Several hundred of you sent me links to various articles and videos in the lay press, reporters discussing the results of the recent paper in New England Journal of Medicine. I gave up acknowledging the individual emails after the first couple of dozen or so. It was good to see our members are wide awake and keeping tabs on new research that may be relevant to our community. Keep it up! In case you have been too busy following the roller coaster ride of the stock market and not paying attention to much else, here are some of the links that you can look up at your leisure. Frankly, I have stopped looking at my savings accounts – it is indeed scary and there is not a whole lot I can do about it. Any case, I would rather spend my time writing about CLL breakthroughs!
MSNBC ; Yahoo News ; New York Times; CBS news ;
The article in NEJM is so new that PubMed has not yet caught up with it and therefore there is no official abstract. In its stead, below is the “Summary” section of the NEJM article, as well as a link where you can access the full text article for free. I must warn you, it is not easy reading since it is clearly written for a professional audience – but well worth a try if you are a science geek like me. I found it very interesting. It is credible research, published in a very credible peer-reviewed journal – definitely not snake oil. That much is clear.
Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia
New England Journal of Medicine, August 10, 2011
David L. Porter, M.D., Bruce L. Levine, Ph.D., Michael Kalos, Ph.D., Adam Bagg, M.D., and Carl H. June, M.D.
Summary
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.
OK, now that we have acknowledged the official paper in NEJM, as well as the TV soundbites, we can get down to business and try to make sense out of this new development. Is this a breakthrough or is it just more hype? Will we be able to declare CLL a curable cancer in the next couple of years? Below is my best understanding of the science, admittedly at first blush and short notice. I will be keeping my eyes peeled for learned discussions on this subject and if anything changes in my understanding, I will be sure to get back to you via the comments section that follows each of my reviews. In the meantime, here is a quick look-see at this interesting research.
T-cells: elite troops, serial killers
Before you can understand what this research is all about, you need to learn a little bit about T-cells, how they work, why they are so important for good health and what can go wrong with them. Bear in mind, this is indeed a cartoon version of a field of immunology that researchers spend their whole professional lives studying. But without even this bit of understanding of how T-cells work, you won’t be able to make sense of the University of Pennsylvania research results. At your leisure, you can also browse earlier articles I have written on the subject. Links are given below for your convenience.
Autologous CD20 targeted T-cell therapy
T-cells are smart troops. In other words, they can learn from prior experiences fighting pathogens and cancerous cells, they can remember, and they can pass on their wisdom to their off-spring. T-cells (and their less numerous but even more potent side-kicks called NK Cells) are among the most important of our immune defenses against all sorts of external threats such as viral infections as well as home grown cancers.
Consider what may happen when a stray photon of UV light hits the unprotected bald spot at the top of your head, in exactly the wrong way. There you were, minding your own business and enjoying a day at the beach and soaking up a little sunshine, trying to get a tan. But as happenstance would have it, that single skin cell on top of your head got damaged by the UV photon and its DNA became messed up. Most of the time, scrambling of the DNA is serious enough that the cell dies immediately thereafter. This is the orderly process of apoptosis, cellular suicide. Without it, we will have all sorts of dysfunctional cells hanging around and gumming up the works. As it is, the dead cell does little more than contribute to a bit of dandruff, skin flakes that you brush off with hardly a second thought.
But what if the cell is damaged just enough to be dangerous? What if the DNA damage is such that it learns how to turn a deaf ear to the suicide signals it gets from its neighbors and friends? What if it continues to live in its mangled state, even thrive and grow a few babies that share its cancerous abilities of avoiding proper cell death? What you have is a microscopically small colony of newly minted skin cancer cells – a really tiny colony of basal cell or squamous cell carcinoma. Left unchecked, this little group of cancer cells would keep growing and pretty soon it would not be such a small problem anymore. That is one reason why defects in the P53 gene are so important. This gene controls the cell’s ability to commit suicide.
That is where T-cells come in. T-cells have the ability to query the cells they meet as they patrol every nook and cranny of your body. They are on the prowl for infected cells and cancer cells. In a healthy individual with properly functioning immune function, the little colony of cancerous skin cells is soon discovered. T-cells go far beyond politely asking the cancer cells to commit suicide. They actually drill holes into the cancerous cells, build a funnel (“perforin”) and pour in a particularly deadly poison (“granzyme”). Talk about irresistible and lethal force – the cancer cell that is attacked in this fashion has no chance of survival. Does it matter if the cancer cell has developed p53 defects? No, because we are not talking of suicide anymore, we are talking of execution! Carried out by T-cells. Once the target cell is dead, the T-cell moves on to the next victim, until every single cancer cell in the little colony is wiped out. T-cells are truly serial killers. A single T-cell on killing rampage can execute many target cells before it runs out of ammo (perforin and granzyme) and needs to recover, re-load as it were.
In fact, T-cells can be such dangerous killers that they have to be kept under careful check at all times. Uncontrolled, they can become hordes of killers that damage healthy tissue as well as cancer cells. For example, many forms of autoimmune disease are the result of an over enthusiastic immune system killing perfectly healthy cells. Being able to tell the difference between healthy cells and cancerous or virally infected cells – that is the fine line between health and sickness. Part of the control mechanism in preventing unwanted T-cell rampages is that they must have several different signals confirming the target cell is indeed infected or cancerous, before they can kill it. Think of it as paperwork that must be filled out in triplicate before execution can take place. This bit of cellular red-tape slows things down a bit, but it makes sure innocent cells don’t get killed for no good reason.
