Breakthroughs in T-cell therapy
Some of you may have read about the University of Pennsylvania researchers treating a very small number of CLL patients with very advanced disease, using a novel T-cell therapy. All of the lay-press carried reports of this new development and for a change the hype was almost justified. We reported on it as well in an earlier article, hopefully with a more readable and balanced description of the technology and its potential value to us down the road.
While the approach was indeed an exciting development, there were some clear problems associated with it as well. Now we are beginning to see modifications that may get around the potential pitfalls. Combining potent therapies such as the new family of kinase inhibitors such as PCI-32765 with T-cell immunotherapies such as this may indeed make chemotherapy obsolete in the lifetime of patients reading this review. This is important stuff – and therefore, I hope you will bear with me as I walk you through the logic of how it is all supposed to work. As always, I will attempt to make the science and jargon a lot less heavy-handed and therefore more user friendly. In the process, I know I will be sacrificing some of the technical detail. Those of you who are up to it are always welcome to read the professional articles for yourselves.
Limitations of conventional chemotherapy
Before we discuss the benefits of T-cell immunotherapy, it might help to highlight the short-comings of conventional chemotherapy.
While different chemotherapy drugs have different mechanisms, by and large they work by damaging and poisoning cancer cells to such a extent that the cells die. Sounds good, but for a small fly in the ointment. The toxicity of chemotherapy drugs is not strictly restricted only to cancer cells. A certain percentage of perfectly healthy cells are also damaged in the process. The differential between the toxicity of the drug on cancer cells versus healthy cells is called the therapeutic window. A good chemotherapy drug is one that has a wide therapeutic window, in that it kills a lot of cancer cells while damaging and killing only a small number of healthy cells.
It always boils down to balancing risks and rewards. Unless the chemotherapy drug kills most or all the cancer cells, relapse is likely. Higher doses generally achieve more cell kill. But if the dosage is increased to improve the percentage of cancer cells killed, it is very likely the toxicity to healthy cells will increase too. In the extreme case, it is possible to give such a high dose of chemotherapy drug that almost all of the CLL cells are killed -probably at the expense of killing the patient too – a case of death by therapy. We cured the CLL, but unfortunately the patient died.
Another limitation of chemotherapy is that very often the drugs are ineffective against CLL cells that are nicely tucked away in enlarged lymph nodes, infiltrated bone marrow or enlarged spleen, liver. Larger percentage of CLL cells in such protected locations survive chemotherapy – one reason why it is relatively easy to clear the blood of CLL cells, but it is a lot harder to eradicate them in enlarge nodes or bone marrow – and these survivors can not only grow back to trigger a full-fledged relapse, the survivors are also likely to have learned how to avoid getting killed the next time around. Drug resistance is a major problem with most chemotherapy drugs. We see it all the time in CLL patients. Over time, patients develop resistance to most of the major drugs available to us, resulting in ever shorter list of therapy options.
Autologous T-cell Immunotherapy
The label given to this kind of therapy is important. It is immunotherapy – suggesting it is therapy based on your own immune system – and therefore very different from standard chemotherapy. It uses T-cells as the smart troops, hopefully on a house-to-house search for cancer cells where ever they try to hide in the body. It is autologous, meaning the T-cells used are harvested from the patient himself.
You have probably heard of another T-cell based therapy that has the ability to cure CLL patients, one that has been around for quite some time. I am talking about mini-allo transplants. In that case, the T-cells are allogeneic, meaning they are derived from the stem cells of the matched donor. The killing of CLL cells by the newly grafted T-cells (and other components of the donted immune system) is called “graft-versus-leukemia” effect. Sometimes, when the GVL is not sufficiently potent, the patient is given an extra dose of donor T-cells to get the job done (DLI – donor lymphocyte infusion). While GVL is very much the desired effect since it is the lynch-pin that brings about the hoped for cure, there is another side to this coin – graft-versus-host disease (GVHD) – which can be potentially dangerous. In fact, GVHD contributes major share of sickness and death in mini-allo transplants. We have yet to figure out exactly how to preserve and increase the GVL effect, but not at the expense of increased GVHD. These two effects, GVHD and GVL, are two sides of the same coin.
All that becomes a moot point when we talk of using autologous T-cells. Since the T-cells are obtained from the patient himself, there is little reason to expect that they would find the patient’s body “foreign” and therefore there is every reason to hope GVHD is no longer an issue. Unlike conventional chemotherapy, it is hoped that autologous T-cell therapy would spare healthy tissue, killing only the cancer cells and thereby toxicity to healthy tissue should be vastly decreased. But how to get the patient’s own T-cells to go after the CLL cells, when clearly they had been sleeping on the job up to that point – the reason why CLL had a chance to establish itself in the first place? That is the million dollar question of all autologous T-cell therapy approaches. Last but not least, it is hoped that the modified T-cells will stay vigilant and on the job for a long time. We need these vigilant smart troops to survive and hang around long enough to finish the job, get the patient into a 100% cure with no CLL cells left behind to trigger relapse.
The game plan boils down to this:
- We need to harvest sufficient number of T-cells from the patient. This is not hard to do.
- The next step is to vastly increase their number in the lab by encouraging them to grow and have lots of babies.
- We need to tweak the armies of T-cells so that they are now monomaniacal killers fixated on killing CLL cells – and nothing else.
- As with the University of Pennsylvania study, it is probably necessary to treat the patient with some chemotherapy regimen ahead of injecting back the doctored T-cell troops. This is necessary to reduce the number of cancer cells in the body to manageable levels. If the newly engineered T-cells infused back into the patient face an overwhelming army of cancer cells that outnumber and outgun them, chances of success become that much slimmer.
- There is another reason for this high impact chemotherapy ahead of infusing back the engineered T-cells. As most of you know by know, chemotherapy damages the immune system. In this case, that is what we want the preconditioning chemotherapy to do. We do not want the patient’s immune system still feisty enough to try and kill off all the newly engineered T-cells when they come back. Same logic is used in mini-allo transplants as well, pre-transplant chemo conditioning is an essential feature. Without it the new graft is quickly killed and the patient is back to square one.
