Date: September 7, 2005
by Chaya Venkat
Once in every little while I come across a clinical trial for other B-cell cancers that does not include CLL patients and I am left feeling frustrated and envious. I came across one such trial about a year ago - a collaboration between the Fred Hutchinson Cancer Research Center (FHCRC) and the City of Hope Medical Center (COH). The good news is that now this trial will soon be open to CLL patients as well. The formal announcement (Research Study 1503) is available at the website of the Fred Hutchinson Cancer Research Center where the Phase I study is being conducted. This approach has the potential for low toxicity and impressive efficacy. But as we all know, in this game there are no guarantees. On the other hand, you can't win unless you are prepared to explore the options, right? (See our article Death by Conventional Wisdom.) I hope you will explore this clinical trial, I am pretty impressed by the technology. First, I will give you a description of how it is supposed to work, then the details of this new clinical trial, contact information, etc. When you call, do tell them CLL Topics sent you. And do write and let us know how it worked for you.
Harvesting T-cells from the patient, growing these into giant armies of killer cells (CTLs or Cytotoxic T- Lymphocytes) in the lab, and then infusing them back into the patient is an idea that has been around for a while. The hope is that once they are back in the body these lab-grown armies of CTLs will engage the enemy and kill the CLL cells they encounter in the patient's body. A company called Xcyte Therapies has used this approach in recent Phase I / II clinical trials. We have first hand report from "Arabella", one of our members who volunteered for the clinical trial using Xcyte technology at one of the CLL Research Consortium sites. (Unfortunately, it appears that Xcyte Therapies subsequently ran out of venture capital before delivering on its technology promise — and as of mid-2006 the company is no longer operational.)
We have several articles on the website that describe the concept, both the pros and cons. The links are given below, if you would like to refresh your memory.
Immunotherapy based on T-cell armies is pretty sexy stuff. For starters, some experts believe that in addition to malignant B-cells, CLL patients also have defective T-cell function, and this contributes to the survival of the cancer. There are random cancerous mutations of the odd B-cell going on in our bodies all the time, even in perfectly healthy people. In the vast majority of such cases, the mutated B-cell is so mangled that it quietly dies on command, or it is helped to its death by T-cells patrolling the body looking for such things. Taking care of the single mutated cell or the initial small cluster of malignant clones right away means these random mutants do not replicate to become full fledged CLL. Inadequate function of this important immune surveillance by killer CTL cells is one of the pathways that lead to full fledged cancer. From this perspective, it makes sense that if we were to grow huge armies of killer T-cells in the lab, train them to be good hunters and killers of cancer cells, then turn them loose in the body, we may have a very effective and low toxicity approach to controlling or even eliminating the cancer. Think of this as giving the body's own defenses a chance to work better. Since the T-cells are grown from cells harvested from the patient's own body, unlike transplants based on cells obtained from donors, there is no problem of rejection. The body will not try to get rid of them as "foreign" cells.
If this is such a neat concept, what happened? Why is our friend "Arabella" not cured after getting massive doses of her own killer T-cells? Why has Xcyte closed its doors to further CLL clinical trials, laid off most of its workers and hunkered down to see if they can continue to stay in business? Why did this approach not become the magical cure that we are all waiting for, the classic "free lunch" of no toxicity and terrific efficacy? The devil is in the details, my friends. Below is my analysis of why the Xcyte therapy did not work better and how some of those problems are fixed in the new clinical trial that is soon going to be open to CLL patients. With each iteration, the technology comes that much closer to working to its full potential. I am not generally a big fan of early phase trials. But this one seems to be an exception. I also like it that the technology resides with the NCI and the Hutch, not with a blatantly for-profit commercial outfit. There is reason to hope this approach will not be a mere flash in the pan or just one more five-day wonder.