Smart criminals can learn to hide from smart police officers
If T-cells are so great, how come any of us get cancer? The reason is simple. In addition to learning how to turn a deaf ear to official orders to commit suicide, cancer cells can also learn stealth techniques that make them invisible to T-cells. The details are complex and I will not bore you with them. But all we need to understand is that for a cancer cell to flourish, it needs to do three things. (1) Avoid committing suicide (2) have plenty of babies just like itself (3) learn how to fool T-cells so that they cannot identify it as a cancer cell that must be killed on the spot. Remember all those careful confirmatory signals that T-cells must have before they can kill, the red tape paperwork that must be filled out before they can unleash their killing fury? That is often the basis of how cancer cells avoid getting killed. Think of it as the police department swamped in bureaucratic red tape and unable to act quickly. Criminals can learn to use that window of opportunity to flourish. Pretty soon, T-cells get so used to seeing these criminals hanging around that they stop paying any attention to them at all! This called “T-cell anergy”.
Bringing in new and better trained police officers
How about if we bring in a fresh bunch of police officers from the neighboring town? Officers who have not become blase to the presence of criminals hanging around, officers with different safety protocols that the criminals have not heard about and therefore cannot use to their advantage? Yes, that may be able to do the job – if there are enough new police officers, if they stick around long enough to do the job, if they are not overwhelmed by too many well entrenched criminals. And if the new police officers don’t kill too many innocent citizens, mistaking them for criminals.
There is a name for such a therapy. It is called a mini-allo transplant. We get rid of the existing useless police force and as many of the criminals as we can (pre-conditioning therapy), bring in new batch of police officers (graft) and hope that they will go after the criminals (graft versus leukemia effect). The single biggest problem associated with allogeneic stem cell transplant is graft-versus-host disease. Even with the best efforts to match donor to recipient, the new T-cells coming in are prone to attack healthy tissue as well as cancer cells. Graft-versus-Leukemia and graft-versus-host disease are two sides of the same coin.
Can we teach our own T-cells to be more effective?
Is there anyway of making our own T-cells work better at spotting the cancer cells? If it is our own T-cells – the term is “autologous” when the T-cells are the patient’s own, not from a donor – then there is little risk of the dreaded GVHD. Can we, for example, give them extra training to recognize a particular kind of cancer, help them recognize the cancer cells better by sharpening their focus to just that one kind of cancer cell? Can we suspend some of the safety rules and give them more discretionary power to carry out executions without having to dither and second guess themselves? You with me so far? Because that is exactly what this new bit of research attempts to do. It makes it easier for the patient’s own T-cells to recognize CLL cells, and it removes some of the hurdles T-cells have to cross before they can shoot to kill.
Autologous, B-cell targeted, rampaging T-cells
Let us take that paragraph heading, one step at a time. Autologous. In other words, T-cells from the patient’s own body are harvested and taught a few new tricks before they are infused back into the patient. B-cell targeted. T-cells are designed by nature to be general purpose smart troops, ready to identify a breast cancer cell, a skin cancer cell, a virally infected cell or whatever happens to be around. But in this case, we want them to focus on just one thing. CLL cells. All B-cells carry CD19 marker. Immature B-cells, mature B-cells, cancerous B-cells, healthy B-cells – it does not matter what kind of B-cell. Think of CD19 as the marker that defines a B-cell, its very essence, the one thing that it cannot hide. This study trains the T-cells collected from the patient to recognize CD19 as a huge red flag, a signal that cannot be ignored, in fact the only signal that matters as far as it is concerned. They did a couple more things to the T-cells. They took some of the safeties off, by providing the confirmatory signals ahead of time. Think of it as filling out the paperwork and signing the execution orders ahead of time, taking that pesky duty off the list of things T-cells have to hassle with. We now have all the ingredients necessary for effective hunting of B-cells: patient’s own home grown T-cells able and willing to recognize any cell carrying the CD19 marker (which means all B-cells), and trained to use lethal force without needing any other bits of confirmatory signals.
The U. Penn. clinical trial
Just three patients underwent this protocol so far. But the NEJM article reports the data with reference to just one patient. This is a single patient case history report, something to keep in mind as we evaluate the results.
The patient was diagnosed with CLL in 1996. After 6 years of Watch & Wait, he was treated with 2 cycles of FR and got a partial response (blood counts looked good, but there were still some swollen lymph nodes). He needed therapy again in 2006 and got 4 more cycles of FR. Same result, blood counts normalized but only a partial response in nodes. By 2009, things got a lot worse. He had rapidly progressive disease, heavily infiltrated bone marrow, and FISH test showed unequivocal deletion in the dreaded 17p region. They tried bendamustine (Rituxan had to be withheld because he developed massive allergy to the mouse juice of Rituxan) with very little to show for it.
