Are You Feeling Lucky?
Developing an effective vaccine that kills off CLL cells in newly diagnosed patients is the ultimate Holy Grail for our patient community. It may not help folks who have already progressed to the point where they need more robust therapy options. But the possibility that down the road we may be able to actually CURE or even slow down this awful disease in new generations of CLL patients soon after diagnosis is the ultimate prize.
As for the folks who are already too progressed to benefit from a vaccine approach, do you have kids and perhaps grandkids you love? Ever heard of Familial CLL? How much would you give for insurance that if and when one of your kids develops CLL you can hope they won’t have to suffer the consequences?
A vaccine trial that gets my vote
Today I would like to tell you about a brand new clinical trial that has started recruiting patients, a clinical trial that will explore a novel vaccine approach that I find very interesting. The trial is offered at the Nevada Cancer Center, Las Vegas. The principal investigator is none other than Dr. Ken Foon of FCR Lite fame. Dr. Foon has moved recently from the University of Pittsburg Medical Center to head the Leukemia section of the Nevada Cancer Center. If you are fortunate enough to fit the inclusion criteria and get into the trial, you can try your luck at the roulette tables as well as a low impact approach to controlling your CLL. Who knows, you might get lucky at both. At the very least you can look forward to having some fun at the casinos (provided you don’t bet the farm, as they say).
CLL Topics provided the major share of financial support for this clinical trial. The generous donations you made to our non-profit (prior to January 2009) are now funding this trial to the tune of $75,000. Talk about putting our money where our mouths are, patients have been writing to me for years asking for any information regarding good vaccine type clinical trials. Here it is. You want in, be sure not to waste too much time dithering before you contact Dr. Foon. There are only 24 slots and I doubt slots in this trial will stay open for any length of time. You should be aware that B-cell lymphomas and leukemias are invited to participate. In other words, you would be competing with all the NHL patients out there (there are many more NHL patients than there are CLL patients in this country) for a spot on this trial.
Why CLL Patients Do Not Usually Respond to Vaccines
We discussed how vaccines work and why they have a hard time of it in CLL patients in our earlier article Jab & Dab. But I think a quick recap is in order. I want you to understand why our guys do not usually have much luck with vaccines and what makes this trial different. There is no way we can make progress unless we have robust participation of patients in clinical trials. But I am also a strong supporter of truly informed consent before you sign on the dotted line. So, here is my attempt to explain the logic behind this trial. I hope we have a good discussion following this article to address any issues I have overlooked or failed to explain sufficiently.
Three strikes and you are out
Let us first discuss the roadblocks to successful vaccination of CLL patients, followed by how I think this trial protocol gets around each of these obstacles.
Know your enemy
The first step in successful vaccinations is identifying the right target. Most often it involves selecting a snippet of the offending pathogen, a small piece of protein that is expressed by the particular bacteria or virus that we want our immune system to kill, a piece of its hide as it were. In the case of the annual flu shot for example, healthcare experts try to guess the likely versions of the flu that will be in circulation the next season and use small snippets of their best guess candidate viruses. This mixture of representative snippets is used in formulating the next year’s flu shot. We can only hope they do a good job of guessing this year since we are most likely to face a tough time of it when flu season rolls around.
As you know by now, CLL patients are unique; one shoe does not fit all and we do not have a good choice of protein snippet that will represent all types CLL cells in all patients. This is Strike one, right upfront.
Companies such as Genotope have opted for a custom made approach, making a one-of-a-kind vaccine for each patient. As you might guess, this is not only very expensive to do but it takes several months to:
- Identify the right snippet to use for a given patient
- Make zillions of copies of that snippet in the lab
- Put it all together and make the actual vaccine
- Give the patient the shot and hope for the best.
As it turned out, the results of the Genitope clinical trial using their customized idiotype vaccine in CLL patients were disappointing. Subsequently the company went belly up. Bummer. Call me a pessimist, but I doubt custom made one-of-a-kind vaccine approaches are going to fly in the future, even if they can be shown to be effective. Most developed countries will be looking at increased healthcare coverage for all their citizens with the necessary efforts at cost cutting to make it remotely affordable. I doubt there will be much venture capital to finance trials looking at custom made vaccines or drugs. Money makes the world go round, my friends.
