Smart Troops That Protect Us

In a recent article we discussed neutrophils. While these immune system cells are crucial “first responders”, they are pretty much a “blunt instrument” when it comes to fighting infections. As we discussed in the earlier article, neutrophils home in on tell-tale signs of inflammation and based on their single-minded assumption that where there is inflammation there is an infection, they shoot off  their weapons with gusto. Sometimes their exuberant and non-specific approach can cause or exacerbate other problems – such as damage to healthy lung tissue.

T-cells on the other hand are the “smart” troops; they are most definitely not inclined to shoot first and ask questions later. T-cells attack only when they are sure the target is indeed a bad actor, a pathogen or an infected cell that must be killed to protect the rest of the body. T-cells live and learn. Subsets of them are focused on killing specific pathogens and they spend their whole lives patrolling the body looking for this particular enemy. They depend on dendritic cells to let them know when there is danger lurking as well as the nature of the danger.

Since T-cells are very efficient serial killers, a single T-cell can kill many victims one after the other. They are very deadly and few targets of full-fledged T-cell attack live to brag about it. T-cells protect us against reactivation of traces of different viruses most of us harbor in our bodies, such as the EBV (Epstein-Barr virus), CMV (cytomegalovirus) or Herpes zoster (think shingles). Since T-cell attack can be so lethal, the body controls their function very tightly. After all, it is not a good idea to have a lot of highly trained and super smart killers armed with deadly assault weapons and unlimited amounts of ammo running around a civilian population without adequate supervision and controls. T-cells must follow pretty tightly defined guidelines and protocols before they can use deadly force.

Nipping tiny problems in the bud, before they grow fangs

T-cells perform a host of defense function, assisted by their side-kicks, NK cells - their name says it all, “natural killer cells”. NK cells are not quite as finicky as T-cells. While they share many of the same characteristics as T-cells, they are a lot quicker on the draw and just as deadly when they attack. Think of them as smart troops with bad tempers and shorter fuses and not bothered too much about following all the protocols laid down for T-cell attack .

In addition to killing invading pathogens and virally infected cells, both T-cells and NK cells also perform another very crucial function. They cruise around the body looking for potential hot spots and signs of microscopic clusters of cancer cells. You might be surprised to know that most of us harbor tiny really tiny clusters of cancer in our lungs, on our skin and lining of our mouth, stomach, gut etc. Such microscopic clusters of cancer cells are more likely as you age, especially if you are a smoker or if you have a lot of sun damaged skin. Fortunately for the vast majority of us, most often such microscopic clusters of cancerous cells do not grow to the point where they cause problems and become large enough colonies of cancer cells to even be detected. One of the ways the body takes care of these tiny clusters of cancerous cells and nips the problem in the bud is through T-cell surveillance. In particular, NK cells and T-cells are thought to be important in controlling basal and squamous cell carcinoma and preventing them from becoming possibly deadly invasive skin cancer. This is why SCC and BCC are not really a big problem in immune-competent people. Aha. But what about immune –incompetent people? There is the rub.

One of our earliest crusades on this site as well as our flagship website CLL Topics has been to inform and educate our patients about their increased risk of skin cancer. I am very glad to see this message is now getting heard, more experts are writing about it in their “best practices” articles, more local oncologists are taking the trouble to advise their CLL patients to avoid excessive UV exposure, more dermatologists are learning that simple cases of actinic keratosis or basal cell carcinoma or squamous cell carcinoma need to be treated with a whole lot more seriousness in immune compromised CLL patients.

Which brings up the important question: why do our patients have a higher risk of skin cancer? There are three reasons for it. First, CLL is by its very nature a cancer of the immune system, immune dysfunction is baked into the cake; which in turn means the T-cell and NK-cell surveillance necessary to keep skin cancer in check is less than award winning in our guys. Second, whether we like it or not, the typical CLL patient is no spring chicken and skin cancer is more likely when your skin has been damaged from excessive sun exposure all those summers on the beach when prudence was not exactly what you had on your mind.

Last but not least, the very therapies that are used to treat CLL are also very unfriendly to T-cell populations. For example, purine analog containing regimens such as FCR, PCR, FR etc are demonstrably toxic to T-cells. Even more so, Campath can destroy T-cell counts to the extent that they are mere shadow of their former counts as much as a year later. Fewer T-cells means the immune surveillance looking for early signs of skin cancer is a lot more patchy. There is a window of vulnerability where a small cluster of BCC or SCC cells may grow quietly undetected and morph into full fledged aggressive skin cancer.

