Therapy Choices el pt

Possible Benefits of IVIg

Date: April 27, 2024

by Chaya Venkat

Proper B-cell Function is Important

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Hypogammaglobulinaemia

As B-CLL patients we get fixated on thinking of all B-cells as bad actors, to be eliminated at all cost. In reality, that is not quite the case. B-cells are a very important part of the immune system and when they are working right they provide crucial frontline defense against many pathogens. Lack of proper B-cell function is one of the reasons for the many infections that CLL patients get. This article describes the major function of B-cells, and what happens when this cell line is compromised by cancer or therapies used to control the cancer.

IVIg stands for “Intra-Venous Immunoglobulin”. CLL patients typically have sub-par levels of immunoglobulins (Ig). In fact, CLL is one of very few indications for which IVIg has been approved by the FDA, a fact you can use in negotiating with your insurance company and local healthcare provider. Unfortunately, it costs an arm and a leg, it is often in short supply and hence the reluctance of doctors to prescribe it. There are several good Ig products on the market and modern manufacturing methods have taken out most (if not all) of the risk in Ig infusions. There is not much chance you will get hepatitis or mad cow disease as a result of getting IVIg. All blood based products carry some risk, but the risk of getting killed as a result of getting some infection from IVIg is not worth worrying about. A few people are allergic to IVIg and that is the reason why it has to be administered carefully and slowly. Take a good book to read when you go for an IVIg infusion, since it takes several hours to administer.

B-cells Are an Important Part of Our Defense against Pathogens

Igs are proteins made by properly functioning, mature B-cells (which go on to become “plasma cells” - nothing more than factories for spewing out Ig molecules), and they are a very important part of the body’s immune system. Plasma cells live for quite a long time, but they do gradually die off. In healthy people the repertoire of plasma cells is maintained by new ones being made by healthy B-cells, as the old ones die off. There are literally zillions of different Ig molecules floating around, each type waiting to find and kill a specific pathogen, its one-and-only prey. This is part of the “memory” function of our immune systems; our bodies can remember a pathogen they met a long time ago, perhaps as a result of a childhood vaccination. After that initial encounter our bodies can remember the offender for years, sometimes for the rest of our lives, often without the need for “booster shots” to jog their memory. The threat is remembered and as the need arises “memory B-cells” create plasma cells to make the right Ig to fight that particular offender. Think of Igs as very specific and unrelenting stalkers, generations of plasma cells and their daughters making these killer Ig proteins - patient, unforgiving killers, with a “fatal attraction” for their particular target pathogen.

CLL Cells Do Not Make Good Ig

The orderly process of making all the varieties of Ig is screwed up in CLL patients. CLL patients have plenty of B-cells, but the vast majority of them are wonky CLL cells that don’t work right. The good B-cells are gradually squeezed out of the picture by defective B-CLL cells. CLL cells do not mature as they should, they do not make good memory cells and they do not go on to become plasma cells, and therefore the numbers of plasma cells gradually decrease over time. If you track Ig levels (typically three broad types of Ig are tracked:  IgG, IgA, and IgM) in CLL patients, you will see a gradual decrease in their levels over time. The disruption of properly formed Ig and a proper balance in the different varieties of Ig is also at the heart of many of the autoimmune problems encountered in CLL patients, such as AIHA (autoimmune hemolytic anemia), ITP (autoimmune thrombocytopenia) autoimmune diabetes, rheumatoid arthritis, asthma, Crohn’s disease and so on. In fact, one of the modern frontline therapies for AIHA is IVIg therapy.

With a Little Help from Our Friends

When you get IVIg therapy, you are getting the Ig isolated from the blood of thousands of healthy donors and therefore you get protection against a wide spectrum of pathogens. You are getting the “antigen experience and memory” of all of these donors, protection against all of the pathogens that these generous people have encountered over their lives. It is a little bit like calling in the cavalry because your own home grown immune system is not up to the job. Unfortunately, the administered Ig does not last for ever, the molecules get chewed up and destroyed after a few weeks (typically 6-8 weeks); hence the need for regularly scheduled IVIg infusions. The process of collecting all that blood, screening it and collecting the precious Ig molecules from it is a time-consuming and expensive process. I am looking forward to the day when some one comes up with a procedure for manufacturing the necessary Ig molecules from scratch, without having to collect it painstakingly from donated blood. (Did you know our favorite drug Rituxan is also an Ig molecule? It is man-made, and it is only just one specific Ig molecule. That is why it is called a monoclonal antibody, it is fixated on only one target, the CD20 marker on all B-cells.)

There has been some really fascinating research in recent months and years that suggests that in a small subset of CLL patients, the CLL proliferation is driven by a viral, bacterial or other pathogen that hangs around, doing mischief (Viral Drivers, Dawn of a New Era). In healthy people these pathogens are easily taken care of by their home-grown Ig, and their immune systems do not over-react to them. But in CLL patients, the particular Ig molecules needed to take care of the problem may not be present, and the problem may persist for long periods. Under the influence of these constant antigen goads the CLL cells proliferate. Think of it this way, the CLL cells are trying, ineffectively, to take care of the pathogen(s). They do this by multiplying, growing ever larger armies of themselves. But they cannot get the job done since they don’t follow through, they are not able to mature to become plasma cells and make the necessary Ig molecules. All we get is a rapid proliferation of the CLL cells, and since they resist programmed suicide, there is rapid accumulation of their numbers. 

