CD20 Shaving with Rituxan
Date: August 28, 2006
by Chaya Venkat
Are Standard Dosages Way Too Much?
Rituxan Therapy: Old Enough to “Shave”?
Recently PC and I were fortunate to attend the UK CLL Forum where Dr. Ron Taylor presented his findings on a very interesting aspect of Rituxan therapy. Describing Ron Taylor as a “live wire” would be a big understatement, he packs a huge punch into a small body. The subject of his talk was clearly the most controversial and interesting one at the meeting, in that he made a strong case for using a whole lot less Rituxan in treating patients. Based on his elegant work, it is reasonable to ask if most of the patients treated with this drug as a single agent are receiving way too much of the monoclonal antibody. Not only is it possible all this Rituxan is not doing them or our healthcare costs much good, it could be setting them up for resistance to this crucial drug down the road.
At the end of his presentation Dr. Taylor asked an important question: Who will support and fund such research? The money trail is pretty obvious in high profile clinical trials these days. Someone (read corporation) stands to make a lot of money based on the success of the drug under study. Does Genentech have an incentive in funding a clinical trial that, if successful, will mean they will sell a lot less of their block-buster drug Rituxan? Do you want to buy the Brooklyn Bridge? Will high profile cancer centers that have made a name for themselves pushing ever higher drug dosages (heard the phrase “maximum tolerated dose” recently?) be interested in using micro doses of drugs?
You would have been proud of me. When Dr. Taylor asked what he thought was a rhetorical question, who will support and fund such research, I raised my hand way at the back of the room and said “we will”. Sure enough, after going through the inevitable paperwork with the nice folks at University of Virginia, we have committed to support Dr. Taylor’s research to the tune of $25,000 of your hard earned contributions.
The timing of this article is dictated by the fact that a clinical trial exploring this concept has just kicked off and recruiting patients as we speak. This clinical trial is a small, early phase study, enrolling only a small cohort of CLL patients. But the detailed information obtained from lab work that will be done based on their blood samples in Dr. Taylor’s lab will be priceless — and that is the part we will be funding. Dr. Taylor presented complex and compelling technical arguments to support his theory at the UK CLL Forum and in several well reviewed papers. Below is my much more folksy and patient-oriented picture of the science, backed up as always with abstracts of his professional articles. If you wish to read the full text of the articles cited, all you have to do is ask and we can help you locate them.
CD20 Shaving Reaction
Let us get a few basics redefined. I promise I will keep it simple. If you are in the market for more detailed description of how Rituxan works, here are some links (Single Agent Rituxan; Rituxan Enhancements) to explore.
- “CD20” is a marker that is present on the surface of all mature B-cells. What exactly does the CD20 do, why is it there? Good questions. Unfortunately we are not exactly sure of the answers — and it is not important for the purposes of this study. So, for now, never mind why it is there, just remember it is there. Each CLL cell may express thousands of CD20 markers, but even this is too few, compared to non-Hodgkin’s lymphoma patients, and one of the reasons why Rituxan does not work as well in CLL as in NHL. Humax-CD20 may do the job better (A Smarter Monoclonal on Trial) on this count.
- The important thing is that the CD20 marker is only present on B-cells. Even immature pre-B-cells do not have it. Drugs that are tailored to target only this particular bulls-eye target are therefore “smart” drugs in that they do not attack other cell lines. However, the targeting is not entirely precise, since healthy B-cells also have CD20 expressed on their surface, not just the nasty CLL clonal B-cells. Drugs like Rituxan and the more recent entry, HuMax-CD20, therefore target all mature B-cells.
- One of the major pathways of cell kill in Rituxan tagged B-cells is called ADCC (antibody dependent cellular cytotoxicity). Quite a mouthful, but the broad brush stroke outline of the concept is not all that hard to understand. In this pathway, the B-cells do not die just because they are tagged by Rituxan. The tagged cells attracts the attention of the killer cells of your immune system, which then engulf the cells, Rituxan and all, and literally “eat” them up. This process is called phagocytosis.
- Think of phagocytosis as garbage removal. The Rituxan tagged B-cells are so much garbage, you want them out of the way and not cluttering up the neighborhood and stinking things up.
