Ball Rolling on T-Cell Replacement Therapy...

I first heard about this type of therapy in a biochem class I took midway through my undergrad degree, and it struck me as an elegant but somewhat sci-fi concept.

For those of you not aware, this type of anti-cancer therapy involves taking certain types of a patient's white blood cells (T-cells), modifying them in the lab to target the malignancy in question, and putting them them back into the patient's circulation. Original efforts saw limited success, because these 'primed' T-cells were rapidly depleted once back in the body.

More recent studies improved upon the method, modifying the T-cells to be more robust and proliferate in the body. It was trialled on a man with refractory chronic lymphocytic leukaemia (CLL), with malignancies widespread throughout the bone marrow. Undergoing T-cell replacement therapy with 5% modified T-cells, he went away with nothing to report, until 2 weeks later when he was hospitalised with flu-like symptoms. It was soon discovered that his body had become a battleground, with now 20% of his T-cells being the 'modified' type, hard at work killing cancerous cells. Within 23 days of receiving the T-cell replacement therapy he had literally shed 1kg of cancerous cell mass, with no malignancies detected in his bone marrow. As far as I know, he is CLL-free today. Three people underwent this experimental therapy, with two going into complete remission. Sadly, the third person did not respond as well to the treatment, and remains with detectable CLL, albiet asymptomatic and non-progressive.

With such promising results, one would really hope that some serious money pushed the therapy towards further development. Well, I am very happy to report that the massive push has now come from Novartis, putting $20 million behind this research at the University of Pennsylvania. Novartis also licenced the chemotherapy agent imatinib (Gleevec) which has had success in treating chronic myelogenous leukaemia and was awarded by TIME magazine (overall survival rate of 89% after five years in patients who received imatinib).

This is quite welcome news, as patients diagnosed with haematological malignancies often have poor outlook and, as we all know, traditional chemotherapy regimens have significant cost and side-effects with a low success rate (ignoring the relatively successful imatinib). I believe this therapy could mean big changes on the treatment of leukaemia and hopefully more cancers down the road. The group have reportedly planned to expand their targets to lymphoma, mesothelioma, myeloma, and neuroblastoma. So keep an ear to the ground on T-cell replacement therapy!

 

That's great news my friend, really glad to hear it.

I wanted to emphasize the importance of funding. The original research was conducted on only three subjects as a direct result of insufficient funds. The National Cancer Institute would not back them then, nor would any pharmaceutical company. The research was funded by a charity, Alliance for Cancer Gene Therapy. So it is significant that now, following very promising results, there is momentum behind expansion of this research.

And in CLL patients, particularly with the genotype of these individuals, the concept of being cured completely or achieving prolonged remission is highly unlikely - requring bone marrow transplants, which in themselves are hugely risky, not always possible, and commonly fail to cure or even improve the patient's condition... potentially leaving them with cancer and some form of graft versus host disease. So this particular result is astounding.

 

It looks like this type of research is showing positive results elsewhere, although in this case against acute lymphoblastic leukaemia (ALL), which is generally more aggressive than CLL.

Four of five patients who had more or less been issued hospice cards are now in remission.

 

As all research (particularly pertaining to disease therapies) can span several years (or decades), people often hear about breakthrough developments, and soon forget them as the hype dissipates. But rest assured, this research continues. CKTony recently posted a thread about it here, also.
 
Now that the group have sequestered a stable funding source to push forward on this incredibly expensive experimental therapy, and have hopefully overcome the unfortunate and inevitable legal battles surrounding prior research contracts (people probably wanting a slice of the pie), more results have surfaced. Initially, updated results looked incredibly bleak, but appear to be showing more promise based on more recent announcements:
 
"Every batch of T cells will be different because each originates with a different patient. But other scientific and manufacturing variables-the vector that inserts the foreign DNA, techniques to grow the cells, how they're transported-can make the outcome unpredictable.
\nJune's group learned this the hard way: After the fanfare around their first three patients, they treated three more in January 2012 with a new vector lot. None responded. "I was just stumped out to the max," June says. He had no idea what had happened and still can't say whether something went awry with the vector material or whether the outcome was due to random fluctuations in the therapy's success. "All we knew was, it worked three times, and then it didn't work three times." All three of those patients later died of their disease.
\nNext in line was patient 7, who turned out to be another roller coaster. She was Emily Whitehead, a 6-year-old with end-stage leukemia whose parents turned to June's cell therapy as a last-ditch hope. The experimental treatment sent her body into a deadly immune overdrive. She spent 2 weeks on a ventilator in the CHOP intensive care unit while doctors tried everything they could think of to save her.
\n"We thought it was over," June says. He drafted an e-mail message to Penn's provost: "It is with regret that I inform you that our first pediatric patient on the CART19 trial will likely die," he wrote. "There is nothing to do at this point other than hope for a miracle." June pledged to "conduct a full investigation." It turned out that he didn't need to, and the e-mail was left unsent.
\nAs doctors parsed Emily's lab results, they found that her revved up T cells were causing overproduction of a molecule called interleukin-6. She was saved, in a tale that became hospital lore, by an arthritis drug that disables it. June knew about the drug only because his daughter Sarah had been diagnosed with rheumatoid arthritis shortly after her mother's death. Grupp happened upon it independently, when a colleague found it by Googling on his iPhone.

