survival rate will be close 100%. I dont have my hopes up though.

Skeng said...

Very clever method, avoiding the release of inflammatory cytokines which would only worsen things.
A wider human study needs to be conducted to see just how effective it can be due to the difference in the results seen in the patients. 40 to 1 is a huge difference.
Truly fascinating.

Skeng Training

Linux and Life said...

although it's beyond my savvy, I'm always happy to know about the cure of any kind of cancer.

Ghevrix said...

That's something my dad would be fascinated to hear about. It's interesting how they used an offshoot of HIV to make it.

That Bastard From Bellingham said...

Didn't we talk of such a thing on a recent post of yours, Genetics? How the American Cancer Society already has a cure but will hang on for as long as they can in order to make more ill-gotten and undeserved money...

Also note, a DIFFERENT group is getting closer to the cure then the ACS.

Anyway, is it me or does that just sound so badassed, the words, "Cytokine Storm?"

Like "CYTOKIIIIIINE STOOOOORM!"

I know that has nothing to do with the actual information on this post, but still...

BDTC said...

Babysteps! We'll get to a cure soon!

xxmugenxx said...

pretty cool, eventually there will be a breakthrough!

Jason said...

Thanks for the information! Was really helpful! Keep up the great blog work!

Michael Westside said...

One thing i like when reading the comments here, is that no-one is hung up over that the T-cells are being modified with the HIV-virus. I've seen this article on so many sites. And most of them got a bazillion comments on how "lol, cured, now you got HIV, haha, stupid" and similar things.

Clueless Dolphin said...

leukhemia, like all cancers, are ever-evolving which is making it so hard to find a goddamn cure

Come At Me Bro said...

This is great!

Neon said...

169 days is damn impressive. Usually, dont they just last about 40 days? Or less

Cool News said...

I love reading up on the latest science, thanks!

Amber said...

That is amazing! I know someone who died of Leukemia and it is a rough disease. Its great to see science making strides toward a cure!

convictus said...

I think that we will "cure" cancer one form at a time as we develop ways of treating that aren't stuff ourselves full of chemo and irradiate the crap out of ourselves.

Kenneth Tso said...

Progress is progress!

Heaven. said...

Wow, awesome!

Sketchar said...

The idea of killing a specific cell type is boggling to me, like how is that working out. If there was a way for the normal tissue to mutate to a new chemical in the body which the cancer cell can't and then dies, that seem plausible.

FinBis said...

More and more we hear about amazing breakthroughs related to many of our most dangerous diseases, truly the human development is amazing!

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