So, we are looking at a patient with pretty bleak future: very aggressive CLL, 17p deletion, prior history of only partial responses to FR and more recently bendamustine, contra-indications for ever using Rituxan again due to hyper allergic reactions. What would you do in his situation? Campath? Revlimid? Mini-allo transplant if you somehow managed to get a good remission ahead of the transplant? Tough calls, all of them.
In Dec 2009, patient underwent procedure for T-cell collection from his own blood. While these T-cells were being modified, he underwent 11 weeks of Campath therapy. The point of the Campath therapy is to get some control over the CLL while he waited for the modified T-cells to be ready. Over the next 6 months, while he waited, his disease came roaring back. Massive bone marrow infiltration, 1-3 cm lymph nodes all over the place. By July 2010, the modified T-cells were ready. Phew. Those six months must have been tough waiting for this brave volunteer!
We will not go into details of how exactly the T-cell modification was carried out. There is no way I can make a cartoon version of that, you have to read the NEJM article if you are interested in the details. For the rest of us, just remember these T-cells are now fixated on CD19 as their target, and they are T-cells on steroids, only too anxious to kill their target cells.
Four days prior to getting the new modified T-cells, the patient got massive doses of pentostatin (another purine analog similar to fludarabine) and cyclophosphamide. The intent is not so much to kill CLL cells – but to kill of some of his remaining local defenses. Same approach is taken in mini-allo transplant, making sure that the new graft coming in is not immediately attacked and killed by the patient’s remaining immune system.
Finally, arrival of T-day. Our patient got his modified T-cells split into three doses on 3 consecutive days. 10% on the first day, 30% on the second day and 60% on the third day. The researchers were being cautious with this very new technology. No toxic effects were noted upon infusion of the souped up T-cells.
Clinical response
Now for the details you have been waiting for, what happened after the patient got his own modified T-cells. Frankly, nothing much happened for the first couple of weeks. I bet the researchers were disappointed, scratching their heads and wondering what they could have done better.
Fortunately for our guy, they did not stop monitoring him, they did not go off on vacation and chalk the experiment to yet another failure in the long list of unsuccessful T-cell therapy approaches. Because all hell broke loose after 14 days. It started off with low grade fever, chills, a little fatigue. All the usual symptoms that we are familiar with, for example, when we have a slight infection and T-cells are doing their thing and stamping it out.
Over the next 5 days, things got a lot more interesting. And dangerous. The chills got worse. The fever spiked to 102.5, there were rigors, nausea, diarrhea, lack of appetite. On day 22 post infusion of modified T-cells, patient was formally diagnosed with tumor lysis syndrome.
If you are inclined to dismiss this incident of TLS as not very important, please don’t. TLS is dangerous, TLS can kill. Notice the sudden spike in uric acid, creatinine and LDH (lactate dehydrogenase). All of these are waste products created when cancer cells are getting killed so fast that the debris created by their death is accumulating too fast for the kidneys to dispose of. The authors note, there was evidence of “acute kidney injury”in this patient.
I wonder if the researchers considered this possibility and had the patient pre-medicated with allopurinol. I did not see any references to that, but perhaps it is a detail they did not report. They do report that the patient was hospitalized after the diagnosis of TLS, hydrated and treated with rasburicase. This is the new drug that is used in place of allopurinol when time is of the essence – as it was in this case. Please refer to our earlier article on tumor lysis syndrome if you want to learn more about it.
Our guy was lucky. Rasburicase worked and uric acid levels came back down within 24 hours. By day 28, positive results of all the modified T-cell induced mayhem could be seen: the swollen lymph nodes were no longer felt, and there was no evidence of CLL in the bone marrow! FISH test showed no 17p deletion. Continued monitoring of the patient at 3 and 6 month post modified T-cell infusion showed no return of the cancer – no swollen nodes, no FISH defect, no bone marrow involvement. Patient had no B-cells left. As expected the CD19 targeting T-cells killed all B-cells, not just the cancerous CLL cells. It is now 10 months since start of the T-cell therapy, and the patinet’s remission is still intact.
There were no other high grade adverse effects. Lymphopenia (too few white blood cells) continues, since the bulk of white blood cells are B-cells and this patient has no B-cells left. Also a consequence of having no B-cells, patient is now low on immunoglobulins. Remember, B-cells mature to become plasma cells, which are nothing more than factories for manufacture of immunoglobulins. No B-cells means no plasma cells, which in turn means no immunoglobulins. This was an expected adverse effect and patient is now on regularly scheduled IVIG (intravenous immunoglobulin) therapy.
The gift that keeps on giving..
Several earlier attempts at using externally modified T-cells failed soon after when the newcomers gradually died away in a couple of weeks. Some of you old timers may remember all the hype associated with “XCYTE” technology that went no where fast. In a nutshell, the problem was that the modified T-cells did not hang around long enough to do much. Not so the little critters used in this trial – and that was the huge surprise.
Notice how the number of modified T-cells (“transgene copies”) shot up after the three days of infusion, by a factor of 1,000 fold! At their peak level, the modified T-cells accounted for more than 20% of all circulating lymphocytes. The timing of the peak in their concentration also coincided with the onset of tumor lysis syndrome in our patient. Makes, sense, highest number of killer T-cells going on a rampage, maximum number of B-cells killed quickly, most damage to the kidneys. The interesting thing to note that 180 days out, there are still 100 times as many modified T-cells as were initially infused. Wow. No question but these souped up T-cells are not only surviving but thriving! The graph above is with reference to whole blood. Similar trends of modified T-cell concentrations were also seen in the bone marrow.