There have been earlier autologous T-cell therapy experiments that met with scant success. Some of you old timers may remember a company called Xcyte. They too grew huge armies of the patient’s own T-cells in the lab and infused them back into the patient. The problem was these were not specially trained to seek and kill CLL cells. Nor were they given sufficient self-protection capabilities. All too soon, the precious new comer T-cells were quickly killed off by the host immune system. The over hyped early phase clinical trials at UCSD (and elsewhere) came to nothing and the company went bankrupt.
University of Pennsylvania – a genuine breakthrough
So, what has changed from the prior generation T-cell attempts? What the U. Penn folks were able to demonstrate is new technology that gave the engineered T-cells the ability to survive – even thrive and grow their numbers once they are infused back into the patient. The prior heavy duty chemotherapy was important too, by softening up the host immune system. For the first time, the engineered T-cells were still around and doing their job months after their infusion back into the patient. The other important thing they were able to do is channel the killing power of the new T-cells into a narrow focus. They were able to graft a specific search / identify tool onto the T-cells, such that they could identify all cells carrying a particular marker, and kill them on the spot. This identification tool is called a chimeric antigen receptor (“CAR”) and the hope is that CARs technology will allow us to engineer T-cells to target different cell types by appropriately chosen tumor markers.
U. Penn folks chose CD19 as the marker on which to focus the T-cell killers. All B-cells carry the CD19 marker; not just CLL cells but healthy B-cells as well. As expected, once they are infused back into the patient the CD19 targeted CARs T-cells killed every CD19 carrying cell they found in the body. As hoped for, the new T-cells not only survived but even increased their numbers over time – a first step if this therapy is to work at all. And they did indeed kill each and every cell they came across that carried the CD19 marker. A couple of patients with very advanced and refractory CLL saw almost miraculous clearance of their CLL tumor load. That is the good news, and it is indeed very encouraging news.
But there were problems as well. Since the new CD19 targeted CARs T-cells killed all B-cells, pretty soon there were no B-cells of any kind. B-cells are an important part of the immune system. They also go on to become plasma cells, which manufacture immunoglobulins. The constant and continuing surveillance of the killer CARs T-cells kept B-cell counts close to zero – which meant no plasma cells down the road, and therefore no immunoglobulins either. Ig levels plummeted and patients undergoing this therapy are committed to a life time of dependence on intravenous immunoglobulin (IVIG) therapy. Immunoglobulin therapy is based on careful collection of these precious bits of protein from huge quantities of donated blood – not a cheap process. IVIG therapy is quite expensive and the product is often in short supply. Long term, this is not a viable approach for large groups of patients, since there is no way we can maintain all of them on regular IVIG therapy for the rest of their lives.
Building upon success
Any number of research groups are looking to see how to tweak the U.Penn CARs approach so as to keep the good parts going but fix the problem areas. Using a different target for the T-cells – something other than CD19 – so that they kill only the cancerous B-cells and spare the healthy B-cells is very much desired. A number of options are being considered and I have no doubt that we will build on the success of the ground breaking success of the U. Penn team.
M. D. Anderson and others are looking at something called ROR1. What makes this marker hugely attractive is that it is expressed by CLL cells – but not healthy B-cells. IF everything goes according to plan, the hope is that ROR1 targeted T-cells will survive long enough in the body to kill each and every CLL cell in the body, but not damage the healthy B-cells. In other words, the patient is cured of CLL and yet healthy B-cell populations can recover and go on to produce plasma cells, immunoglobulins etc. By using ROR1 as the target of the killing power of the engineered T-cells, we can hope for avoiding the IVIG dependence baked into the cake of the U. Penn approach.
Blood. 2010 Nov 25;116(22):4532-41. Epub 2010 Aug 11.
The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor.
Hudecek M, Schmitt TM, Baskar S, Lupo-Stanghellini MT, Nishida T, Yamamoto TN, Bleakley M, Turtle CJ, Chang WC, Greisman HA, Wood B, Maloney DG, Jensen MC, Rader C, Riddell SR.
Clinical Research Division, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. mhudecek@fhcrc.org
Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.
PMID: 20702778
As expected, the abstract above reports ROR1 is nicely expressed by CLL cells, mantle cell lymphoma cells and fetal embryonic cells – but not healthy adult cells. (In other words, this approach is a definite no-no if you are pregnant or likely to be pregnant in the near future). Healthy B-cells do not express it. In fact, the only group of cells that express it other than CLL cells and MCL cells are adipose cells (fat cells) and pancreatic cells. The expression of ROR1 on fat cells and pancreatic cells is lower than its expression on CLL cells.
Potential risks
That ROR1 gene is expressed to any level by adipose cells and pancreatic cells may pose a problem with this technology. In fact, one of the Canadian doctors at the conference asked Dr. Keating this question. Is he worried that administration of ROR-1 targeted CARs T-cells will not only attack CLL cells, but pancreatic cells as well? I thought this was a clearly relevant question. And I was very chagrined that Dr. Keating brushed off the question with a joke. He said that since ROR1 is also expressed by fat cells, a side effect of the ROR-1 based CARs technology may be that heavy patients with a few pounds to lose may find themselves getting slender, since their adipose cells express ROR1 as well and therefore targeted.
Well. He was kidding, of course. But the prospect scares the heck out of me. One of the major (and I mean life threateningly major) risk factors of the U. Penn study was tumor lysis syndrome. When too many cells are killed at a rapid pace, the quantity of debris created by the dead and dying cells can become a huge problem. Eventually, all this stuff must be handled by the body’s garbage handling systems. TLS can become life threatening if the load becomes more than the kidneys can handle. Even with urgently initiated dialysis, kidney failure can kill patients a whole lot faster than CLL.