- Any one who has lived in New York City in the summertime when a garbage strike is on can appreciate the need for prompt garbage removal. You can imagine what happens when the amount of garbage exceeds the capacity of the garbage removal system of the city. Dr. Taylor proposes something very similar happens in CLL patients with large numbers of easily tagged CLL cells in the peripheral blood, when massive doses of Rituxan are infused by intravenous methods. All of that lovely Rituxan and all those nasty B-CLL cells: a match made in cancer heaven. Suddenly there are zillions of B-cells tagged with Rituxan, demanding attention and efficient disposal.
- Macrophages and neutrophils are wonderful garbage disposal units. They literally ooze around and surround the target cell and ingest it, and then move on to the next piece of garbage that needs to be cleaned up. The CLL cells in blood circulation are the first to get tagged by Rituxan pouring into the blood, and therefore they get eaten up first by the hard working macrophages. But over time more CLL cells are released from their cozy locations in the lymph nodes, bone marrow, etc., and pretty soon the process of garbage removal breaks down. Even macrophages can eat only so much and this all-you-can-eat buffet of zillions of Rituxan tagged B-cells is too much even for their impressive appetite. It's matter of timing and numbers.
- Now what? In short order, the Rituxan festooned CLL cells find themselves transported to your liver. The human body is a marvelous contraption. Garbage removal capacity overwhelmed by sudden and excessive amount of garbage generation? Not to worry. In the liver, the B-cells festooned with Rituxan are stripped off of the offending CD20-Rituxan pairs on the surface of the B-cells. These are very tiny snippets of protein compared to the tremendous size of the entire B-cell. Presto, the garbage situation is now under control. Instead of having to eat the whole shebang of zillions of B-cells and all the CD20 markers and Rituxan molecules hanging on these B-cells, the body now only has to deal with the mere snippets of CD20 bonded to Rituxan molecules. No big deal at all.
- Net result: under these circumstances, “cleaned up” B-CLL cells minus their CD20 tags are re-circulated out of the liver and back into your general blood circulation. B-cells shorn of their CD20 decorations.
- OOPs! If this is the way it plays out, you may still have lots of CLL cells in your blood circulation. It is just that many of them no longer display the CD20 marker that is the target of Rituxan. They can no longer be recognized as cancer cells (or even B-cells) by the magic bullet of Rituxan and therefore cannot be killed. All that expensive Rituxan still swishing around in your body will eventually be pissed away, literally and figuratively. OOPS indeed.
- Moral of the story — do not generate garbage faster than the rate at which you can clean it up. You don’t have to be a tree-hugger or card-carrying member of Greenpeace to understand how this concept is important in daily life and it seems to have some relevance to cancer therapy as well. How do we get around this bottleneck? Simple. Administer the Rituxan in tiny doses (say, 20 mg doses, as opposed to the “normal” dose of 800 mg or more now used routinely), administer the drug as a subcutaneous injection three times a week (rather than main-lining it as a intravenous infusion once a week) and thereby allow the drug to leach into the blood circulation ever so slowly over time. As the Rituxan trickles in slowly over time, the circulating CLL cells are gradually tagged by the monoclonal antibody, and the macrophages get to eat at a leisurely pace they can sustain without barfing up CD20-stripped CLL cells. No more an over-the-top and all-you-can-eat buffet but right-sized nutritious meals of tagged cancer cells at regular intervals. Most important, this may prevent the formation of “stealth CLL cells”, CD20 stripped CLL cells that can evade detection by Rituxan. Time and this clinical trial will tell if slow and steady will do a better job of winning the race.
I would have apologized for the cartoon version of his theory, except for the fact that the best cartoon version of the “Shaving Reaction” comes from Ron Taylor himself. One of the dogs below is the hapless B-cell, the other dog is the macrophage, and the rope between the two of them is the CD20-Rituxan pair. One can only hope the “macrophage” is happy to run off with the rope, shave off the CD20-Rituxan pair, and leave the other dog untagged and uneaten.
J Immunol. 2006 Feb 15;176(4):2600-9. Links
The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes.
Beum PV, Kennedy AD, Williams ME, Lindorfer MA, Taylor RP.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA
Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcgammaR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20(+) cells with acceptor THP-1 monocytes. After 45 min at 37 degrees C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab')(2) of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcgammaR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.
PMID: 16456022 [PubMed - indexed for MEDLINE]
J Immunol. 2004 Mar 1;172(5):3280-8. Links
Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.
Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA
Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20(+) cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20(+) cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20(+) cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.