The good news is that these new modified T-cells are able to survive and even grow their numbers by huge amounts in the patient’s body. That means there are enough of them to do the job of killing CLL cells, and they are sticking around long enough to complete the job. And if they stay around forever, the remissions will hold forever.
The bad news is that these new modified T-cells are able to survive and even grow their numbers. Controlling dosage of T-cells infused is going to be tricky. TLS will be a huge risk factor, if the numbers increase too much, too quickly, and therefore kill too many B-cells too fast for the kidneys to handle. If they hang around forever, and continue to target all CD19 carrying cells, that means the patient will continue to have zero B-cells – forever. B-cells are an important part of our immune system. Even Rituxan therapy (which targets CD20 marker) does not totally wipe out B-cell populations, and the counts recover in any any case a couple of months post Rituxan therapy. Live with no B-cells for very extended lengths of time will be tricky. For starters, patient will become dependent upon regular IVIG infusions, for the rest of his life. Even with that, long term B-cell deficiency means there will be increased risk of infections.
Down the road, more work will establish dosage, safety monitoring, better protection against TLS ahead of time. They may also build in a suicide switch into the modified T-cells, so that an externally administered signal can cause them to curl up and die, once they have finished their job and CURED the CLL. Such technology is known and has been used in other approaches. The bottom line take home point is this: in a very refractory and 17p deleted patient with few therapeutic options, they managed to actually eradicate the nasty CLL cells. That is a huge accomplishment. How can we not cheer that?
Editorial
This has been a long article. So I will keep my editorial short and to the point.
- Is this “snake oil”? No.
- Is this credible research? Yes.
- In its present state, can it be dangerous? Yes.
- Is the research promising? Very.
- Is there a lot more work to do? Yes.
- Grounds for optimism? Most definitely yes.
- Will it be available to treat you in the next year or so? Not outside of carefully conducted clinical trials.
- Should we be rooting for this approach? Absolutely!
Wonderful breakthrough, lots of press visibility, kudos from their peers and patient groups like us. Did the authors thank the single patient whose life hung in the balance in this clinical trial? No. Well, that is nothing new. So, please join me in a very heartfelt round of applause for this pioneer. His courage may one day pave the way for the rest of us beating this awful cancer.
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65 comments on "T-cell Therapy: Research Breakthrough !(?)"
Thank you so much for your quick insight into this new CLL research. Thanks to the patient that survived this, and may the time not be too distant for this new technology to be available for more of us. I know it will take time for this to come to fruition, but there could be a small light at the end of the tunnel.
Anne
Chaya,
A GREAT REVIEW…insight…pros and cons. Excellent.
Thanks again,
William Bates
Chaya
Since I was one of the hundreds of people sending you the article; I want to thank you for taking the time to explain the article in more detail. As I read the first article it was like wow the cure is here but having you explain it in detail really helped me understand the article better. While more research needs to be done with regards to this new approach it is heart-warming to know that researchers are trying so hard to help those of us afflicted with CLL. It is so nice that you are so willing to take the time to help us understand these scientific writings so we can better understand them. I so appreciate you.
The news reports on three patients but the paper only mentions one.
Great promise, lets hope for accelerated trials.
Thanks Chaya for all your dedication. This patient seems to be a mirror of my wife.
Pat Carey
Thank you Chaya for your excellent explanation! Do you know if they are recruiting for more clinical trials now? even with the risks-there are those who may be facing no better choice for treatment!
How realistic is it to forecast a sufficient supply of IVIG should this treatment ever become standard practice?
nlbeem:
Here is the link to the clinicaltrials.gov site that has all the information with regard to this trial:
http://clinicaltrials.gov/ct2/show/NCT01029366
As you will notice, while it says they are still recruiting patients, the total number of patients to be recruited for this very early phase trial is just 10. And they are recruiting patients with all sorts of cancers, not just CLL. With all the publicity the NEJM article got, I doubt they will have trouble filling any remaining slots.
We lucked out for a change, that the first patient they treated and reported on happened to be a CLL patient. And that too, one with the dreaded 17p deletion. It would have been a lot harder to assess the value of this technology for CLL patients, if this first patient had been afflicted with one of the other cancers.
qb:
The problem is not just availability of IVIG for all comers. IVIG therapy handles only part of the problem of having total B-cell depletion for the rest of the patient’s life. I am pretty sure they will find a way of tweaking the modified T-cells so that there is a built in suicide switch in them – a switch that can be triggered once it is clear the cancer has been completely eradicated.
What makes this research so interesting is that it is potentially able to cure all sorts of cancers. Just change the CD19 target to whatever new target that is needed for a different cancer. We live in exciting times.
Chaya,
Thanks so much for your quick and complete parsing of the information currently available on this trial. When I first saw links to the abstract, I saw that CD19 was targeted, with no way of differentiating malignant from normal, so had concerns when it was clear the serial killer was hanging around and possibly propagating. Can’t wait for the next installment in this exciting story. And like everyone, I want to thank the very brave CLL-er who chose this trial. We really do have to find a way of making it clear to the researchers that they MUST thank patient participants.