So, how would you like to get slender at the risk of TLS? Notice, the U. Penn researchers deliberately set out to reduce the tumor load in their patients by means of pre-conditioning chemotherapy. The idea was to decrease the number of CLL cells left over for the CD19 targeted CAR T-cells to kill. Even with that precaution, TLS was an issue with their patients. Each and every one of us has adipose tissue – fat cells – in our bodies. Some of us have more than others, but there is no way of taking adipose tissue to zero levels ahead of CARs therapy. Is there a risk of TLS as the engineered T-cells go after fat cells, even though they express only low levels of ROR1? This would not be my chosen way of losing a few pounds. Along the same lines, pancreatic inflammation if the ROR1 targeted T-cells go after pancreatic cells would not be a trivial matter either. The question asked at the conference was quite valid and I wish Dr. Keating had chosen to answer it seriously.
Mol Ther. 2010 Apr;18(4):843-51. Epub 2010 Feb 23.
Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. rmorgan@mail.nih.gov
In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.
PMID: 20179677
Editorial
As you can see in the discussion and abstract above, CARs technology is immensely powerful. It has the ability to cure, but it also has the ability to kill just as quickly. We are in early stages of developing this technology, we need to build careful understanding of the science, so that we can benefit from the curative potential but avoid its lethal power that can cause mayhem. Full fledged late stage clinical trials using ROR1 marker (and other target candidates being explored by other researcher groups) are several years out. I have no doubt that down the road high powered immunotherapy regimens using this and similar approaches will finally cure CLL and many other presently lethal cancers. Will we get there in the next 2-3 years? Will chemotherapy become passe and CLL patients cured in droves in the optimistic time frame Dr. Keating mentioned at the conference? I am willing to bet several dollars to a single high fat donut that the vast majority of CLL patients will still have to deal with less than perfect chemotherapy options for many years yet.
When pressed on the time horizons, Dr. Keating said we as patients and patient advocates can help the process by getting regulatory agencies off his back. He said, and I quote, the only animal experiments he wants to do are in human animals . I beg to differ, humbly but quite vehemently. Without proper pre-clinical work in the lab and appropriate animal studies, in my layperson opinion it would be highly unethical to recruit “human animals” for the studies. A couple of well publicized disasters where patients died as a result of poorly vetted technological errors can also set the whole field back for years. All of us want success, all of us want it yesterday. But there is good reason for the checks and balances in place to protect human subjects volunteering for such cutting edge technologies. When is it OK to sacrifice the lives of early volunteers, cut corners on safety concerns so that we can speed up the process for folks further back in the line?
Never, not on my watch, not if I have to say anything about it. There are these little things called the Helsinky Accord and the Nuremberg Code that were established soon after the second world war. In 1948, German physicians who conducted deadly or debilitating experiments on concentration camp prisoners underwent criminal proceedings in the Nuremberg Trials. That same year, following the Nuremberg Trials, the Nuremberg Code was established. The Nuremberg Code was the first international document that supported the concept that “the voluntary consent of the human subject is absolutely essential”. The emphasis that was placed on individual consent in the Nuremberg Code was aimed at keeping participants informed of the risk-benefit outcomes of experiments. No, I will not support “human animal experiments”, not without due diligence to scope out the risks and rewards through well conducted pre-clinical work and animal studies. Not one of my members is expendable, not in this way.
You know my thoughts about patient volunteers who participate in cutting edge clinical trials. Progress is not possible without their courage and generosity. But precisely for that reason, it is our sacred duty not to sacrifice their lives without doing what needs to be done to protect them as well as possible. Informed consent is the at the heart of human clinical trials. How can consent be informed if we do not have a good handle on the possible risks and rewards? I doubt ROR1 based CARs technology will ever get FDA approval as a way of controlling obesity. The flip comment may be OK as a one-liner to lighten a speech and introduce a bit of humor to spice up a talk to cancer patients, but dismantling regulatory and ethical oversight in order to speed up development of a pet theory – that may or may not pan out – is not something I will support. There have been plenty of other sure-fire sounding medical theories that have not done so well in actual practice. Trust but verify, be hopeful but don’t buy every pig in a poke, be generous in volunteering for clinical trials but be damned sure you have a pretty good handle on the risks involved – this is my advice.
What say you?
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44 comments on "End of Chemotherapy in Our Lifetime?"
Chaya:
I applaud your closing statements! I saw your email in my inbox and the subject line made my heart beat a little faster. Its so difficult to be patient and prudent…but we all new these new therapies to succeed. We cannot be sloppy with the process so that potentially game-changing therapies are tossed in the trash. I am so excited about this new approach and I know we will all follow its progression with crossed fingers. I must admit – I read the fat-cell-killing part with a touch of optimism as well. However, Dr. Keating was too flip, given the importance of this therapy. We have bigger fish to fry (or steam since frying makes you fat) than muffin-tops.
Barb & Blair
Chaya,
Again, you bring reason and light to the CLL world. Thank you, thank you,
Dan Hill
Thank you Chaya, hopefully I can watch and wait it out till
they nail it down.
Wow! This article gives me hope.
Like Boomer, I hope to be able to watch and wait until they nail it down!
I can’t thank you enough for what you do, Chaya. Thank you so much for sharing this information.
JM
Chaya,
Glad you wrote this, especially now. We all need to balance our real need for treatment with the very unknowns you mention. The older treatments have both known good and bad… the new ones have hoped for good and unknown bad…. not apples to apples. For a patient who has seen the better side of several treatments and may be running out of various resources, risks may be weighed very differently than for those who have not, and who are weighing ‘fear’ on that scale… ALL choices are to be reasonably feared, and patients need full information on ALL choices. Trial or not.
the gaping hole in this entire topic is what constitutes “informed” consent? especially if we’re speaking of highly sophisticated scientific ‘experiments’, which trials are. This very question was brought up at the joint houses of congress hearings in 1978, when the US goverment was brought into scrutiny for massive numbers of experiments involving various forms of radiation delivered in some rather macabre ways to US citizens, from 1948 ON into the 1970s. Many US citizens and even doctors deny to this day that this occured, or believe it was ONLY done to ‘prisoners’ or other ‘undesirables’ (which would be counter to our national ethic as we understand it) but I was one such patient as a 2 1/2 year old child.