A mechanism for distributing the “mug shots”
OK, let’s move on to the next hurdle. Let us assume we have identified the snippets of proteins that exactly identify your particular brand of CLL and we can inject this vaccine into your body. What happens next is very important. There are messenger cells in your body called “Antigen Presenting Cells” (APCs) whose whole purpose in life is to look for suspicious snippets of proteins that may have been shed by pathogens – bacteria or viruses. A particular type of cell called “dendritic cell” is very good at doing this. Healthy B-cells (not CLL cells!) are also good at presenting antigens.
When APCs find a suspicious looking piece of protein they pick it up and carry it to the nearest lymph node. Think of lymph nodes as the local police station, where T-cells hang out with their brother officers. APCs must do their job and bring the suspicious looking protein bits to the lymph nodes, put up “mug shots” of the bad guys on all the bulletin boards in the police stations, thereby alerting law enforcement to what’s going down.
Without APCs bringing in accurate mug shots of possible bad guys out there that must be apprehended, the T-cell officers complacently go about their business of eating too many donuts. Unfortunately for us, CLL often subverts the APC community. Many of the chemotherapy drugs used to control the CLL also damage APC cell lines. Dendritic cell compartment is often compromised in CLL patients, especially if the disease has progressed. This is one of the reasons why vaccinations of any kind (flu shots, pneumonia shots, tetanus shots etc) do not work worth a dime in late stage CLL patients, especially if they have been treated with multiple courses of chemotherapy drugs. We have Strike two. The abstract below from no less than John Gribben clearly identifies this roadblock
Best Pract Res Clin Haematol. 2008 Sep;21(3):421-36.
Vaccine therapy and chronic lymphocytic leukaemia.Ramsay AG, Gribben JG.
Institute of Cancer, Barts and The London School of Medicine, University of London, Charterhouse Square, London EC1M 6BQ, UK.
B-cell chronic lymphocytic leukaemia (CLL) should be an ideal target for immune-mediated responses. CLL arises from B cells that can act as antigen-presenting cells (APCs), expresses unique tumour antigens, and has been shown to be a target of the allogeneic T cells which mediate a graft-versus-leukaemia effect. Despite these potential benefits, immune responses against CLL cells have been difficult to elicit. CLL induces immune defects in the host, the tumour cells are inefficient APCs, and therapies given to patients with CLL are themselves immunosuppressive. Successful vaccination approaches in this disease will require steps to overcome these difficulties, including identification of the targets of immune responses in this disease to enable monitoring of the immune response after vaccination, improved presentation of antigens, and steps to improve the immune defects that accompany this disease.
PMID: 18790447
Strike three, you are out
Even if we successfully negotiate the first and second hurdles, there is still a third hurdle to get over. Let us assume we have the right target snippet identified, a perfect mug shot of the CLL cells in your body. Let us further assume APCs do their job, take this critical information to lymph nodes and post the mug shot on all the police stations’ “most wanted” bulletin boards.
But what if law enforcement is asleep on the job, too fat and lazy or corrupted to go out and kill the criminals even when they are correctly identified? What if the Mayor has recently cut the police department’s budget to the point where officers were laid off in droves, and morale was terrible?
Drugs such as fludarabine and Campath are notoriously bad for T-cells. As we have pointed in earlier articles, Campath therapy can leave T-cell populations flat on their back for many months. Even a year after therapy critical subsets of T-cells can be greatly depleted. T-cells are the smart frontline troops in defending our bodies, other cell lines such as neutrophils, macrophages etc also participate in the process. All of these cell lines take a hit in CLL patients, especially if they have been through therapy using immune suppressive drugs. Strike Three. Kiss your chance of successful vaccination good bye.
The Nevada Cancer Center Vaccine Trial
Bottom line, for any vaccine approach to have the possibility of working against an established colony of CLL cells, we need to reverse each of these three strikes. That is precisely what I like about this new vaccine protocol at Nevada Cancer Center. It is a rational attempt to fix all three problem areas.
Here is a very simplified (almost cartoon) version of what the trial attempts to do. I strongly advise you to read the full patient information document and discuss it with Dr. Foon to get a more detailed explanation.
- Step one is to identify a clearly swollen lymph node close to the surface, one that is bound to be choke full of your CLL cells and easily reached.