Eight-year-old Emily Whitehead was the first child on the experimental Penn protocol, and she's now cancer-free 1 year later.
\n

Grupp has treated 14 children with acute lymphoblastic leukemia so far. Of the five reported at scientific meetings or published, four went into remission but one of those later relapsed. Porter's most recent data on adults, presented at a meeting in May, includes 10 responders out of 17 treated, with five of those in complete remission for at least 3 months."
 
The treatment is inherently patient-specific, working well in some but not in others for no clear reason. It is unsurprising that the group have had difficultly attracting funding in the past, and it remains to be seen how their therapy will translate to a workable treatment post-clinical trials. Money being a huge factor, also.
 
"The expense of CAR treatment has plunged, but it still costs $20,000 to $40,000 to generate the cells. That doesn't include supportive care in the hospital after patients receive them.
\nIn March, Sadelain reported on five patients with acute leukemia in Science Translational Medicine. That disease is more aggressive than chronic leukemia in adults, and oncologists were heartened by what they read: Four of the patients went into remission, a necessary precursor to getting a bone marrow transplant, which they then received. Three are still alive at least 5 months after treatment. "That it was verified at another center, at Memorial, was very important," says Bhatia at the City of Hope. It was "not just something strange that happened" in the people treated at Penn.
\nStill, physicians like Porter and Grupp are mindful that this isn't life-changing for everyone. "When I'm doing informed consent with these families, the first thing I say is, 'Forget everything you've read about this,'" Grupp says. "Nothing could possibly be as promising as the various articles about this make it seem." Only four people, including Emily, have been followed for more than a year. A looming question is whether CAR therapy can work in solid tumors, and June and others are opening clinical trials to try and find out.
\nNearly 3 years after the summer that changed everything, the Penn group is still working flat out to keep up: enrolling as many patients on the trials as they can, working with drug regulators to discuss how best to study the cells with an eye toward approval, collaborating with Novartis to train their employees and streamline the cell-generating process. "I'm tired," says Porter, and he sounds it. June, a serious bike racer and runner, has scaled back his hobby, though he did manage to fit in a 34-mile ultramarathon last weekend. "I didn't used to work as many hours as I do" now, he says. "I mean, I used to work, but I'd take more time off." He's eagerly waiting for the handoff, the day when Novartis starts processing T cells and making CARs. Neither June nor Novartis can say when that will be, but for June, it will mark a return to normalcy. "Until then," he says, "it's overdrive.""

 

Keeping my ear to the ground as promised... some newer technology surfaced in the world of T-cell therapy which answers certain shortfalls of the therapy. Namely, the difficulty in generating the T-cells themselves. Some clever biologists have developed a method to mass produce them from donor stem cells!
 
http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2678.html
Yes it's behind a paywall, but someone has saved me the job of summarizing here

 

Since the T-Cells were produced outside of the body, did this aid the body in creating memory T-Cells? I didn't find any mention of it in your post, but since it was a time-dependent response (i.e. it took awhile for the body to completely remove the cancerous cells), during that time, the body must have aided the external stimuli by creating memory T-Cells, no?
 
 

 
Finally being cured by western medicine, that is. Non-patent based cures produced by nature have been around longer than we have.
 

 

 
It wasn't until a specific protein was chosen that the T-cells not only stayed in the body, but were multiplied. Previous T-cell therapies were failing specifically because the body was not employing the cells as its own, and so they were quickly leaving the bloodstream. The key was apparently using the 4-1BB co-stimulatory signal in the protein (chimeric antigen receptor or CAR). This was in fact chosen partially to be different from the rest of the herd, which proved to be a very lucky decision.
 

 
We've been over this time and time again as a forum of scientists and enthusiasts. The sad truth is that there is currently no effective cure for cancer, patent, off-patent, synthetic or naturally occurring. There are treatments that are effective for some and fail on others. I'd appreciate that this thread stuck to the topic of T-cell therapy and didn't derail into romantic anti-establishment nonsense, to borrow Sam Spade's phrasing. Use the search feature if you want to participate in a thread about natural cancer treatments or pharmaceutical conspiracies, there are too many already.

 

 
I did a quick search on it, but I just want to make sure - the individual will be able to fight off the same tumor cells (if they start to multiply again) in the future effectively, but not necessarily a nonidentical tumor? Not that that would be a problem, seeing how the replacement cells can be engineered to target any tumor antigen. Very good news if I understood it correctly.
 
I know first hand of three survivors, but heard of many more success stories. I was just being logically correct, from what I've been exposed to, and assuming they are honest stories. These are human lives that were saved and spared the process chemotherapy, is that not as beautiful as T-Cell Replacement Therapy?
 
 
edit: Any possible side-effects?

 

 
 
Presumably so. The cells behave in the body as if they're natural, which is what makes it such a powerful treatment when it works. The ability of the treatment to afford long term 'surveillance' against future malignancies can only remain a hope at this stage, it is too early to know, and it would seem all responders are still living CLL (or ALL) free.
 
This persistence of cells is also a possible avenue for side effects, of course. The modified T-cells detect an antigen that is highly expressed in cancerous white blood cells, but it is also present in non-malignant cells too. The fear is of course that these modified cells may result in autoimmunity-like side effects. Again, too early to say.