The government argued consistently, in all 700 pages, that they had obtained ‘consent’, but had they? Telling a patient that they hold a ‘cure’, a magic bullet, which is sure to fix what’s wrong and involved less cutting, or less toxicity, or less pain etc is stacking the deck toward a ‘consent’ being granted.
Doctors have argued this and still do. Even well meaning doctors, researchers, who are enthused, and hopeful, hate having to try to explain to the average patient what they’ve been spending years of trial and error on in a lab. HOW, afterall could patients even know what questions to ask? All the patient needs to know is we CARE, and would never harm them knowingly…. or would they? Does some part of them justify helping even a few for the ‘greater good’? These are highly charged ethical questions which we must not lose sight of, not even in our own eagerness and enthusiasm, and when we buy into the hype and so badly want things to work that we encourage others to join in. Be careful what we wish for may apply here.
Keeping up with writings such as yours is of tremendous value to us as patients. At least, if we keep our minds open, we may be less vulnerable to the ‘hope’ vs ‘fear’ elements of these crucial decisions. There’s far more to it than either of those hold.
All of these developments are encouraging and at SOME point volunteers will be needed to ‘prove’ them right, or wrong, but I agree here that we are quite far from a ‘cure’ with no risks…. the window is still too wide open.
beth fillman
Chaya,
Once again, thank you for your very clear and thoughtful analysis of yet another hopeful but flawed proposed treatment. Yes, someday our wonderful doctors and scientists will find a cure but I do not care to be one of those sacrificed in a trial that did not take all possible known factors into account. Thank you.
Jean Morford
Chaya,
Again, a very important article. Your explanation is of so much value.
I read and read almost holding my breath.
Thank you again, dear friend, and Many Blessings.
Rita
Chaya –
As always, I appreciate your updates and insights. You have made having this disease much easier to deal with. That’s huge. Thank you again!……I am wondering if ibrutinib or one of its btk competitors will soon take the place of FCR as the “gold standard” to treat us – which hits me as an improvement over chemo, but one that falls short of an absolute cure. The recent news out of ASCO regarding ibrutinib seems very positive. I guess what I am wondering aloud is the question: “Will a btk inhibitor such as ibrutinib safely and effectively keep this disease at bay until curative procedures can be perfected at the safest possible pace?” While I understand that Phase III for this drug has not yet begun, I am hopeful that this will supplant chemo in the near future? Am I crazy or what?
Chaya,
I often fumble through the CLL board posts and feel totally overwhelmed by what I do not know. As the spouse of someone with CLL, I feel very lost at times. This article made so much sense to me in understanding some of the different medical jargon-and yes, I’ve read your ‘new to CLL’ article as well. As we get ready for a STEM cell transplant in the near future, I am torn on other options. Our doctors at Stanford feel like he is a very good candidate. My husband just turned 55. His cousin is a match for him as a donor. It doesn’t seem like he has any other choice because of the severity of his CLL.
Anyways, thank you for your in-depth and valuable articles!
Terri
Chaya,
I agree with you. Moving too fast, using humans for reseach and by-passing the use of lab studies could doom the potential of the T-cell vaccines. This could turn into scary stuff and CLL is scary enough. Thanks for pointing this all out to us. I wonder if there is a marker on CLL cells that could be targeted that is not on any normal cells in our bodies? Would be nice if that were the case.
Chris R
This may be a stupid question, but why not introduce a very small amount of cars T-cells to minimize TLS, and simply prolong treatment. Heck, if a cure was in view I wouldn’t care how long it takes.
WillB425
Chaya,
Well written.
Thanks…as always,
William Bates
Dosing of the number of CARs T-cells would be the scope of early first stage clinical trials. Unfortunately, it is not always easy to guess at the right therapeutic dose – enough to do the job but not such a big dose that it creates problems. The age old goldilocks dilemma.
As for TLS, the risk maybe as much dependent on the number of targeted cells available as it is on the number of CARs T-cells doing the killing. We are taking the first steps on this learning curve, there is a lot we do not know. Exciting times we live in.
Many thanks for the update and for staying with us as we wait and watch. Hope is a powerful drug and you have given us another good dose – with appropriate realizm on the time lines.
Ken
I found your article very interesting and clearly explained (as always.) This may be a “dumb” question, but, since no one seems to know what caused our dna to mutate in the first place, how do we know that eradicating the CLL B-cells in the entire body would keep the bone marrow from making the CLL B-cells again?
Finding the right combination of BTK inhibitors such as PCI-32765 with T-cell immunotherapy is the real challenge. So many variables to consider: dosage, sequence, timeline …
Thank you for another readable and thought-provoking analysis. You are providing a real service to your readers.
Carter
Thank you Chaya for the review of the article as well as for your most important editorial.
If the ROR1 doesn’t attack healthy cells, then I’d be asking Dr. Keating which one or two or three of his relatives he’d be offering up for the clinical trials. After all, the only “possible” side effect could be loss of a few fat cells, right? I mean since it’s so safe that he wants all of those pesky regulatory agencies off his back so he can do trials with human “animals” (and yes, I am highly offended at the use of the term, Dr. Keating) it’s only fair that he offers up his relatives so he can show that the drug is worthy of shuffling to the market in two to three years. Ooh, I’m guessing the answer would be a resounding NO. (And not just “NO” but a few other choice words thrown in.) But I’m also guessing he wouldn’t have any qualms about asking any of us “human animals” to sign on the dotted line for a trial. (Hmmm, I wonder if Dr. Keating’s clinic refers to the trial participants as “Human Animal #1”, “Human Animal #2”, etc.? I can just see the salutation on the letter — “Dear Human Animal #2, Your appointment time is 8:30…” Sorry for the snarkiness, but I truly am offended by the use of the term and the utter lack of respect it conveys…)
If a doctor can’t see the value of a human life in his clinical research then perhaps it’s time he step out of research for a while. If he thinks that perhaps sacrificing a few of the human “animals” needs to be done for the betterment of the whole then it’s time to step back for a while. Those human “animals” are people. They have names, feelings, families. When we volunteer it should be done with informed consent. But the researchers shouldn’t be doing all they can to hoodwink us by trying to conduct research the has skipped steps that should have been performed long before it reached the human trial stage. Regulatory agencies were created to protect us — sure they can draw out the trial process and make it costly but they can also save us from drugs and protocols that can kill us off faster than the disease.