Perhaps each of us who is in or has been in a trial should make it clear to their research docs that they expect a published thank you to “the patients who bravely participated in this trial / study”. There are so many consent forms to sign for a study. Why don’t we create one that the study docs sign saying they will thank the group of participants in their study.
Thanks again to Chaya
Lynn Samuels, San Francisco
Thanks Chaya for cutting through the verbiage and out lining this into easily understandable terms.
Also, Thank you for remembering the trial participants- those currently enrolled, and those that blazed the trail -sometimes paying the ultimate price.
Good news and a cause for hope.
Chaya-
Thanks for weighing in with this summary and your thoughts on this latest news. Excellent as usual.
Chaya,
Thank you for providing details into this research and trial. I had family members calling me last night after watching the network news. You make all this information so much easier to understand. As a newly diagnosed CLL patient this potential breakthrough gives me hope. I do have the 11Q deletion so my cancer will most likely be more aggresive. I am thankful for this web-site and sincerely appreciate your hard work and dedication.
David Burkett
Stockbridge, GA
Thanks so much Chaya for being so prompt with the research and the explanation. We are keeping our fingers crossed ! Ronald Hynes
Chaya,
Again! Your brain has cut through, destilled the product andclarified it. Remarkable; thank you again.
Wouldn’t it be wonderful if there really were a cure for this curse; even hope would be wonderful!
Another article you wrote, about the, if you like, secondary effects of this kind of cancer, the loss of peace of mind; the loss of hope, would that this could restore some of that, as well as possible cure.
Take care of yourself; you are a wonderfully sane voice and a humerous one.
Stock-markets, interst-rates, famines and wars, over here we have aquired some insanely rampaging, thieving and seemingly uncontrollable youth-gangs, (not all youths of course)as well. It is a strange world, thanks heaven for humanity like yours!
Mette
thanks for jumping on this so fast. While my last science class was as a freshman in college, you make this understandable! Thanks for all U do!
I doctor on television today was commenting on the fact that funding for this new research was practically nil. No big pharma or research facilities wanted to touch it because of cost.
The doctor said that one of the patients in the study had wealthy relatives who donated large sums to keep the research going.
If true,this should be a sobering wake up call to all of us. Even the most promising research costs money, and in a sick economy,more than just our 401ks are affected.
fredm:
You could not have said a truer thing. All of us want the best of everything. So long as we don’t have to pay for it. So long as someone else does the heavy lifting, at no cost or hassle to us.
If the AIDS community had not been a cohesive group willing to work together and fight for their lives, I wonder how much of the retroviral research would have been done.
Periodically I get depressed about the low key participation of our own CLL patient community. I know from personal experience – not too many step up to the plate when it comes to making their own personal commitment to research or even patient advocacy. Just so long as someone else does the work, someone else does the heavy lifting, someone else pays for it all – that seems to be the guiding principle for too many people.
Believe me, this site would not exist if I took the same approach. People, wake up! Each one of us is just a single voice, a victim of forces we cannot control. Together, we might actually learn a thing or two, influence otherwise bleak prospects. If you are not part of the solution, you are in danger of becoming part of the problem.
Dear Chaya,
If I understood well, we are now in the presence of 2 trials trying to make T-cells kill all B-cells using CD19
– bispecific antibody (BITE your june article)
– this technique
Regards
Jean-Pierre:
Not quite. The technology reviewed in this article does attempt to make CD19 targeting T-cells.
BITE technology on the other hand does not make modified T-cells. It makes a smaller version of monoclonal antibody, with two targeting arms. In that sense it is closer in concept to other monoclonal antibodies such as Rituxan, ofatumumab, Campath etc. Such monoclonal antibodies are not living cells, they cannot reproduce themselves, increase their numbers a thousand fold – as was done in the case of the T-cell study.
Chaya, brilliant presentation with such a down to earth approach. As you put the pieces together, I was able to see where you were headed. This approach to communication is so often missing anymore. Thank you for allowing the reader to anticipate your end point.
I too, as I read articles in two newspapers, asked the same question you did. Why didn’t they use allopurinol as a pretreatment? I wonder how much experience these guys had with tumor lysis syndrome in blood cancers.
I will fight my way through the Internet and get a copy of the paper just to feel “dumb.”
Again, brilliant! Thank you.
Barry
Chaya
Thank you so much for continuing to share your time and knowledge with us. I also want to say a huge THANK YOU to the man who participated in this clinical trial. I hope that his remission lasts for a very long time.
Pam Peterson
midget@aol.com
I think the simple reason why they did not use allopurinol prophylaxis is that they did not expect the level of cell kill they saw!
Prior adaptive T-cell therapy approaches failed miserably, with little by way of tumor cell kill and the modified / infused T-cells dying too soon to do any good. THIS is the first time I have seen the modified cells flourish – heck, they increased their numbers a thousand fold and were only too eager to kill B-cells!
Success caught the researchers by surprise – they did not expect to see tumor lysis! Odds are this “error” will never happen again, in future versions of this technology!