PMID: 14978136 [PubMed - indexed for MEDLINE]
The Clinical Trial
Here is the link to the clinical trial on the clinicaltrials.gov website. It has all the background information, inclusion criteria and contact information. I have also provided a quick cheat sheet of the highlights: http://clinicaltrials.gov/show/NCT00366418.
- This is a small, Phase I / II trial. Only 12 CLL patients will be recruited. If you are interested, you might want to get on the horn quickly, check it out before the slots are all filled.
- The trial is open to patients who have already had fludarabine therapy. These patients would not be expected to have much of a response to conventional mega dose weekly infusions of Rituxan, I expect that is the reason why they are chosen for this study. If they respond to the new protocol, the difference would be easier to spot.
- Even though this not for chemo-naïve patients, I would think they are looking for a relatively healthy bunch, not the folks who are reaching the end of the chemotherapy road.
- We are talking about thrice weekly injections, 20 mg each, for a period of 12 weeks, a total of 720 mg of Rituxan. Compare that to ~800 mg each week for 4 or 8 weeks!
- Bethesda, Maryland is the only site where the trial is offered. This may not work for you if you are planning to fly in from the West Coast for each injection. However, they do talk about the ability to self-inject, which may mean you may be able to administer at least some of the injections yourself! This point is worth checking out if you are more than a car ride away from the trial center.
- The exclusion criteria are detailed: no more than one prior regimen containing Rituxan, no other cancers, no allergic reactions to Rituxan, no therapy in the past 3 months, no Rituxan in the last 6 months, no HIV, got to be able to give informed consent, yada yada. Surprise, no mention of being pregnant or breast feeding as exclusion criteria! All you pregnant or breast feeding moms out there, you may be in luck!
Risks and Rewards
So, what’s in it for us, you ask. I would like to see the day when each and every patient questions therapy decisions on the basis of the risks and rewards involved. Let us examine this clinical trial from that perspective.
- Rituxan has been used in hundreds of thousands of human patients, for a variety of diseases and syndromes. Heck, Genentech won’t mind if it is the best thing next to sliced bread for ingrown toe-nails. (May be it is good for toe nail fungus? Enquiring minds want to know!) On a more serious note, Rituxan has been used as single agent and in combination with a mind-numbing array of chemo agents in thousands of CLL patients. This is a drug whose toxicity in humans is well understood. We think.
- Giving Rituxan ever so slowly has been demonstrated to reduce significantly infusion-related adverse effects. Patients get into trouble when they (or the infusion nurses) get impatient and let it rip at too fast a pace. Subcutaneous injections mean the drug is injected under the skin, and from this reservoir the drug is then released slowly into the general blood circulation. “Slow release” is the operative phrase here, easy does it.
- The same effect of reduced infusion related adverse effects has been amply demonstrated in the comparison between subcutaneous injections of Campath versus intravenous infusions of it.
- Delayed hypersensitivity reactions of the type that “Harvey” saw (Rituxan Roadblock) are often dependent upon the dose of the drug. Lower doses are less likely to get your body into all-out revolt.
- While this clinical trial protocol calls for thrice weekly injections for 12 weeks, there seems to be a possibility of self-injection of the drug in the comfort of your home. Unless you are the type that welcomes a chance to catch up on your snoozing in the infusion chair, spending 5 or more hours there is not anybody’s idea of fun. Perhaps (like “Harvey”, our favorite hypothetical patient) you like chatting up the pretty nurses — but then how dashing can you be anchored to the infusion pole?
- The clinical trial is recruiting fludarabine relapsed patients. Generally speaking, these patients get next to no remission from the usual hefty-dose Rituxan infusions every week for 4 or 8 weeks, as a single agent. Chances are slim that we will see huge responses to this low dose administration either. But who knows, may be we will get lucky and see better than expected responses in these “old timers”? In any case, the information learned from the lab work of this pivotal trial will be priceless, and those of us who follow in the footsteps of our brave volunteers will thank them.
- One of the intriguing things we may learn from this trial is how to avoid developing resistance to this important drug, perhaps through the shaving reaction described above or some other mechanism.
- Even if single agent and micro dose Rituxan infusions don’t do a whole lot in these late stage patients, the detailed lab work may show promise for better results in early stage patients.
- If we can get away with so much smaller doses of Rituxan, (1) Genentech will make less money, (2) infusion room charges and related costs will be lower, (3) your HMO, National Medical Service or Medicare will love you, (4) so much so that a few of the more thrifty countries / insurance companies may even approve Rituxan use for CLL patients.
