Hyperthermia – the deliberate increase in temperature of a part of the body or the whole body as a therapeutic measure – has been around for a while.  Today I would like to talk about how hyperthermia may be of relevance to CLL patients.  I will provide some provocative leads to support my hypothesis, but please be aware this is only a hypothesis at this point.  I am not aware of any formal clinical trials looking into hyperthermia as a possible therapy option for CLL patients.

The 2006 article in the prestigious Journal of American Medical Association (JAMA) asks this question: “How could Lance Armstrong, who was diagnosed with very advanced metastatic testicular cancer, be treated so successfully that he could subsequently win multiple grueling Tours de France?”  The abstract of the JAMA article is below.

JAMA. 2006;296:445-448.

Hyperthermic Biology and Cancer Therapies. A Hypothesis for the “Lance Armstrong Effect”

Donald S. Coffey, PhD; Robert H. Getzenberg, PhD; Theodore L. DeWeese, MD

Department of Urology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Md 21287, USA.

There is perhaps no more important question in cancer research than to understand the molecular basis of how the majority of patients with testicular cancer can be treated so effectively. For instance, how could Lance Armstrong, who was diagnosed with very advanced metastatic testicular cancer, be treated so successfully that he could subsequently win multiple grueling Tours de France? Although such therapeutic success is now common for many patients with this type of advanced testicular cancer, this type of outcome is unattainable for the majority of patients with other types of advanced solid tumors. What accounts for the astounding therapeutic success with testicular cancer, and can this outcome be explained both at the cellular and molecular levels? Understanding the basis for the “Lance Armstrong effect” may provide therapeutic targets to enhance cures of other common advanced solid tumors that remain so refractory to the best systemic treatments.

PMID: 16868303

The JAMA article is interesting reading.  Send me a personal email if you would like to read the full text of the article. I have excerpted some of the highlights below.

  • Warm-blooded animals like us evolved with normalbody temperatures that are often far higher than the ambient temperature. Maintaining this temperature differential is a very costly energy price for the animal.
  • When mammals are infected with pathogens, they have adapted to produce increased body temperature (fever), which increases the proper function of the immune system and therefore ability to kill off invading pathogens.
  • Fever temperatures are lowered to make us feel better but might be detrimental in fighting infections.
  • Many cancer cells are more easily killed than normal cells if they are incubated above 42°C (107.6F)
  • Human testes are a few degrees lower in temperature than the rest of the body and testicular cells are very sensitive to temperature increase.
  • The Lance Armstrong effect might be due to the fact testicular germ cells die when heated to even the normal body temperature of 37°C (98.6F).
  • When testicular cancer metastasizes to other parts of the body (in Lance’s case to his lungs and brain), it therefore becomes stressed by heat, making the cancer easier to destroy when it is treated with radiation or chemotherapy

Do CLL cells also like to be slightly cooler than normal?

Extrapolating from the JAMA article, the million dollar questions for us are these:  are CLL cells also temperature sensitive?  Do they also prefer to be slightly cooler than “normal” body temperature of 37C (98.6F)? Are they easier to kill by chemotherapy if at the same time they are also subjected to higher temperature?

Anecdotal information from patients

I started pondering about this whole business when looking over my huge database of anecdotal CLL patient stories.  It struck me that many patients report their “normal” body temperature is significantly below 37C. Unfortunately this is only anecdotal information and you are smart to bear that in mind as you read the rest of this article.

In my husband PC’s case, I know his temperature used to average just about 98.4 before the diagnosis of CLL.  Below is a chart of his temperature over a period of little over 3 months.  First couple of weeks is baseline (color coded black), when he had pretty high tumor load.  Subsequent months (colored red)  represent his temperature as he went through monthly cycles of Humax-CD20 + fludarabine therapy. (HF can be considered to be similar to RF; since PC was hypersensitive to Rituxan he had to substitute Humax-CD20 in place of Rituxan).

As you can see, his average temperature gradually increased as therapy progressed and then stayed at the higher level for the period of time while he was getting therapy – and presumably the CLL tumor load was significantly reduced over this period of time.

Are CLL cells temperature-sensitive?