For starters, patients who participated in the Xcyte therapy trials went in with full-blown CLL — with lots of tumor burden. Some of these folks had classic CLL, with high counts of CLL cells in the peripheral blood. Some had more of the SLL variety (as did "Arabella") with most of the tumor load in enlarged lymph nodes. Most patients had CLL cells in the blood, lymph nodes, bone marrow, the works. Bottom line, there were very large number of CLL cells in the body. Even though several billion "Xcyted" T-cells were infused back into the patients, this was a bad case of out-numbered and out-gunned army. There were too many bad guys and not enough good cops around to control them. The results were discouraging. With 20-20 hindsight, "Arabella" felt she would not have made the decision to participate in this trial. As a therapy it did not have sufficient bang for the buck.
Another issue that bothered me was this: how can we be sure that the armies of killer CTLs going back into the body are going to kill only the CLL cells? How can we be sure that some of these killer T-cells won't go on a rampage, rogue cops going berserk and killing perfectly innocent citizens? This is the single biggest worry of all immunotherapy approaches, the risk of autoimmune disease. Uncontrolled killer CTLs attacking for example, red blood cells (resulting in AIHA) or platelets (resulting in ITP) or connective tissue in joints (resulting in rheumatoid arthritis) are all too familiar to CLL patients. I am not sure this actually happened in the Xcyte trials, but then I have not seen full articles with all the details, published in peer reviewed journals. It is also not clear whether the patients were followed long enough to look for such adverse effects.
Another problem was identified in the Xcyte Therapies trial. It seemed the vast majority of the newly minted killer CTLs swiftly found their way to their lymph node homes. In fact, several of the patients who participated in the Xcyte trials had significant reduction in lymph node size, an encouraging bit of news. But the clearance of the peripheral blood CLL cells was not as impressive. In other words, the technology had no way of controlling "chemotaxis", the cookie-crumb trail that controls where T-cells roam.
The first problem of out-numbered armies is fixed by the way this new trial is structured. T-cells are harvested from patients by means of leukapheresis. This is a relatively simple procedure, with blood drawn from one arm, circulating through a gizmo that collects the T-cells in the blood, and the rest of the blood put back into the patient by means of a needle in the other arm. The patient then goes in for conventional therapy to reduce the tumor load as much as possible, reduce the number of CLL cells that will have to be killed by the armies of killer CTLs down the road. The difference between the Xcyte clinical trials and this new approach is that Xcyte tried to do the heavy lifting of killing truly large numbers of CLL cells. The new approach only looks to take care of minimum residual disease. Makes sense to me. Chemotherapy is good at getting the bulk of the job done, but not very good at hunting down and killing the last traces of cancer cells. Immunotherapy is a finely calibrated instrument; it can do the detailed hunt and destroy missions but not the heavy lifting. This is the same principle used in many of the idiotype vaccine approaches that have shown promise in NHL patients (Idiotype Vaccine for CLL). With a better ratio of good cops to bad criminals, we avoid the problem of out-gunned and out-numbered armies.
The second issue of indiscriminate killing by CTLs is a more serious one. And this new trial has come up with a new technical twist to get around it. After collecting T-cells from the patient, they are "engineered" so that they are deaf and blind to all cells except those that carry the CD20 marker. Aha! I can see the light bulb going off in many of your brains. CD20 is the marker that is carried by each and every mature B-cell, and only mature B-cells carry this marker. That is one of the reasons why our favorite monoclonal Rituxan has been so successful in treating B-cell cancers. Rituxan, too, targets only CD20 carrying cells. That is why it is such a smart drug. But unlike Rituxan, which does little more than tag CD20 carrying cells, and needs proper function of the rest of the immune system to carry out the actual cell kill, T-cell therapy using killer CTLs with their homicidal fixation on CD20 can do the whole job of seeking out and destroying CLL cells. It won't matter if the rest of the patient's immune system is not working as well as it should. I will not even try to explain exactly how the killer CTLs are treated to make them so specific in their choice of targets. For now it is enough if we understand that this new twist on the technology means the therapy will not unleash indiscriminate killers and therefore there is less risk of berserk killing and autoimmune disease.