I’m so very young but this has made me think twice about participating in a trial should that time come. The very lack of respect is appalling to say the least. And how that lack of respect spills over into this particular trial is anyone’s guess. But, in this particular instance, I know what my feet would be telling me and they wouldn’t be going anywhere near that door.
Thanks for this very enlightening article. As always, I appreciate your clear prose and prudent weighing of risks versus benefits. And, as others have pointed out, it is always gratifying to have a little infusion of hope. I am at the end of the final cycle in my first course of chemotherapy for CLL and a participant in a clinical trial, and while my experience has not been as difficult as that of other cancer patients I know, neither has it been a cakewalk. It is hard not to dread the future having watched my mother die of CLL in the mid-90’s. Your posts offer much-needed encouragement. Thank you!
Unfortunately, I still have not heard whether Dr. Keating has been taken to task for his inappropriate remark, and what his response would be. I would certainly hope that he would recognize that the community (including the CLL, medical, and community at large) would not or should not tolerate the cavalier attitude towards his “human/animal” bretheren. I would hope that at his level of expertise, knowledge and experience that wisdom would prevail.
Thank you for bringing this information forward and for questioning almighty authority, but I also think we need his response to decide whether he should be trusted at this point.
Chaya – Thank you for this wonderful article. I was so encouraged to read that with the U Penn study we really do see something remarkable in terms of helping. I have no doubt that we will see great things develop as a result of this study. Using human subjects as a fast trak to a cure, however, is something else. This doctor must have been having a bad hair day.
Chaya,
This is a very exciting breakthrough. Scientists have now identified a gene – ROR-1, expressed only on CLL cells and not normal B-cells, making it possible to target only cancer cells. Furthermore, I like the idea of growing my own T-cells to go after cancer. In theory, CLL cells can be destroyed without ruining immune system and this therapy represents a cure. Presently, normal B-cells are killed with FCR, the gold standard treatment using a combination of chemotherapy. It has been reported that 55% of CLL patients die because of infections after loss of their immune systems.
Praise the scientists! Agree that there is a lot more work to be done, especially in determining the right dose of T-cells to target the B-cells with the ROR-1 gene, but if I had a 17p deletion or a therapy relapse, I would consider volunteering for this clinical trial. Hard work and good minds are paying off.
Chaya,
Thank you for your clarifying analysis as usual.
Hi Chaya,
It was such a pleasure to meet you in the Midlands at the end of last Month. Thank you for such an undertaking for us. I hear your voice when I read your words now, captivating, ( : I remember when the Pennsylvania results hit the headlines last year I enjoyed your article then.
So after they can find a truly CLL cell specific CAR, replace preliminary high dose chemo with a novel agent that can deplete defence mechanisms sufficiently, get it through animal testing and into humans we have a chance?
Could the high cost involved in developing this process and the prohibitive cost of this type of therapy be a reason to prevent it becoming a mainstream treatment option(should it become viable)? Professor Terry Hamblin raised such a point in his blog Mutations of Mortality last August when he followed your review of the news of the Pennsylvania results: A cure for CLL – what do I think?
“Finally, celluar therapy is extremely expensive. There will be few for whom it can be afforded, especially at present.”
You certainly didn’t pull your punches in today’s article.
I guess regulatory, appraisal and approval processes that add to the burden of discovery and development and delay look after our safety, but in the UK cost could prevent a procedure from approval for the majority.
2-3 years! Or In our life time? Mmnnnn
Thank you for such direct thoughts
Exciting times indeed they are. Chemo has saved my life once already but it does seem a medieval principle to poison the whole body rather than targeting the few bad cells.
I don’t understand what the problem is with us humans being animals? Personally I like animals and if we’re not animals then what are we? We certainly aren’t vegetables or minerals!
Like Judi earlier I too wonder what makes this treatment a cure? Post treatment with the RORI cells what stops the CLL cells coming back again and being reformed in the bone marrow? Or would the treatment have to be on going?
Wow, Chaya, as many of the readers responded, we live in an incredible time and may be very fortunate that medical science hits the mark for us once and for all. I am a newbie to CLL and am truly excited about our future prospects. Yep, we need to have these therapies properly vetted with the findings provided to us prior to signing up as potential guinea pigs. Super glad for your site and all the insight you bring to us as these incredible findings begin to stir. Keep up the great work and just a quick thought for everyone else, donate, donate and donate! Our additional dollars may to help in bringing a cure sooner than later and will certainly get the word out to all the patients and care givers via “CLL TOPIC Updates”.
Thank you Chaya for this article. I am still in watch and wait so hopefully all this will be fixed when I need it.
Thanks for the article Chaya.
Dr Keating is my doctor and I have had no problem listening to and taking his advice for my own treatment. I go to him because he is on the cutting edge of research. Never once has he recommended any dangerous experimental therapy as an option. His bedside manner is positive in the extreme, and perhaps not to everyone’s taste. But when we were at a cross roads in my treatment, he leveled with me in very serious terms. In that discussion he said he had to imagine what his advice would be to his own son (near my age) and he gave it to me straight. I am not particularly put off by the flip comments made in the given context, because I know and trust him. I don’t think we are in any danger of the FDA loosening standards in spite of all the calls for doing so from researchers in a wide variety of fields.
From your report (I wasn’t there, obviously) I think he did answer the pancreatic cells question: that is, they don’t have an answer. The fact that he chose to answer it with a joke, is actually one of the things I like best about his bedside manner.