If for the sake of argument we accept that like testicular cells CLL cells too prefer to be at a slightly cooler temperature, the next question is whether they are more readily killed when forced to be at higher temperature. The second part of this question is equally important:  do CLL cells die more readily at elevated temperature, compared to normal B-cells?  In other words, is there a window of opportunity here?  Can we kill CLL cells preferentially?

Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.

Vol 23, No 16S (June 1 Supplement), 2005: 6693

Abstract # 6693

Differential sensitivity of B-CLL cells and normal B cells to hyperthermia

D. Schoeler, C. Weber, A. Tornack, F. Schriever and F. Ringel

Charité Campus Virchow, Berlin, Germany

Background: Inhibition of apoptosis is a major cause why B-cell chronic lymphocytic leukemia (B-CLL) still can not be cured with conventional chemotherapy. Therefore, innovative approaches to this clinical enigma are needed. Whole body hyperthermia (WBH) as a part of a systemic Cancer Multistep Therapy (sCMT) is under investigation in a variety of advanced solid tumors. The aim of the current study was to examine whether B-CLL cells and normalperipherallymphocytes have a differential sensitivity to hyperthermia in vitro. Methods: Peripheral blood B cells of patients with B-CLL (n=38) and normal donors (n=21) were isolated by Ficoll gradient centrifugation and were incubated in vitro at different temperatures (37-42°C) over defined time periods (15-300 minutes). Apoptosis and necrosis of anti-CD19-labelled B cells were quantified by Annexin-V-FITC and Propidiumiodide respectively, using flow cytometry. Nuclear fragmentation demonstrating apoptosis was visualized by DAPI-staining using fluorescence microscopy. Apoptosis via mitochondrial pathway was monitored by JC-1. Induction of cDNAs encoding for the heat shock proteins (hsp) 27, 60, 70, 90, and 105 was quantified using RT-PCR. Results: In B-CLL cells apoptosis was induced at 40°C and higher with an optimal temperature at 42°C. Induction of programmed cell death could be observed as early as after a 15 min incubation at 42°C. Interestingly, B-CLL cells differed in their ability to undergo heat-induced apoptosis from normal B-lymphocytes. After a 2 hour incubation at 42°C 56 ± 15% of all B-CLL cells but only 12 ± 9% of normal B cells underwent apoptosis (p<0,0001). Of note was, that in both, normal and malignant B-cells, heat-treatment induced hsp 27, 70, and 90. Interestingly, high hsp 27 levels in untreated CLL cells were shown to be positively correlated with hyperthermia induced apoptosis. Conclusions: B-CLL cells are more susceptible for heat-induced apoptosis than normalperipheral B cells. We hypothesize, that our data may encourage innovative studies examining whole body hyperthermia as an experimental approach to treat patients with B-CLL.

It seems this temperature sensitivity is not limited to CLL cells alone.  Below is an abstract that says pretty much the same thing about AML (acute myeloid leukemia) cells. In fact, they suggest this difference can be used to clean stem cells collected from patients for autologous transplants.  Contamination of stem cells with cancer cells is one of the major problems associated with autologous stem cell transplants.

Differences in heat sensitivity between normal and acute myeloid leukemic stem cells: Feasibility of hyperthermic purging of leukemic cells from autologous stem cell grafts

Experimental Hematology, Volume 31, Issue 5, Pages 421-427

PK Wierenga – 2003

Objectives. In autologous stem cell transplantation contamination of the graft with malignant cells is frequently noticed and necessitates the use of in vivo or in vitro purging modalities. The hematopoietic recovery after transplantation depends on the number of stem and progenitor cells in the transplant. Therefore, in the present study the effects of hyperthermic treatment on the human normal and acute myeloid leukemic (AML) stem cell compartment were investigated.

Methods. Normal bone marrow and AML blasts were heat treated up to 120 minutes at 43°C. The surviving fractions of the different stem cell subsets were determined using in vitro methylcellulose and cobblestone area-forming cell (CAFC) clonogenic assays, as well as the in vivo NOD/SCID repopulating assay. The leukemic nature of the colonies from AML cells was confirmed by RT-PCR analysis. In order to increase the therapeutic index of the hyperthermic purging modality, the heat treatment was preceded by a 3-hour incubation at 37°C with the ether lipid ET-18-OCH3 (25 μg/mL).