- Step two is to subject the lymph node to low level and very targeted radiation. The idea is kill a whole bunch of CLL cells in that particular node, mash them up good and proper, so that there is plenty of debris of dying CLL cells generated. An accessible lymph node will be selected by the principal investigator. Patients will then receive two doses of low dose irradiation (2 Gy per day) to that single site on days 1 and 2.
- Notice the idea is not to try and kill all of the CLL cells, just enough to create plenty of snippets of protein characteristic of your particular brand of CLL. We have just gotten around strike one – namely, trying to identify exactly what snippet(s) of proteins to use in the vaccine. Heck, use a whole lot of snippets, throw in the kitchen sink for good measure.
- Step three is to goose up the activity of APCs. This clinical trial uses a proprietary drug called Poly-ICLC ( full name is a tongue twisting “Polyinosinicpolycytidylic acid stabilized with polylysine and carboxymethylcellulose”) that is hoped to increase both the number and efficiency of APC cells. Poly-ICLC will be dosed on days 3 and 4 by the physician during weeks 1, 2, 3, 4, and 8. The intent is to make sure the mash of protein fragments created from dying CLL cells after getting radiated on days 1 & 2 are effectively carried to the lymph nodes, alerting the rest of the immune system to the dangerous CLL cells that must be attacked and killed. This approach will hopefully get around the strike two we discussed above.
- Step four is restricting trial participation to early stage patients whose immune systems are in good shape, relatively speaking. Old timers who have been around the chemo block more than a few times are not included. The reason for that is very simple: the trial wants to treat CLL patients that still have an intact T-cell army that can respond to a dangerous pathogen once it is properly presented to them by accredited APCs. Without this proviso we would still be facing the third strike we discussed above.
Are there concerns about the effectiveness of this approach? Yes. Obviously, each of the steps outlined above has to work just right for the whole logic to succeed. Will it work? Only time and a well conducted clinical trial can tell for sure. That, my friends, is the whole point of doing the clinical trial, to answer this million dollar question.
Are there risks involved? There are always risks involved in any early stage trial and this is an early stage trial. But my assessment is that the risks are significantly smaller than there are with many early stage trials looking at new therapeutic drugs trying to treat the underlying CLL.
One concern I had when I first started discussing this trial protocol with Dr. Foon was the possibility of Poly-ICLC in goosing the APCs way over the top, so that they start picking up any stray protein snippet, say a bit of a perfectly innocent red blood cell or platelet and tagging them as dangerous enemies that need to be killed at all cost. If that were to happen we might see autoimmune disease such as AIHA or ITP as a potential risk factor. I am happy to report that after our conversation Dr. Foon modified the protocol to exclude any patient that already exhibited potential risk of developing any kind of autoimmune disease.
How does Poly-ICLC work? I have not gone into detail on this subject in this article. If there is a great deal of interest in understanding the science of how this works I will do my best to give a synopsis. For now, here is the link to the full clinical trial protocol that describes the science and rationale, all 54 pages of it. You will also find a list of journal articles cited at the end of the protocol. Happy reading all you type A personalities and science freaks out there!
Contact Information Etc.
Title: Phase 1 Study of Intratumoral Poly-ICLC plus Low Dose Local Radiation in Low Grade Recurrent B -and T-Cell Lymphoma.
Clinical Trials Citation: http://clinicaltrials.gov/ct2/show/NCT00880867
Sponsors: UPMC Cancer Center, Oncovir, Inc, Washington, DC, CLL Topics (that means you guys! Take a bow folks.)
Princepal Investigator:
Kenneth Foon, MD
Nevada Cancer Institute
One Breakthrough Way
Las Vegas, NV 89135
Email: kfoon@nvcancer.org
Inclusion Criteria: Please refer to the www.clinicaltrials.gov citation shown above for a full and accurate listing of all the inclusion and exclusion criteria.
It is my understanding that patients who have had Rituxan therapy are not excluded (but Campath is a definite no-no). If you have also had just the smallest smidgeon of chemotherapy in addition to Rituxan and you want to be in this trial, I strongly urge you to write to Dr. Foon (his email address is provided above) and pop the question. There is no harm in asking, right? The trial will also accept completely chemo naive CLL patients, even though that is not clearly spelled out. When in doubt please contact Dr. Ken Foon. He is The Man and has the final say.