My $.02 but YMMV
Thanks for analyzing the new direction the treatment for CLL is taking. Just a few months back i had my cycles of Chemo with Rituxan and Bendamustine which have succeeded in bringing down the level of the ailment, within acceptable limits. The information provided shall keep me abreast with the developments in the field if the relapse happens.
Hi Chaya,
As always thanks for all you are doing. You have made this journey less lonely for me and my family. It is my prayer that these advances will continue and a cure for cll will happen in my lifetime. Thanks again
David Burkett
Regarding your final comment (There have been plenty of other sure-fire sounding medical theories that have not done so well in actual practice. Trust but verify, be hopeful but don’t buy every pig in a poke…) reminds me of the fight within FDA regarding Thalidomide for pregnant women in the 60s. Only one person, Frances Oldham Kelsey M.D., stood up against pressures from the german manufacturer and refused FDA approval, citing further studies were necessary. Only because of her stand it was never approved for sale in the US, but how many tablets were given to MDs during clinical testing? and how many women traveled to Europe for the pills? And we all know the heart breaking results of that.
You are both very wise women.
Dear Chaya, I think CLL still has plenty of tricks up it’s sleeve, missing out steps is not the way to go. Slow and steady wins the race. How many times have you read how science has come up with unexpected and confusing results.
Thanks Chaya for bringing up some land breaking events. While almost in total agreement, I bring up a different perspective. Please, lets not let this get into name calling or personal attacks. You have always been my hero and still are.
As someone who wants to see the Drug developement process improved, I have a keen interest in the topics brought up.
First, I love the Cart-19 study not only for the absolute astounding result and future implications, but how it was done. i believe it should be/could be a model for how drugs get first tested most of the time when it comes to lethal disease.
It was funded with private donations and thus, As I understand things, it was on a frugal budget compared to average phase I studies. Despite trying unsuccessefully to find out how much it cost, I suspect it was much less expensive than most Phase I trials. I would love to know if anyone out there knows that info. Only three patients were used in this trial, unusual compared to most trials. But three patients were all that were needed to bring world wide focus onto the results. i suspect using only three patients also contributed to lowering the cost of the trial what ever that amount was. Has I understand it, It was a trial that almost didn’t happen. As I understand it, the funding barely made it.
When we consider how expensive it is to develope a drug today, (over one billion in many cases) we have to understand how that is going to slow down developement of new drugs. Especiallly in today’s world of contentious and limited funding. I would argue that intelligently tweaking the drug developement system such that we make it less expensive and more efficient is especially in our best interest with lethal desease genes ourselves and especially so with children who carry our same genes.
I suspect that some of the the arguments Dr. Keating could make in response to the human animal coment could be as follows. These are at least my own feelings that probably to some degree match those of Dr. Keating.
Animal studys are problematic. The DNA of a Mouse is somewhere around 90% of our own. We have gotten pretty good at incorporating human DNA into mouse model systems which arguably increases the DNA match closer than the 90 %, yet it is still mouse DNA. when you consider the complexity of so many reactions in humans, for example: one protein setting off a chain reaction setting off another enzyme, that inhibit protiens xyz, that block function of enzymes XX, and so forth, ect. ect. Thus, we have a long chain reaction involving many genes, many protiens, and other molecules until the targeted response we’re looking for finally happens.
Thus, even if the DNA is off just a bit, (just one link in that long chain as you’d have in mouse or Chimpanzee DNA)) in such a long and complex chain reaction of molecules the response doesn’t happen due to that one of link. The fact that it is not human DNA means you will often can get a different response than what you get with that same drug or molecule in a human. Especially in a more complex reaction.
In some cases, this is why so many drugs fail even though they have successfully passed animal studies, then only to fail when they are used with humans. When this occurs the converse is true as well. How many drugs were successfully tested in the lab on human cell lines, and then failed animal studies because of the differences in DNA of animals compared to human DNA and human physiology. Yet had they moved dirrectly to humans after human cell line studies, they possibly would have worked. How different would the drug world look like today if we had incorporated this approach 3 decades ago? No one knows, but I believe we’d be seeing many better drugs than currently exist today. And I understand the complex moral issues involved.
No matter where you stand on the position of new drugs and when they should first enter a human being, (I believe that each of us would greatly differ morally on this issue)………sooner or later someone has to be that first “victim”………… or “hero” as we prefer to call them.
Every one can agree that since that first time use of a new molecule can be fatal, whomever that person is should be pretty close to their final days. When there is no health protect, it seems humane and fair that those well informed, close to death patients have more options than they currently have. How many times Chaya in past writtings have you yourself used the words,”The system is broken.”
those words of yours Chaya inspired me to learn more. To seek out, to meet with other groups, and even to influence for good andimprovement.
I’ve had the impression that most phase I trials do stear towards those where accepted treatments are no longer working.That is morally correct. Yet, when so many in CLL are dying with out the chance to try a phase I new drug and so many new molecules and stratagies are out there, couldn’t some like me argue that if we tested more of these drugs, we’d be improving our odds as a group? that cures could/would come sooner and more often?
Your comments about informed consent are right on and you have been a great communicator in this regard.
This summarizes a bit some very complex issues in drug developement.
some, including myself will argue that biotechnology today is so much better targeted that it truly deserves a system that is also better targeted as well. Not a system that is based on technology of 50 years ago. In some cases one can argue that elinimating animal studies, lowers costs on each study so more can be done, quickens the process, and most importantly will be more accurate.
Maybe, just maybe, Dr. Keating is so tired of seeing people die around him so much, that he really would like things streamlined to help keep them around longer. Of course. I’m speculating. But, I’d bet you dinner that he’d agree generally speaking with these coments and add so much more.