Results. It could be demonstrated that normal progenitor cells are far more resistant to hyperthermiathan leukemic progenitor cells (56%±7% vs 9.9%±2.6% survival after 60 minutes at 43°C, respectively). Furthermore, normal hematopoieticstem cells appear to be extremely resistant to the heat treatment (94%±9% survivalafter 60 minutes at 43°C). In contrast, in the leukemic stem cell compartment no significant differences in heat sensitivity between the stem cells and progenitor subsets could be observed (12.3%±2.9% vs 9.9%±2.6% survivalafter 60 minutes at 43°C, respectively). The combined treatment resulted in a survival for normal progenitor and stem cells of 32%±6% and 85%±15% after 60 minutes at 43°C, respectively. Under these conditions the number of leukemic stem cells was reduced to 1%±0.3%. After 120 minutes at 43°C, no AML-colonies could be detected anymore.

Conclusions. Our data demonstrate that leukemic stem cells have an increased hyperthermic sensitivity compared to their normal counterparts and that this difference can be further increased in combination with ET-18-OCH3. These striking differences in heat sensitivity warrant the use of hyperthermia as a clinically applicable purging modality in autologous stem cell transplantation.


Theoretical explanation for temperature sensitivity

Most of us know by now that high ZAP70 is not a good prognostic indicator.  Patients whose CLL cells express high levels of ZAP70 have more aggressive CLL.  ZAP70 protein is thought to facilitate signaling through the b-cell receptor (BCR) which in turn turns up the ability of the cell to have lots of baby cancer cells. It is proposed that ZAP70 protein comes unglued when the temperature is increased. At higher temperatures the protein is not folded properly and cannot do its job. 

The abstract below from Kipps et al suggests that when ZAP70 gets all messed up, it requires the services of a heat shock protein (HSP90) that acts as a busy housekeeper re-folding the ZAP70 protein just right.  This raises the immediate question:  what if ZAP70 becomes unglued due to higher temperature and at the same time we prevent the housekeeper HSP90 from doing its job and re-fold the ZAP70?  Without the constant stimulation of the ZAP70 protein can we bring to a halt the ability of CLL cells to multiply?

Bottom line, will treatment with drugs such as 17-AAG which block the function of HSP90  be more effective if at the same time we also use hyperthermia forcing the ZAP70 protein on CLL cells to get messed up? Please read an earlier article we published on our CLL Topics website that discusses in detail the clinical trials underway at Ohio State using 17-AAG and its sister drug 17-DMAG

Blood. 2005 Oct 1;106(7):2506-12. Epub 2005 Jun 21.  

Full text

ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia.

Castro JE, Prada CE, Loria O, Kamal A, Chen L, Burrows FJ, Kipps TJ.

Moores University of California San Diego (UCSD) Cancer Center, University of California, CA 92093-0960, USA. je-castro@ucsd.edu

The zeta-associated protein of 70 kDa (ZAP-70) is expressed in patients with aggressive chronic lymphocytic leukemia (CLL).We found that ZAP-70+ CLL cells expressed activated heat-shock protein 90 (Hsp90) with high binding affinity for Hsp90 inhibitors, such as 17-allyl-amino-demethoxy-geldanamycin (17-AAG), whereas normal lymphocytes or ZAP-70- CLL cells expressed nonactivated Hsp90. Activated Hsp90 bound and stabilized ZAP-70, which behaved like an Hsp90 client protein only in CLL cells. Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cellsbut not in T cells, and also impaired B-cell receptor signaling in leukemia cells. Transduction of ZAP-70- CLL cells with an adenovirus encoding ZAP-70 activated Hsp90 and specifically rendered the leukemia cells sensitive to 17-AAG. These data indicate that Hsp90 is necessary for ZAP-70 expression and activity; that ZAP-70 is unique among Hsp90 clients, in that its chaperone-dependency is conditionalon the cell type in which it is expressed; and also that ZAP-70 is required for cell survival and signaling in CLL. Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL.