Thanks, as always, for the ‘Readers Digest’ version. I guess I better rethink blowing my retirement fund!
Chaya
Thanks for the extremely clear and very readable interpretation of this research—particularly liked your description of how the T-cells work. Once we understood that, your explaination of the ‘therapy effects’ followed logically. As I have said in the past, your the best communicating scientist I have encountered.
Al Sullivan, CLL survivor and fellow Chemist
Chaya,
Thank you for reviewing this new study sp quickly. I am glad that you feel this is not “snake oil.” Maybe after more in depth study it will be available to us. The number of new clinical trials that seem to have merit is very encouraging. Again, thank you for your wisdom.
Training T cells to attack and selectively wipe out ALL B cells is quite an accomplishment and offers immediate hope to those with 17p deletions and others who have run out of options and whose every extra year of survival is a blessing. Living without the very integral “B” part of our immune system seems like quite a challenge to me. Programming these modified T cells to self destruct and to 100% leave the stage after they have done their work would be another huge hurdle. Specificity is the holy grail and all the ideotype vaccine companies and trials have pretty much died out and I wouldn’t expect much funding in the near future in this economy.
If only we could train these T cells to specifically go after CLL “B” cells. Is there a common target or a small set of common targets most CLL cells present? I anxiously await further improvements to this interesting and promising approach. For now, Cal101 and PCI-32765 combined with other drugs and mabs seem to be the new frontier for prolonging the dance with the bear.
Thanks Chaya,
WITH SO MANY CLL DIAGNOSED INDIVIDUALS OUT THERE ,HOW MUCH MONEY WOULD BE RAISED FOR RESEARCH IF EACH ONE AND EACH OF THEIR FAMILY MEMBERS AND GOOD FRIENDS GAVE $10.00? HMMM?
Where do we donate?
Janet
Chaya,
This is such exciting news. A cousin called me yesterday to watch TV about Leukemia. I immediately thought it was for some other leukemia and not CLL. A very important time for us.
Thank you for your excellent(as usual)article.
Many Blessings,
Rita
Wow, you did it again. You took a compound/complex report and made it make sense with your fabulous grasp of the language and the jargon. I spent hours yesterday trying to understand exactly what and how those T cells were doing, looking up words I failed to understand. I did “get” that this is a giant step (one of the biggest in many years) and that there were serious consequences and hurdles to maneuver around.
Thanks for the clarity and your dedication again. And for the patients’ sacrifices.
I was diagnosed with CLL two weeks ago and Chaya’s information helped me so much to understand CLL from scratch. It was great to see CLL and this research mentioned on NBC. Thank you Chaya for all you.
Reading Chaya’s blunt words in the comments about stepping up to the plate to support research, help in patient advocacy, “doing the heavy lifting,” made me realize once again how much I (we!) depend on this source for all of these. There isn’t a place I know of that does anywhere near what this site does on all these fronts. So I clicked the button once again and donated what I could afford.
(If the more wild-eyed doomsters are right about our stock markets, our money won’t be worth anything in a little while anyway, so what better thing to do with it than send it where it is sure to do some good?)
Thank you Chaya for your quick analysis of this new study. I too was surprised when the leukemia feature on the NBC news turned out to be about CLL. Let’s hope the work will continue and remain positive, so we can one day soon live our lives without that gray cloud hanging over our heads.
Thank you Chaya for getting to the details of this new research.. My sister sent me the article that her husband saw while he was at the VA having treatment for his skin cancer. He also ,like myself and my husband is cursed with this disease.. Hopefully this will be a way to cure CLL in the near future for most of us. I will send your take on this to my sister and brother in law as well.
You really are very helpful in showing us what is out there and then dissecting it for us to understand it better.
Thank you thank you thank you once again for all of your hard work and time in helping us digest the facts. And huge thank yous to the very brave patient who went far out on a limb for all of us, and to Barbara Netter for funding the study when no one else would. Angels on earth all of you!
Hi Chaya
I knew we would be getting an Update from you on this topic–once I saw it on the network news I knew you would be all over it!! Thank you for helping us understand, and I say thank you also to Barbara Netter.
John
Thanks. Do you think there will be a lot more trials soon. I would like to volunteer probably along with many others.
To all of us CLL patients who rely on Chaya to help us to understand the research and give us hope, please donate to her as a thank you for all of the time she takes to help us. We have to realize just how difficult it must have been for Chaya to write this because of her loss of PC. We cannot thank you enough for what you do for all of us. Please consider giving to this wonderful woman. Donate!
Great article and thank you for writing it so quickly! I know that wasn’t easy. Carl June and I emailed each other a couple of times a few years ago regarding this treatment. Just so everyone understands, this has taken MORE than a few years to get to this point. It will also be a few more years to tweak and trial and get FDA approval and move it into the population of CLL patients. Perhaps with a lot of informed CLLer’s and caregiver’s, we can push this through quicker! I hope so. I have a lot of faith in Dr. June’s work.
JLOU
Chaya, what can we do as patients to raise the voice of the CLL community, specifically to advance research and investment, aside from participating in trials? I’m already doing that but fully appreciate your point about the AIDS community mobilizing on their own behalf. Just looking for additional ideas we can put into action.