When I read pub-Med 6 years ago I saw some of the earliest studys on ROR-1. I talked to Dr. Kipps about it in 2008. They sounded so promising based on that unique target that only the cancerous cells manifest. I am disapponted to hear that adipose cells and pancreatic cells express them as well. I suspose if there are 100 ROR-1 sites on Cancerous CLL cells to 1 on the addipose cells, it may turn out to do well. Currently, with drugs that target both heathy and cancerous b-cells, A ROR-1 seems worth the effort, and I would gladly try it if my options were dwindling down to nothing.I would hope that they’d have been honest about the pancreatic and adipose cell issues. I would insist on extremely small dosages and gently slowly move up to higher and higher doses.
The main point here though is that when I read about ROR-1 in PUB MED back then, there were also many other specific targets mentioned in the studies. These targets are sitting there. Stuck in research papers. It is simply too expensive to test them all. We hope that they the pharmacueticals or university research facilities pick the right targets. they can’t pick them all.
I quite reading PUB Med because I became frustrated with all the molecular targets that simply can’t be tested and sit waiting.
I have always felt that if we fine tuned the system, More drugs for the buck can get tested. More years of life can be saved. And that those obvious very personal and difficult morals issues be left to each person individually than the way the powers that be have the system at this time.
it’s not a bad system…………We still pump out 80% of the world’s new drugs. I believe it can be better.
I am thank ful for how things are slowly moving forward. Sad for those who won’t make it to see those true cures and hope that isn’t me. And maybe regreatably, still believe that we can make a difference.
Thanks for the topic. Sorry for the miss spellings………. wrote too much already……….Need to go to bed.
Leo
Hype, Hope, Profit, Ego and the Dynamics of the Game all need balance, which you have supplied in superior measure in this article.
Having been at the Conference and heard the Q & As I applaud your strong stance and perspective on some of the attitude and considerations confronting a CLL patient on his/her journey. Part of being a successful self or CLL caregiver advocate is to be aware of how the game is played and who the players are. Doctor researchers are on treadmills where the pace is set by a complex of personal ambition, institutional pressures, prestige and their own sense of the boundary between safety and efficacy in the therapies they employ. None of the factors are insignificant and all compete at the table of decision. The take away message from this reality is for the patient/caregiver to be educated to the nature of one’s CLL, the therapy options available and the nature of the doctors who will be delivering those therapies or advice. Know Thy Self but Know Thy Doctor also!
Yes, it takes nearly one billion $ to develop and market a new drug for which the successes must carry the costs of the losers, however, it stick in my craw that roughly half of that one billion is spent on advertising! The successfully FDA approved drug should expand its use due to the documentation of its efficacy and not because of its poster advertising accompanied by a sexy name and often not even identifying it with a disease as in the case of Treanda (Bendamustine) which I witnessed on a poster in the Philadelphia Airport in 2008. The only conclusion from this form of marketing is, there must be a large segment of basically ignorant oncologists who will use a drug based more upon marketing BS, than what it actually does for a patient.
Regarding clinical trials I could, on a limited basis, defend Keating’s crassly stated view recognizing the difference in the nature and purpose of early Phase I Trials vs Phase III trials because the condition of the patient population for a phase I Trial is often desperate with very limited options that may work for others. Provided that a patient facing the abyss is properly educated to the risk/reward of a novel therapy to the best of a doctor’s knowledge, novel therapies in Phase I Trials should remain an accessible path.
What is more troublesome, in my uncredentialed opinion, is some of the comparative later Trials that pit drugs with track records against each other. My first Canada CLL conference in 2007 found me listening to drug company reps and others discussing the situation of untested patients for 17p-(TP53) deletion being recruited for comparative Trials using Fludarabine vs other drug combos. One drug rep was actually defending the placement of untested patients in an arm of Fludara monotherapy. These later Trials can pose hazards to the unknowing patient. How often they occur I cannot say but…
The issue of Keating’s perennial statements of a CLL “Cure” in 5 years or less becomes less of an issue to the educated patient/caregiver than the newbie. All you need to know to evaluate his statement is that CLL is an incurable leukemia without a proven cause. CLL is highly individualized (heterogeneous) suggesting that any true cure will be elusive. Should the cause for CLL be found in the hematopoietic stem cell, the research to test this idea is at best two to three years away and that must be evaluated before any curative approach can be formulated. Keating’s proposing a cure in a relatively short time may buoy the spirits of those in W&W but prove to be a bitter pill of betrayal to those who will lose the battle or slack off on their vigilance and efforts to help themselves. Having said that, we should all tip our hats to all that Michael has done and in particular, give recognition to MDA efforts in creating the CLL Global Research Foundation under the leadership of Micheal Keating and acknowledged by you (Chaya) in one of your articles in 2005.
The very real hope is that we are entering an age of CLL management for many patients in a less toxic manner prolonging quality of life.
A Phase I Clinical Trial Lab Rat’s perspective, glad for the opportunity to try a kinase inhibitor (PCI) and accepting the responsibility for my fate. Mine was a deliberate choice in going to OSU under John Byrd’s care for he was a good fit for me and so far, been all I could hope for in a straight talking doctor.
WWW
Dear Chaya, thank you for your excellent overview of the promising U. Penn CAR research.
You bring a dose of much needed reality to the table. All of us with CLL desperately want to believe a much improved treatment is close at hand. Yet looking at past history – treatment improvements are generally incremental and cover a longer time horizon than we would want.
It will most likely take time and effort to work through the current issues with ROR-1 CAR technology.
Patti Kruse
It’s all been said by now, so I will just say THANK YOU Chaya, and BLESS YOU.
Lawrence
Dear Chaya, You do a “mitzvah” by following the literature and promise of treatment for CLL for all that are here. Since I’m writing here for the first time, I shall tell you a little about myself as I too have followed the literature of Cancer immunotherapies since I was a Urological Resident at NCI in the late 60’s. The promise of Immunotherapy for my specialty, Kidney and Prostate Cancer, has not been fulfilled as I have watched all the Clinical Trials progress from research using Lymphokine Activated Killer cells to the FDA approval of Interleukin-2. I had a few patients in these trials and the morbidity was intense, although most succumbed to their cancers. Now almost 40 years later, the CRs of metastatic renal cancer are still rare. Now I have one of the heterogenous cases of CLL for over 15 years, which WWW speaks about. My WBCs are >100,000 and platelets 200,000 without symptoms, I think, so I’m waiting for a physical indicator before treatment. Kidney failure at the end would be nice as that’s something I’m familiar with and have witnessed. CLL is still incurable IMO. I listen to my Oncologist, but keep her informed.