The third problem we identified, namely the question of how to get the killer CTLs to go where we want them to go - that problem is yet to be solved. This new clinical trial gets around the problem to some degree by having stringent inclusion criteria. After going through the pre-conditioning conventional chemotherapy to reduce the tumor load, patients must have no more than 5K of absolute lymphocyte count (ALC) in their blood. This is pretty darn close to "normal" ranges. The lymph node size restriction is a bit more forgiving, patients can go ahead so long as the largest lymph node is no bigger than 5 cm across. Actually, this makes sense from our perspective. Most chemotherapies are pretty good at clearing out the blood, it is the lymph nodes that are a problem. Since CTLs like to home in to the lymph nodes, they have an easier time of clearing them. There is potential here for good synergy between the bulk tumor reduction by chemotherapy, followed by fine tuned MRD clearance by CTLs, especially in the hard-to-reach lymph nodes.
I will give you some of the inclusion criteria here, but you can certainly refer to the study listing on the Hutch website for more details: Research Study 1503. For clarification on any of the details you will have to contact the Hutch (part of the Seattle Cancer Care Alliance) where the trial will be offered: the contact information appears below. Unfortunately, the Hutch is the only site where this trial is presently offered. And the trial design requires a number of trips up to Seattle for getting the T-cell harvested, CTL infusions, booster shots of CTLs, and follow-up visits. The good news is that I am impressed by how closely patients will be monitored. Not the cavalier give-you-a-jab-in-the-arm-and-tell-you-to-go-away philosophy I hate to see in clinical trials. The bad news is that unless you live close to Seattle, making this many trips to the center can quickly get to be an expensive pain in the wallet. This is a Phase-I trial. Hopefully, by the time later phase trials are initiated, the technologyl will be offered at more centers and that will make the logistics easier for patients. We look forward to this technology being developed at multiple locations in partnership with the City of Hope Medical Center and possibly other institutions.
Here are some of the details of who is eligible. Before you can have your T-cells harvested, you must fit these criteria:
It takes about four months for the lab to train and grow the large armies of CD20-fixated killer CTLs. During this time you can go ahead with the therapy of your choice to get the tumor burden low enough that the CTL armies will not be out-numbered. The therapy can be done back home, under the supervision of your local oncologist. I wish this was truly "therapy of your choice". Unfortunately, that is not the case. This preconditioning therapy ahead of getting the CTL infusion must not include Rituxan or Campath. Fludarabine is OK, so is cyclophosphamide and chlorambucil. Surprised? There is good reason for this. All of these conventional chemotherapy drugs are very good at two things: they can do "bulk" killing of tumor cells, do a good job of reducing tumor load substantially, which is important to leave behind only minimum residual disease for the CTLs to handle. The second thing these drugs do is kill T-cells. In other words, by the time the CTLs are ready to be infused back, there are only traces of CLL left behind to kill, and most of the eco-niches occupied by regular T-cells are empty as well. There will be very few home-grown T-cells left over after chemotherapy, to fight turf battles with the new armies of trained CTLs coming in. When all is said and done, you must have less than 5K absolute lymphocyte count in the peripheral blood, and no lymph node larger than 5 cm across. According to Dr. Chen, another reason for these exclusion criteria is safety. If a patient had 500K CD20+ cells floating around the blood at time of the T-cell infusion, there was concern that the massive cell death might lead to tumor lysis syndrome or a cytokine storm. Since safety and toxicity are the primary objectives of this phase I study, the Hutch is intentionally trying to avoid this situation by setting the bar at 5K at time of the T-cell infusion.
Oh yes, the protocol calls for bone marrow biopsies before and after, to judge how well the approach is working. Also, there is provision for lots of blood tests and even a couple of CAT scans or PET scans to really get a fix on those pesky lymph nodes.