Thanks,
Judy
Other than the EGCG trials, this is the most hopeful info we’ve received since my wife was diagnosed with CLL a year ago. Thank you Chaya, for making it easier to understand. Please never stop doing your wonderful work.
Tommy
Thanks Chaya. Again you do an amazing job. I have not read everything, but I will be curious if those of us who have had FRC will have different results.
I have no TV, so my email box was filled with links to media coverage of this study! I was prudent enough to come to CLL Topics before I sent you yet another email. Thanks, Chaya, for this really wonderful article. I can’t believe how incredibly lucky we are that the patients were CLLers!
Great analogy about HIV! Thanks for the “poke” about organizing ourselves for a common voice. I second Judy’s comment and question about how can we be more active/effective? At the same time I suggest that money is a powerful tool in swaying decisions. The perfect exampe is the trial participant, whose wealthy relative assured the continuity of the research.
The other powerful tool is a cohesive and vocal stand on issues (patient advocacy), such as when Chaya stood up at the FDA board for…(I forget which trial we were rooting for…three years after FCR I still have horrible brain fog.)
I think it’s up to us to poke each other to rally for donations (hey, I am up to eyeballs in these hard times, but a few dollars a piece will not hurt much, but adds up). Aamster, Masbach, keep it up!
But I’d like to hear Chaya give her sharp point of view on how she wants our help in other ways as opportunities arise.
Lastly, can we send the 3 participants a collective “Thank You” card? Chaya, is it proper if you buy a card and send in our name? I just made a small donation, I think we can afford it (just kidding of course.)
Dear Chaya,
this is an excellent review, as usual. I would just like to add that the NEJM article was a CASE REPORT and as we know, it is impossible to draw definite conclusions from these. I sincerely wish that all or at leas most of the patients would benefit from this type of treatment but it is necessary to point out that this is only beginning and much more data is needed before we can call this approach effective and safe for the CLL patients. So we should be, I´d say, mildly optimistic and I would definitely like to warn CLL patients against too much optimism as there are hundreds of phase I trials but only a handful of drugs usually make it to the market.
Best wishes, Lukas Smolej
Per other comments, thanks for the quick analysis. Do you have any sense why they did not try to target CD23 as does Lumilixamab? Is this much more complicated for some reason? Or is it because unlike CLL, the other cancers they are looking to be effective with are not bright with CD23?
Dear Chaya,
Thank you for all you do! I am one of those who made a donation a couple of years ago and haven’t done so since. Tonight was the night! Last summer and fall I spent a good part of my life in James Cancer Hospital at OSU. I didn’t know if dared donate then until after the bills rolled in. Fortunately social security and my teacher’s retirement insurance were very good to me. I did 6 rounds of FCR and really didn’t mind that too much at all. But then the Doctor discovered a lymph node that actually increased in size — a biopsy showed Richter’s Transformation. The lymophma is gone now due to radiation, but they come back! My question is “since this is a B-cell cancer also, is this new treatment likely to be good news for those of us that are in the sinking Richter’s boat?
Best wishes to you and your family,
marycc
tsvieps:
CD23 would be a particularly poor target. This marker is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets. Killing off all of these cell lines would be a fatal disaster.
marycc:
The modified autologous T-cell approach described in this study is going to be widely applicable, if I read the tea leaves right. It is a matter of matching the right marker to each target cancer.
jlou:
Terrific that you know Carl June. Any chance you can introduce us? I would like to learn more about their future plans, perhaps see if there is anything we can do to help them.
A couple of you sent me emails that said you would much prefer this type of approach to getting “chemo” poisons. Let me point out, this therapy regimen included massive amounts of pentostatin and cyclophosphamide, four days prior to getting the modified T-cells. This approach is very similar to pre-conditioning regimen required just ahead of stem cell transplants. Without doing this, the patient’s own immune system is too strong and will effectively kill of the newcomers (modified T-cells and donor graft, respectively) before they have a chance to do any good.
For now, the best comparison of this technology is with mini-allo stem cell transplants. In this case, the cells given back to the patient are his own, autologous in other words, and therefore we have the advantage of getting very powerful modified T-cell versus leukemia effect, without the pesky problems of GVHD (graft versus host disease) associated with allo stem cell transplants.
No doubt this technology would be expensive. But if one is to compare the cost with the cost of stem cell transplants, I think we might come out ahead on that front as well. The other big hurdle with mini-allo transplants is finding a well matched donor. Not everyone is able to find such a donor. This technology removes that hurdle, since the T-cells are the patient’s own cells.
Yes, these are early days and much work remains to be done. But there is no question it is a breakthrough that may end up being a game changer. Pooh-poohing the technology because it wont be available off the shelf for patients needing therapy in the immediate future is both short sighted and self centered. Yes, we have to focus on our own personal needs. But we also need to think of the needs of the patient community at large, and the generations of new patients as yet un-diagnosed. It is not all about feeding our own faces. Supporting research that may not develop soon enough to make a difference to you personally, but may help others down the road – that is the definition of altruism and generosity.
This new treatment is very exiting. I’ve benefited from research and many volunteers by getting mini-allo stem cell transplant just 6 months ago at Hutch. I also signed up for all research they offered to me and I do not want a “thank you” – just do it or explain to others the importance of the research!!!