Sidney W. Ecker, M.D., F.A.C.S.
Clinical Professor of Urology (Retired)
Georgetown University Medical School
Washington, DC
I don’t know why your site abbreviated my comments, so I’ll try again. THX Sid
Dear Chaya, You do a “mitzvah” by following the literature and promise of treatment for CLL for all that are here. Since I’m writing here for the first time, I shall tell you a little about myself as I too have followed the literature of Cancer immunotherapies since I was a Urological Resident at NCI in the late 60’s. The promise of Immunotherapy for my specialty, Kidney and Prostate Cancer, has not been fulfilled as I have watched all the Clinical Trials progress from research using Lymphokine Activated Killer cells to the FDA approval of Interleukin-2. I had a few patients in these trials and the morbidity was intense, although most succumbed to their cancers. Now almost 40 years later, the CRs of metastatic renal cancer are still rare. Now I have one of the heterogenous cases of CLL for over 15 years, which WWW speaks about. My WBCs are >100,000 and platelets 200,000 without symptoms, I think, so I’m waiting for a physical indicator before treatment. Kidney failure at the end would be nice as that’s something I’m familiar with and have witnessed. CLL is still incurable IMO. I listen to my Oncologist, but keep her informed.
Sidney W. Ecker, M.D., F.A.C.S.
Clinical Professor of Urology
Georgetown University Medical School
Washington, DC
Jerry Fisher
You are a remarkable person, such a well written, understandable exposition and analysis of recent CLL treatment developments. Because I have just started the MEDI-551,a monoclonal targeting CD 19, trial, I am concerned all B Cells express CD 19 and the consequences you discussed, if they are eliminated, particularly losing the ability to manufacture immunoglobulins. Have you heard of the MEDI-551 trial and whether or not this drug will be as potent in wiping out CD 19 cells as the U of Pennsylvania CAR T-cells?
Regards,
Jerry
Jerry:
Yes, I am aware of the MEDI-551 trial. Like Rituxan, the famous monoclonal antibody that targets CD20 marker, MEDI-551 targets CD19. Both of these markers – CD19 and CD20 – are expressed by all B-cells. In other words, treatment with either Rituxan or MEDI-551 will target all B-cells, not just the cancerous CLL cells. The consequence is that during therapy with either of these two monoclonals, all B-cells are targeted.
The big difference between these monoclonal therapies and the CARs T-cell therapy we discussed above is that there is a definite time period over which the monoclonals survive in the body. After that, their concentration falls gradually to zero. Once the monoclonal is out of the body, new B-cells are free to be created again. B-cell populations therefore recover (along with CLL cells, unfortunately) once this window of monoclonal presence in the body is over.
The new technology CARs T-cells, on the other hand, survive and even thrive in the body for very long times, perhaps for the rest of the life of the patient – though that is yet to be documented. The good news is that they can therefore monitor any potential recovery of CLL cells and kill them as soon as they are observed. Remissions with CARs T-cells are therefore likely to be full fledged CURE of the cancer, with little risk of relapse. But the downside is that the same cancer curing CARs T-cells will also kill off any new, healthy B-cells that the body tries to create. Long term cure is the good news, long term B-cell depletion is the bad news. Two sides of the same coin.
9 years ago we traveled to MD Anderson to seek the advice of Dr. Keating.
After our meeting my wife knew that I was upset that Dr. Keating told us that he was going to “cure” her CLL with his FCR. We started her chemo in Houston because he told us that as a patient of record he could be contacted by both us and our local oncologist who would administer the subsequent 5 sessions of chemo. When she relapsed 6 years later he was ignored our phone calls and e-mails and those of our CLL specialists at home. He finally called our home the day we were to begin a new regimen and told me that we should not start that protocol and should redo his FCR. We followed his advice .This time she only was in remission for slightly more than a year.
We were informed that not only had the CLL returned but she now was suffering from treatment acquired MDS . We do not know whether the MDS was caused by the 1st or second administering of FCR. We again went to Houston and Keating told us could get her CLL under control at any time but we needed to treat the MDS 1st. Without going into detail we tried 5 other courses of treatment including 2 clinical trials. She was admitted to the hospital for a fever and unexpectedly died 18 days later, her MDS having changed into AML.
Now you relate that Keating wants to by-pass new drug studies on animals and experiment only on human subjects. How arrogant of him. It is possible that if he and Anderson had contacted patients in his FCR study and informed them that some of the participants had contracted MDS from FCR that we could have tested for disease earlier and could have possibly had more treatment options before it had moved to a more advanced stage.
I always found Dr.Keating arrogant, flip, and quick to state that he was going to cure a disease that at this time as well as 8 years ago is considered incurable. This last year I felt that maybe Dr. Keating should stop treating patients and stick to research. But now after you related his comments and thoughts on research studies maybe it would be safer if he just retired.
As a CLL patient having encountered relapse after 3 years of Chemo Theraupy, I am at a loss to understand that my candle is now burning at both ends and I may be possessing hardly 3 more years.
My oncologist at RGCI Delhi advise W&W. I am just today accidentally in touch with CLL topics.
Such a dedicated contribution by an Indian !
Chaya I have no words.
Any thing that I must read/do, please suggest.
Regards,
Sudhir Bhatia
Hello,
So glad I found this site again, after 11 years’ remission following FCR, which was then a clinical trial. I’m out of remission, so looking again at treatment options. Grateful for the readable information, as I’ve been away from scientific journals for quite awhile.
Best wishes to us all!
Margy Hand
It looks like this T cell therapy is getting a lot of press these days.
I’ve caught TV & radio programs discussing some pretty amazing results. Mike
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