The latest research coming out of Long Island Jewish Hospital (Rai, Chiorazzi, et. al.) suggests that there are clusters of CLL patients who have very similar CLL cells. Each cluster may represent patients whose CLL is driven by a particular pathogen. If this pathogen happens to be one that is around all the time (as would be the case with antigens such as EBV, HSV, HPV, even “self antigens”, bits of our own home grown proteins, etc.), the CLL cells see this as an ever present threat. They have only one answer to this situation, grow more copies of themselves, and this makes matters worse.

Getting IVIg infusions from the pooled blood of healthy donors may get around this problem. If your CLL is driven to proliferate because of the constant goading action of a ubiquitous antigen, then getting across-the-board Ig protection (IVIg therapy) from the general healthy donor population may help. You may be one of those CLL patients whose CLL responds to IVIg! I have not found any published data, but I have heard from several patients whose CLL counts gradually decreased and normalized after getting regular IVIg treatments. This is anecdotal information and does not begin to have the value of a full-fledged clinical trial.

Below is a press release from a company called GammaCan that is doing clinical trials in Israel, I believe, using the same logic I have described above. As best as I can tell, there is not anything special or magical about their particular brand of IVIG. Every company claims it has the best handle on how to manufacture IVIg just so, and surely it makes sense to use one that has highest purity ratings. Down the road, we may get more sophisticated about this whole process. For example, we may be able to pick and choose the donors whose blood goes into the pool used for IVIg manufacture, to target specific antigens. 

But for now, if you have documented low levels of Ig, and you are prone to get frequent infections (mouth and skin sores, chest congestion that does not go away even after antibiotic therapy, frequent “fevers of unknown origin”, all of these count) then you may be a candidate for IVIg therapy. In fact, use of IVIg for this group of CLL patients is one of the best practices listed by Mayo (What You and Your Doctor Need to  Know). It may take some negotiating with your doctor and you really want to make sure your healthcare insurance covers the cost of the IVIg. It is not cheap and you may need to get it at regular intervals. The good news is that for a subset of patients the benefits may go beyond reducing infections. IVIg may help with autoimmune disease (remember, preventing the on-set of autoimmune disease is a lot easier than correcting it once the wrong pathways are established and the patterns set in place). If you are really lucky, IVIg may even help keep a lid on the rate at which your CLL proliferates, by controlling the pathogen that is driving the growth rate. Do write and let us know if you fall into this group, we would like to collect more anecdotal information on this subject.

Press Release:

Biopharmaceutical Pioneer GammaCan Develops Anti-Cancer Immunotherapy Based On IVIg

11/9/2004
Source: GammaCan International, Inc.

GammaCan International, Inc. (BULLETIN BOARD: GCAN) , a developer of immunotherapies for cancer and other serious conditions, today announced it may have discovered a new weapon in the fight to keep melanoma, carcinoma, sarcoma, lymphoma, and other deadly cancers from spreading or returning in patients. The patented therapy, based on Intravenous Immunoglobulin (IVIg), is a concentrated form of disease-fighting antibodies naturally occurring in human blood. Based on the Company's preclinical results and year-long clinical experience with IVIg, the company believes that this new therapy may open an exciting new treatment option that is safe, effective, and minimally toxic.

GammaCan's therapy is based on GCAN 101, its IVIg product. The company intends to soon commence Phase II human clinical trials to demonstrate GCAN 101's strong cancer-fighting potential. On the basis of the preliminary Phase II results, GammaCan hopes to enter a licensing agreement with a yet-to-be- determined major pharmaceutical partner for Phase III trials and commercialization, that could ultimately result in widespread clinical use of GCAN 101 for cancer treatments.

In recent years IVIg therapy has been used effectively for treating a variety of autoimmune diseases. IVIg is made by pooling immunoglobulin G from the blood donations of a large number of qualified donors, typically between 6,000 and 10,000. Because IVIg contains the entirety of antibodies present in such a large donor set, it is effective at treating both immune and autoimmune disorders by significantly raising the patient's natural ability to fight disease. The U.S. Food and Drug Administration (FDA) has already approved IVIg for use in treating several autoimmune diseases.

"GammaCan's proprietary research has demonstrated that GCAN 101 treatment reduces the spread of a broad spectrum of cancers and cancerous tumors with virtually no side effects," said Professor Yehuda Shoenfeld, M.D., GammaCan Chief Scientist and a world-renowned expert in immune deficiencies and autoimmune diseases. "Approximately 50% of all cancer patients experience metastases, or the spreading of their cancer from its original point of occurrence. While IVIg therapy with GCAN 101 is not a cure for cancer, it holds great potential for improving and prolonging the quality of life for cancer patients not only because it is expected to prevent metastases, but also because it's safe and minimally toxic."

GammaCan's therapeutic approach, which has been awarded two U.S. patents, involves periodical GCAN 101 treatments in the years following initial diagnosis and treatment. The company's laboratory studies with cancerous mice have demonstrated that chances for long-term survival by preventing the return and spread of cancer is increased with IVIg therapy. Experiments have also indicated the therapy is effective at much lower doses than is commonly used for treating immune deficiencies.

"According to the NIH (National Cancer Institute) there are presently almost 10 million cancer survivors alive in the United States. More than 3.7 million of these were diagnosed within the last five years. Our target population are cancer survivors, and we are hopeful that GCAN 101 can improve the prognoses for many of these patients," said Dr. Dan J. Gelvan, Chief Executive Officer and President of GammaCan. "What is especially encouraging is how this treatment can be added to existing treatments to prevent cancer recurrence. As many as 25-40% of all cancers reoccur during the critical five-year period after initial treatment."

Link: GammaCan Website