Patient information package: Ask for it when you write to Dr. Foon expressing your interest in this clinical trial.
This has been longer than most of my usual articles on Updates. But I wanted to explain the logic of this vaccine trial and why I like it. I hope we will get more CLL patients (as opposed to NHL folks) recruited into this trial, so we will have a larger cohort of our guys and more dependable results to look at. Early bird and worms and all that stuff. You get my drift?
RSS Feed
28 comments on "An Interesting Vaccine Trial for CLL"
Very interesting trial indeed. Not sure if I meet the criteria. I’m going on 7 years since DX of B-cell CLL, with 17p deletion, but I’ve had no treatments. Plt stays around 60-70, but WBC seems to be on a slow upward progression, up to about 135-140. Usually have a couple of sinus infections a year, that are getting a little harder to shake – a couple of rounds of antibiotics for one of the more recent infections. I do have plenty of swollen lymph nodes – pick your region – neck, arm pits, groin. I haven’t checked the inclusion criteria, but am keenly interested in this trial, if not as a participant, as a very interested and hopefully bystander.
I would be very concerned about a possible autoimmune response. While CLL B cells do contain pathogenic proteins, I would think that most of the material from dying CLL cells would be just like what one would find in normal cells. What would keep the immune cells from identifying these as targets?
Chaya, Thank you so much! My husband Rick just emailed Dr.Foon and hopefully we will get a quick response back…You are truly an amazing person Chaya..and deeply appreciated..
I have SLL, & was treated with Rituxan twice. Also have plenty of swollen nodes, so this might be an opportunity.. Very intriguing premise, & good point by mikej – how does the Poly-ICLC distinguish the pathogens from the rest?
I agree, Mikej has a good point. I passed along the question to Dr. Foon to see what he has to say. I will publish his answer as soon as I get it.
Well, my lymph nodes aren’t swollen yet that I can feel, so I guess I’ll have to sit this dance out. Good luck to the brave souls who try it out!
Here is my attempt at a very simplistic explanation to address Mikej’s concern. I will gladly defer to Dr. Foon’s explanation once it becomes avaliable.
For a more in depth explanation, I would suggest Janeway’s Immunobiology, 7th ed. The first chapter is devoted to an overview of the immune system. It is comprehensive but well presented and has great diagrams. It is relatively easy to read if you take it a couple of pages at a time. The rest of the book expands on the material presented in chapters 1 and 2. I have found it a great resource of basic immune function. It has been extremely helpful in developing my base knowledge of the immune system and allow me to better understand the lingo used in transplant textbook chapters and journal articles.
T-cell immunity is a dynamic process. The immune system is only interested in preserving T-cells that may be useful to the body. Each developing T-cell has a genetically derived, unique T-cell receptor. A developing T-cell is eliminated (programmed death) after a period of time if it is not presented with an antigen that matches its receptor. In this way, the immune system makes room to continually develop and maintain an extensive repertoire of useful T-cells to fight off likely pathogens.
On the flip side, the immune system must also be able to recognize “self” antigens since the body is constantly replacing old cells with new ones and recycling some of the parts of the old cells to make new cells. When the system is working properly it eliminates developing T-cells whose receptors too closely match “self” antigens before the T-cell matures. The process is called clonal deletion. Immunological tolerance to self is achieved by selectively removing the potentially harmful T-cells.
When this system malfunctions, autoimmune disease results.
Using Chaya’s analogy, the harmful cops (self recognizing T-cells) are kicked out of the police academy before they graduate so that they are not around to harass the good citizens (cells via self antigens) of the body. This is more efficient than the good and bad cops setting up a check point and searching every antigen that comes along.
There are also checks and balances in what the antigen presenting cells recognize as foreign so that they are less likely to present self cell fragments to the developing T-cells.
I am glad that we have an advocate like Chaya with a keen eye and quick mind to identified a potential risk for patients that may be at risk for autoimmune disease. As in all cases of clinical trials, you never know what will happen until the study is completed. The trial is intriguing and if I were in the position to consider participation, it would warrant further investigation as a possible course of action.