There is another aspect of T-cell dysfunction that does not get a lot of press: while the smart troops are struggling to make a come-back, our guys are even more at risk of infections. There is ample evidence that viruses can cause a variety of infections. We discussed some of them in earlier articles. Viral reactivation of EBV and others is well documented in CLL patients undergoing T-cell depleting therapy. Here is a short list of cancers that are known to have viral connections.

Taking care of your T-cells

I would like to bring to your attention an interesting case history out of M. D. Anderson. One of the authors is none other than Dr. Mike Keating. It is about a CLL patient who was treated with FCR, relapsed after a few years, and now faced a two fronted war: CLL and a bad case of skin infection caused by an organism called mycobacterium marinum. This is a bacterial infection that usually happens in fishermen or people messing with salt water aquariums. Normally, it is not a big deal and the body heals itself with a little help from a healthy immune system - including T-cells and NK-cells. But in our case history, this CLL patient was facing “life after FCR” and was not having much luck fighting this infection.

The researchers decided to treat the patient with Revlimid (lenalidomide). As you know by now, Revlimid is not your standard issue chemotherapy agent. It works by goosing the patient’s own immune system, setting off high alert alarms so that every available cop and law enforcement officer is forced to work overtime without even stopping for a donut break. The not so wonderful side effect of this “red alert” is that patients treated with Revlimid often feel like they have a massive case of the flu, accompanied by body aches, fever, tender glands, the whole works - the technical name for this syndrome is “tumor flare”. Massive amounts of histamine may be released, causing a rash in a significant percentage of patients. But the other side of the coin is that as immune system surveillance increases, the chances that any hitherto undetected and unchallenged enemy is engaged, and with a bit of luck, defeated. And before I forget, Revlimid also does a reasonable job on controlling CLL.

In this case history I think the researchers kind of knew what they were looking for and wanted to prove. They took the trouble to measure the patients T-cell counts before start of Revlimid therapy, followed by a similar census after completion of Revlimid therapy. Lo and behold, what did they see but a dramatic increase in T-cell counts?! That by itself is not worth writing about, but here is the punch-line: the patient’s entrenched mycobacterium infection that had refused to budge earlier on became a tame little thing, on its way to healing. How do you like that for a happy ending? The short abstract is below, but you really should click on the link below where you can read the full text of the article and look at the before and after pictures of the guy’s arm.

Clin Infect Dis. 2008 Apr 1;46(7):e69-71.

Rapid resolution of Mycobacterium marinum chronic skin infection during lenalidomide therapy for chronic lymphocytic leukemia.

Awais A, Tam CS, Kontoyiannis D, Ferrajoli A, Duvic M, Cortes J, Keating MJ.

Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, USA.

Abstract

The immunomodulatory drug lenalidomide is currently being evaluated for its antineoplastic properties in treating hematologic malignancies. However, its potential role in augmenting immune reactions against opportunistic infections has not been explored. We report the rapid resolution of chronic Mycobacterium marinum infection in a patient following initiation of lenalidomide therapy for chronic lymphocytic leukemia.

PMID: 18444808

Boosting other parts of the immune system

Immunoglobulins (Ig) are a huge part of our immune system. These proteins are secreted by “plasma cells”, which in turn come from healthy mature B-cells. One of the built-in problems with CLL is that as the cancerous clone grows, it kicks out  healthy B-cells. Fewer healthy B-cells means fewer plasma cells and down the road that means lower counts of immunoglobulins. As CLL progresses to higher Rai stage, patients become increasingly deficient in immunoglobulins – and more prone to infections.

A simple blood test can tell you whether or not you have sufficient immunoglobulins. The test measures three kinds of immunoglobulins: IgG, IgA and IgM. For practical purposes, the number you should focus on is your IgG levels. If these are well below normal levels, you may want to discuss with your doctor the need for intravenous immunoglobulin infusions (IVIG). But bear in mind, IgG products are manufactured from blood donated by thousands of generous donors. Like all blood products, there is an unavoidable risk of contamination, even though that risk is quite small and getting smaller as manufacturing protocols improve. IVIG continues to be very expensive and in short supply, a good reason why it is not a huge favorite with insurance companies.