- All in all, this is as good as it gets in terms of risks and rewards, in my opinion.
One of our members wrote and asked the criteria by which we select the projects CLL Topics chooses to sponsor. Good question, I think it is worth answering in public so that all of you can decide what you think of our logic. So far, we have sponsored three clinical trials:
The ongoing green tea extract (EGCG) clinical trial at the Mayo Clinic, Rochester MN (see Project Alpha Kickoff) was our first project. The interim reports look promising: EGCG seems to be beneficial in a subset of our patient population with little or no adverse effects. I will take each and every “free lunch” we can get!
We have announced a formal clinical trial to try and improve the efficacy of annual flu shots by means of an immune modulator adjuvant (Imiquimod, trade name “Aldara”), under the guidance of Professor Terry Hamblin in the U.K. We are pleased that the British patient group UK CLL Support Association is our partner in that effort. We hope to be announcing the recruitment details of this double arm trial before the flu season for this year (Improving Immunizations).
The support announced here for the clinical trial to explore very low dose subcutaneous Rituxan therapy to judge the validity of the shaving reaction proposed by Dr. Taylor is our third project.
A fourth project that did not require cash outlays from CLL Topics is the recent Quality of Life survey that we championed as partners with Mayo Clinic. If you have not taken this survey yet, please do so right away. Here is the (QOL Survey).
All three of these projects have very common features that we find important.
- They are all projects that have the possibility of terrific pay-out to patients, big time, if they pan out.
- They are likely to be low toxic routes that can improve matters for our patients, whether it be a low toxicity green tea extract as daily supplement to control the rate of growth of the CLL, or more effective annual flu shots to keep our guys out of the hospital with influenza or worse, or micro doses of a crucial drug that may work better than when given in massive amounts.
- Absolutely no one stands to make a lot of money if these approaches pan out. EGCG in various forms can be had over the counter, a small dab of imiquimod (Aldara) once a year as you get your flu shot is not going to make 3M (the manufacturer of imiquimod) rich, Genentech will absolutely hate it if patients are better off using micro doses of Rituxan. For these obvious reasons, if we don’t support these trials, no one else will.
- Each of these trials uses technology or products that are here now, in commercially available quantities, not a gleam in someone’s eye. EGCG, Aldara, Rituxan are all commercially available and well researched products with long track record of low toxicity in humans. We are not qualified to judge the validity of extremely cutting-edge materials, with completely unknown risks in real live patients. “DO NO HARM” is an important criterion for our selection.
- Each and every one of these projects is headed by unimpeachable CLL researchers, at top rated research institutions. Credibility and pedigree matter when it comes to good science. If these projects pan out, the results will be that much more convincing and readily accepted by the general research and physician community as “best practices” if they carry the name tags of these well regarded institutions and well known experts.
- Each of these researchers have demonstrated track record of prompt publication of their research results and calling it like it is, whether the results be good, bad or ugly. Truth in research is the single most important thing we patients should be rooting for: enough with the sound bites, glad handing and press releases loaded with spin, foot dragging and biased reporting that does not pass muster of peer review for publication in prestigious journals.
- Leverage is important! We are not a large or wealthy patient group. We do not accept money from deep pocket drug companies or any one remotely connected with the pharmaceutical and healthcare industries. Each and every dollar we collect is real money, earned by real people doing an honest day’s work. We do not have millions to throw at projects. That is why I am proud that more often than not our money is the “seed money” that gets the project going. The NCI, Mayo Clinic, NIH and the like are our partners. These are the big boys that contribute the lion's share of the money needed to pay for projects such as this. I would like to think the moral weight of patients putting their money where their hearts are is the driving force that gets these projects off the starting block.
CLL Topics has extremely low overhead costs. We are all volunteers here - and none of us get paid a dime for this work. In fact, most of us pay out of our pockets for the privilege of doing this labor of love. We take very seriously the responsibility of spending your money wisely. Last count, 426 generous donors from all over the world have sent in over $153,000 tax-deductible dollars as of the end of July. You can look up the details of our financial statements by clicking on the document links in the About Us page. Total transparency is another thing we take seriously.
Fund-raising is not a huge part of our charter. I would like to think patient education is our single biggest driver. If, in the process of doing the digging, we come across a worthwhile project that absolutely needs our support, it is wonderful to be able to say “we will”. Take a bow, ladies and gentlemen. Your hard earned dollars make it possible for us to fund these important projects.
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