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?