CLL patients today are more likely to be deficient in immunoglobulins than comparably staged CLL patients a decade or so ago. Reason? Increasing use of anti-CD20 monoclonal antibodies such as Rituxan. As you know, Rituxan targets CD20 marker on B-cells. Healthy B-cells are just as easily killed by Rituxan as the CLL variety. It take some time for B-cell populations to recover after completion of Rituxan therapy, a period during which no new plasma cells are being made, which in turn impacts immunoglobulin production. Long term and repeated treatment with Rituxan leaves most patients with chronically low IgG counts.

Revlimid’s ability to improve immune function is making a few researchers wonder if this drug can be used as a chemoprevention drug - something with which to delay need for more convention chemotherapy in high risk CLL patients. A couple of months ago we brought to your attention the abstract below. It seems that not only does Revlimid increase T-cell numbers and their efficiency in killing cancer cells, Revlimid does a good job of getting the remaining few healthy B-cells motivated enough to cause increased production of immunoglobulins – also known as antibodies.

Of course, this effect would not be there if Revlimid therapy is given along with Rituxan therapy, a popular combination. Rituxan would effectively kill of any B-cells, goodbye to any chance of increased production of immunoglobulins. Another popular side-kick for Revlimid therapy is dexamethasone. Use of this corticosteroid was more common earlier on, when it was thought to decrease the adverse side effect of “tumor flare”. Makes sense, dexamethasone reduces the oomph of Revlimid, thereby decreasing the massive flu like symptoms. But the other side of the coin is that co-administration of dexamethasone also decreases the immune boosting effects of Revlimid – no pain, no gain.

Blood. 2010 Apr 1;115(13):2619-29. Epub 2009 Nov 24.

Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway.

Lapalombella R, Andritsos L, Liu Q, May SE, Browning R, Pham LV, Blum KA, Blum W, Ramanunni A, Raymond CA, Smith LL, Lehman A, Mo X, Jarjoura D, Chen CS, Ford R Jr, Rader C, Muthusamy N, Johnson AJ, Byrd JC.

Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.

Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-kappaB (NF-kappaB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells up-regulate BID, DR5, and p73, become sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials.gov as NCT00466895.

PMID: 19965642

Editorial

  • The importance of healthy T-cell and NK-cell populations in maintaining good immune function is undisputed. Lack of these important smart troops means increased risk of infections and a host of cancers. That much is clear.
  • CLL patients are at higher risk of aggressive skin cancer than the general population.  A simple case of BCC or SCC can become dangerously aggressive skin cancer in our patient population.  By the way, did you know you can have melanoma where the sun don’t shine?  For example on the sole of your foot, between the toes, under your nails, inside your mouth, deep within your gut and elsewhere?
  • Revlimid is now generally accepted as one of very few drugs that work on very high risk patients, those with17p deletions or dysfunctions.
  • In this article I would like you to focus is on the immune boosting effects of Revlimid – especially if it is given without the dampening effect of dexamethasone – resulting in increased number and function of crucial T-cells and NK-cells.
  • Will this immune boosting nature of Revlimid translates into fewer infections down the road (if antibody counts improve) and more importantly, will this decrease the risk of aggressive skin cancer? That is the million dollar question.

Will Revlimid therapy help CLL patients fight increased risk of skin cancer? That is the hypothesis I am making in this article. No one has done this research, yet. No one has taken a group of untreated CLL patients with a history of BCC or SCC and treated them with Revlimid, to see if they got benefit for their underlying CLL as well as skin cancer risk. No one has yet done this clinical work to the best of my knowledge, focusing on increased number and killing efficiency of  T-cell / NK-cell, before and after Revlimid therapy – and correlating this improved immune surveillance to decreased skin cancer risk. So, please be aware that this is just a hypothesis from yours truly at this point, give it the credence you think it deserves. The logic works for me – a possible way of finessing the increased risk of skin cancer in this patient community. Will this research ever get done? I do not know. I hope so, we badly need some solutions other than immune suppressive therapies for CLL patients at high risk of skin cancer.

Got CLL?  Got skin cancer worries? I hope you take ownership of this issue, get motivated enough to do something about it.