My interest in this approach was first piqued when I read the article below about a year ago. As always, the abstract is reproduced below, write to us if you need help locating the full-text article. This article describes the scientific basis for initiating the clinical trial for follicular lymphoma patients in the fall of 2004, at the Fred Hutchinson Cancer Research Center.
You can browse the details of the earlier follicular lymphoma clinical trial by clicking on the following clinicaltrials.gov link: NCT00012207 . But do remember the details are going to be different for the newly configured protocol that includes CLL and SLL patients, especially when it comes to the specifications of the exact nature of the pre-conditioning chemotherapy needed prior to getting the CTL infusions.
There is a detailed patient consent form which I am sure you can get from the Hutch if you are interested in trial.
Mol Ther. 2004 Apr;9(4):577-86.
Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8+ cytotoxic T lymphocytes
Wang J, Press OW, Lindgren CG, Greenberg P, Riddell S, Qian X, Laugen C, Raubitschek A, Forman SJ, Jensen MC
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109
Humoral immunotherapy using the monoclonal
anti-CD20 antibody rituximab induces remissions in
approximately 60% of patients with relapsed follicular lymphoma; however,
most patients eventually relapse despite continued
expression of CD20 on lymphoma cells. We have hypothesized that
cellular immunotherapy targeting CD20(+) cells might
provide a more effective mechanism for eliminating lymphoma cells than
anti-CD20 antibodies and are therefore investigating the
utility of cytotoxic T lymphocytes (CTL) genetically modified to target the CD20
antigen. Peripheral blood mononuclear cells were activated with anti-CD3
antibody (OKT3) and recombinant human interleukin-2 and electroporated with a
plasmid containing a CD20-specific scFvFc:zeta chimeric T cell receptor gene and
a neomycin phosphotransferase gene (neo(R)). Transfected cells were selected
using the antibiotic G418 and cloned by limiting dilution.
Using this approach, we have generated CD8(+) CTL clones with CD20-specific
cytotoxicity, which specifically lysed CD20(+) target cells, including actual
tumor cells from patients with follicular lymphoma, small lymphocytic lymphoma,
splenic marginal zone lymphoma, diffuse large B cell lymphoma, and chronic
lymphocytic leukemia. The CTL clones have been expanded to numbers sufficient
for therapy (approximately 109 cells). Our data indicate the
feasibility of generating and expanding CD20-specific CTL and, for the first
time, demonstrate that such CTL exhibit specific cytotoxicity against actual
tumor cells isolated from patients with a variety of B lymphoid malignancies. In
view of these promising findings, a Phase I clinical trial for relapsed
follicular lymphoma is being initiated.
As I mentioned before, the only location where this trial will be available is at the Hutch in Seattle, WA. Dr. Eric Chen is the Principal Investigator. My dealings with this young man have been a real pleasure. I understand he has received a very nice cash award from the Lymphoma Research Foundation, your generous contributions doing us some good, for a change. I think this is going to be an interesting trial.
Research Nurse - Donna Kelly, RN, FHCRC
Principal Investigator: Dr.Eric Chen, MD, PhD, Research Associate FHCRC & Acting Instructor, University of Washington.
Editor's Note: Subsequent to the date of this article, Dr. Oliver Press, MD, PhD, has replaced Dr. Eric Chen as the Principal Investigator for this clinical trial. As of September 2006, this phase I study is recruiting patients with a total enrollment target of 12 patients with refractory B-cell malignancies which may include follicular lymphoma, SLL and CLL, MZL and MCL.
If you have an interest in this trial, we suggest you contact the research nurse, Donna Kelly. She can help with many of the screening type questions for eligibility for study enrollment. Please keep in mind that the research team conducting this trial is not set up to respond to general questions about CLL. Their focus is on the CD20-targeted T-cell approach to treat B-cell malignancies. So if you do contact them, keep your questions focused on the study. Your usual sources will have to do for more general education and strategizing on CLL - your CLL specialist, chat groups, your CLL buddies, the Internet and last but not least, CLL Topics.
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Topic: CTL Therapy