Had semi-annual physical yesterday. No lymph nodes detectable for past 10 years (WBC 29,000). I guess I fall into the “not quite ready for prime time” but still in the EGCG daily dosage catagory. A super research idea. You do such good work Chaya.
I’d be really interested in this trial, unfortunately I’m living in Sicily and the commute would be painful! My wbc is around 140K, all other numbers are okay, spleen mildly enlarged, minor lymph node involvement, and no previous treatments. Well…maybe next time around!
Thanks for all your great work Chaya!! You’re awesome!
I have lots of swollen lymph nodes, esp. in the neck (too many for the radiologist to count). My WBC bounces between 11,000-24,000 (3 yrs post diagnosis) and I’ve yet to encounter any kind of treatment other than lots of antibiotics for an incessant sinus infection that simply won’t go away. Nevada is 7 hrs. away by plane and I’m currently going through a contested divorce. I pray that this will be the answer we are looking for. I am also concerned about the risks associated with this trial. Praise the Lord for all the people that are willing and able to participate, and for the scientists that are doing this valuable work. If we don’t reach out and attempt to solve the pieces of this complex puzzle, we will never know the answer.
I too do not have any swollen lymph nodes and am in stage 0, feeling well. Does this mean that those without swollen lymph nodes could not participate in this trial?
Chris
I’m a candidate for the Natural History study in Bethesda – won’t know if accepted until couple appointments starting this month. No symptoms – stage 0. Would this vaccine trial exclude me from the Natural History study? If so, which option assuming I got accepted in both would you pick? Should I be trying for both and decide after I know whether accepted?
I’m all for participating in trials to help those after me, and perhaps/hopefully myself also.
Ken Miller
Ken:
In your shoes I would apply to both trials. If and when you get accepted by both, you have a choice to make.
By the way, it is not entirely clear to me that you cannot participate in the vaccine trial and follow that up with many years of follow-up on the Bethesda trial. You have to check with the NCI to see if that is allowed. But for now, no need to get people riles up with hypothetical questions. As they say, having multiple options is a good thing.
Chaya,
after reading the above i emailed the Nevada group for the trial.
One doctor said i had borderline Lupus but thought i would ask anyway.
My mother had the lupus gene but never had the disease.
they said i was perfect?told me to call them?
My question is’t this a “history” of family immune problems?
i never had any lupus problems
thanks for all your support
ondrea
I am very interested in getting more of the CLL community (healthcare providers and patients alike) involved in worthwhile clinical trials. I believe that this trial is worthwhile and I am grateful to have helped in some small way through my support of CLL Topics and (mainly) through Chaya’s ceaseless efforts.
It should, however, be pointed out that this is a Phase I dose escalation trial (escalation of the adjuvant drug in succeeding cohorts of patients) designed to see if the theory of inducing “autovaccination” in lymphomas works. Participation will likely help many people down the road, but it is not a sure bet to provide immediate benefit to the participants who, nevertheless, should be thanked endlessly for their bravery and altruism.
I thought that Steven Karan’s explanation was a very good one and will be surprised if Dr. Foon has much to add.
Once again I encourage those who can (alas I cannot because of prior Campath and lack of peripheral adenopathy at present) to participate.
Steve and Rick make good points.
This is indeed a phase -1 trial and that is something you should bear in mind. I personally think the risk of autoimmune complications is low in this trial (and Dr. Foon confirmed that in his response to me), especially since they exclude patients with a history of autoimmune disease. (Ondrea, it is your health history that matters, not your family’s. But you should check with Dr. Foon).
I am a strong believer in truly informed consent. No one individual should be exploited to serve the good of the community. It stops being exploitation and starts being idealism and philanthropy when we make decisions with our eyes wide open. Yes, there a chance that this trial may benefit you personally. But that is not the point of early phase trials. It is to improve on existing technology to serve other patients down the road.
I read some where that as we breathe our last breath, when we come face to face with death as each of us will one day, the last question that matters is this. Was it worth it? Did our lives make a difference to anyone? Did it matter that we lived for a while on this beautiful planet?
Not all of us get a chance to make a real difference, be a hero in the true sense of that word. It does not matter if you do not get your 5 minutes of fame on TV. It does not matter if authors on professional articles fail to thank patients. What matters is this. Each and every patient that ever volunteered for a clinical trial, knowing full well that his participation may or may not help him but that it improves chances for those that come after him, they are the real unsung heroes among us. I salute each and every one of you.