Chaya – Thank you for the excellent article!
GV
Between BiTE and this T-cell modifying treatment it looks like the future of treatment may change to focus entirely on T-cells. I suppose BiTE might be used as a first pass because it’s less radical and unpredictable.
Chaya,
This important discovery does not leave of being very exciting and enthusiastic.
Perhaps here is the key that in the future will be able to open the door for the cure of the CLL.
A word for the Chaya article.
It is fantastic as Chaya explain these subjects in a way that become so clear and understandable for all, going to search examples and images from the real life.
It is incredible as a scientist and university teacher has this aptitude.
A word also of support and applause for this patient who was submitted to this study. Thank you.
It as time to believe(we hope so) that now, new studies in the Trials Clinics start from this important experience.
Chaya has reason. The union makes the force. Community CLL must be joined for one cause.
Desires of Good Health to Chaya and Thank You.
The latest article in Science Translational Medicine, cites 3 patients and is more recent data from the Laboratory. The Patients are also varied. So, there is something to say about the efficacy of the method employed. While there is something to triggering death of the engineered T cells, the authors of the study state that the propensity for replication and sustenance may be derived from the presence of CD19+ cells in the milieu, thus, they may exhaust or extinguish with time…without a need to tailor such a mechanism. I think this is truly a breakthrough in immunotherapy…
Usha:
Thank you for the citation of the Science Translational Medicine article. I just finished reading it. It has quite a few more interesting details than the NEJM article. Perhaps I will write a sequel to my review of the NEJM article.
For those of you who cannot wait and want to read all about the other two patients treated in the protocol, here is the link to the full length STM article. You can read it free of charge.
http://stm.sciencemag.org/content/3/95/95ra73.full.pdf
“tsvieps:
CD23 would be a particularly poor target. This marker is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets. Killing off all of these cell lines would be a fatal disaster.”
Most interesting. Shows how a little knowledge can be misleading or dangerous. I thought that a big part of the promise of Lumilixamab was that CLL was bright with CD23, which it targets, but good B cells and other good cells had few.
A heartfelt “Thank You” to the courageous patient-volunteer, and to Chaya for keeping us well informed and on our toes!
As we are reminded to appreciate all those battling on our behalf, I am struck by the minimal attention given to the person and organization that funded this research. Fox News did an interview with Barbara Netter that has been posted on the Alliance for Cancer Gene Therapy site http://www.acgtfoundation.org . As with our own Chaya, losing a daughter-in-law to cancer energized the Netters to fight back and make a different, better outcome possible for others.
As grateful as we are for government funded research at NIH, what if ACGT hadn’t stepped in when the government couldn’t or didn’t chose to?
It is an object lesson in the power of personal dedication and another opportunity for those who wish to convey appreciation for what has been given to us.
it is comforting to know that some amazing research is being done to find a cure for cll.i am cautiously optimistic this will eventually happen.hopefully a cure will be simple as taking an antibiotic to cure an infection.
Chaya
I picked up on the U Penn trial a few days ago, but had trouble coming to grips with its conclusions / relevancy (3 patients).
You do a wonderful and balanced job of helping me, and I can see others, get to grips with intricate details but also how results may impact conditions and lead to even larger steps down the road.
Your site is an unbelievable resource in many ways.
Thank you so much.
Chaya,
thank you for your ‘translation’ of the U of Penn trial and its results.
There is one particular result of the study however, which calls into question my understanding (misunderstanding?) of chromosomal aberrations.
I have assumed that such aberrations in the chromosomes, identified by FISH, would be found in every cell of the body. The results of the recent trial involving modified T-cells showed not only the disappearance of swollen lymph nodes and the absence of CLL infected B-cells in both blood and marrow, but also the absence of chromosomal deletions ( 17p). Were my assumption totally wrong? Can you clarify this for me?
With thanks for all you do for us CLLers.
Martin
Ivy:
You misunderstood. Chromosomal abnormalities – identified by FISH – are only present in the cancerous CLL cells. Not in every cell of the body.
Q – HAS ANYONE ASKED ….”Why is CLL the most common of the Leukemias?”
A – Because a Radiographic Study is the most common diagnosis tool for many medical issues !!!!! DUUHH..
Thanks Chaya for another lucid explanation, and thanks to the patient. You have an amazing talent to make the complicated clear. Hopefully some doctors are following you and learning how to explain things in ways that patients can understand.
Gordon
Thank you Chaya for your wisdom, insight, clarity and for your wonderful generous heart.
Blair Milton
Chaya, Do you think they will loosen up the testing requirements for the new approach, scientists useing the patient’s own T-cells to be used on people that are in only the watch and wait time of their CLL progress? Why not start early?
Brad Salzwedel
Do you have any updates on this research?
Sorry, no definitive information as of yet. A lot of preliminary research is being done at different institutions, using different targets for the souped-up T-cells. You may want to read a recent article describing the use of the ROR1 target – “End of chemotherapy in our lifetime?”
All of these approaches are several years out from large scale clinical trials, let alone full commercialization of the technology.
Hi Chaya, its been a little bit of time since these three patients received treatment. Any word on how they are doing?
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