Chaya,
I have had CLL for 6 years, still no chemo therapy. I have noticed a node behind my left ear, at least I think this is one. I am having a ck up tomorrow with my ONC. If it is, will one lymph node pass as a trial recipient? I am also on a waiting list for the clinical trial in Bethesda. SO hopefully I can be involved in both.
Thanks for this very hopeful update. many of us who are in the W&W stage can appreciate the possibility of a cure or at least the beginnings of one for future patients struck with this disease. I am so thankful that I found this CLL Update website.
Many Blessings to you,
Anita
I just spoke with Dr Foon and Karen the Clinical Coordinator-both very nice people. On paper, I qualify for the trial although the acceptance comes after they see my medical records that I Fed Ex’d them.
There is a time commitment to this trial and since I fly for free and live in California, I’m going to speak with Dr Foon and see if I can benefit.
Will keep you all posted
Wanda
RE: “Yes, there a chance that this trial may benefit you personally. But that is not the point of early phase trials. It is to improve on existing technology to serve other patients down the road.”
Question – I realize this is a bit of a tangent, but as a general matter, what do you consider “early phase.” Phase 1 only? Or phase 2 as well.
Sounds like a worthwhile trial. I have no swollen lymph nodes near the surface, so I’ll have to wait for a later time.
Jim
Go Chaya – it sounds good. Carolyn Bookspun
I have had CLL for 5 years. I have many lymph nodes in my neck that have easy access. My white blood count is stable at 120,000. All other counts are in the normal range. No history of chemo. But unfortunately I have rheumetoid arthritis; an autoimmune disease. I believe there is some correlation between CLL and the propensity for autoimmune diseases. I hope in the future that those of us with CLL and autoimmune disease will be able to use this vaccine. The idea is great!
Richard
Richard:
The reason for excluding anyone with autoimmune disease in this trial is an abundance of caution. It is an Phase-I trial and we do not want to blow it by taking chances. If things look good in this trial I am sure they will be able to extend the inclusion criteria in later stage trials.
Chaya,
You state:
• “Step one is to identify a clearly swollen lymph node close to the surface, one that is bound to be choke full of your CLL cells and easily reached.
• Step two is to subject the lymph node to low level and very targeted radiation. The idea is kill a whole bunch of CLL cells in that particular node, mash them up good and proper, so that there is plenty of debris of dying CLL cells generated. An accessible lymph node will be selected by the principal investigator. Patients will then receive two doses of low dose irradiation (2 Gy per day) to that single site on days 1 and 2.
• Notice the idea is not to try and kill all of the CLL cells, just enough to create plenty of snippets of protein characteristic of your particular brand of CLL. We have just gotten around strike one – namely, trying to identify exactly what snippet(s) of proteins to use in the vaccine. Heck, use a whole lot of snippets, throw in the kitchen sink for good measure.”
I do not currently have any swollen nodes however my WBC is very high (over 200) and my platelets are heading under 100. My peripheral blood is choke full of CLL cells. Would it be possible to radiate some blood ex-vitro and immediately re-infuse it? Also do you know if those who participated in the MyVax trial are eligible?
mschwalm48
I do not believe their protocol allows for irradiating the blood rather than a chosen lymph node. As for the prior MyVax participation, I do not think it would exclude you by itself – but you should ask Dr. Foon.
What kind of radation is used to kill the B-cells in the lymph nodes?
Joost
Same type of radiation as is used in treating lymphomas, mini-allo transplants etc. Its the dosage and targeting that are important and in this case it is low and very targeted
hi Chaya,
Great job in keeping us informed and up to date. I just passed by 5th year since diagnosis and my wbc is still under 30 and the rest of my counts are normal. I noticed my Cll has slowed down after I started eating a healthier and vegitarian diet and lowered the stress level. My immune system has definetly worked better and I haven’t been sick in 5 years. I believe that an eventual cure will come from reving up the immune system and having your own body clean up the CLL. I pray this clinical trial leads to a cure. All the best and let’s celebrate a cure in our lifetime. bb
Leave a Comment