PMID: 15972449

How hyperthermia is done

Hyperthermia can be limited to small portions of the body, or it can be applied to the whole body.  Temperature can get as high as 107F! WARNING: Do not do this at home on your own!  When the body is raised to high temperatures such as this it is quite possible to have heart attack or do damage to your brain.  I am very serious about this warning folks. 

But under strictly supervised medical conditions it is possible to increase body temperature to these levels with little risk.  The question is this:  will medically supervised whole body hyperthermia increase the effectiveness of chemotherapy in CLL?

Below are some links that can teach you more about use of hyperthermia in treating cancer.

NCI – hyperthermia 

Hyperthermia and breast cancer (Video)

Hyperthermia as cancer therapy article

Cancer treatment Centers of America – local hyperthermia

An expensive book on hyperthermia  (May I borrow it if you decide to buy it?)

New approaches to hyperthermia

In much of the prior work whole body hyperthermia is done by immersing the patient in hot baths, wrapping him in warm blankets etc.

More recently new approaches have been suggested for raising body temperature.  For example, it has been suggested that if metallic nano particles (very tiny particles of metals such as gold) are attached to targeted drugs such as Rituxan, it might be possible to tag CLL cells with these metal particles, which can then be heated to higher temperature by means of radio-frequency fields.  Anyone who has used a microwave oven knows better than to put a metalcontainer in there and switch on the microwave.  In this approach we are proposing tagging the CLL cells with tiny metal particles (the CLL specific tagging is brought about by Rituxansince it targets only B-cells carrying the CD20 marker).  Turn on the RF field and every B-cell tagged with a metal particle will cook to a much higher temperature and get killed.

Low tech approaches to hyperthermia

As I said above, whole body hyperthermia can be very dangerous without medical supervision. But how about heating only small sections of your body to higher temperature?  Using heated poultices to reduce pain and increase healing is an ancient practice.  Many “alternate medicine” sites talk about heated castor oil packs effective in shrinking swollen nodes.  Much is made of the need for castor oil of a particular level of purity etc.

Frankly, I think the same effect can be achieved by using a small electric heating pad or hot water bottle.  As long as you are careful not to give yourself a burn by jacking up the temperature too high, a heating pad kept at a nice warm clip held in place for an hour or so can possibly heat up the local CLL cells in the swollen lymph node to the point where they are more likely to die.  The role of the castor oil is merely to increase the thermal capacity of the bundle of rags soaked with it, so the whole mess stays warm for quite a while.  You can get the same effect without the mess by using a warming pad or hot water bottle.

How about vigorous exercise? 

Heat stroke is a concern primarily during hot weather, but even in the relatively cool environmental temperature of 50 F, healthy marathon runners can have body temperatures as high as 103.8 F.  One runner who was still conscious is reported to have developed a temperature of 107.8 F after finishing a marathon, but most people cannot tolerate temperatures that high.

I cannot conclude this article without a tip of the hat to our exercise jock and Rituxan poster boy Malcolm.  I have lost count of the number of times Malcolm has had single agent Rituxan therapy.  This single drug has been sufficient to keep Malcolm out of trouble for 7 – 8 years now.  The other bit of the puzzle?  Malcolm insists of biking to and from the doctors office.  20 miles of biking at a good clip is surely sufficient to get Maloclm’s body nicely heated, right about the same time as his CLL cells are being attacked by the Rituxan.  Way to go Malcolm! It seems he has developed his own technique for getting synergy between Rituxan therapy and whole body hyperthermia.

Did Lance Armstrong win multiple grueling Tours de France races becasue his testicular cancer was cured, or was his testicular cacner cured because of all the high intensity exercise involved in preparing for the races and winning them?  Which came first, the chicken or the egg?  I wonder if anyone kept track of Lance’s body temperature after one of his marathon biking sessions.  Must have been toasty in there, way too hot for testicualr cancer cells I would think.

If regular and vigorous exercise helps kill CLL cells, terrific.  If all it accomplishes is improve your metabolism, make your heart and lungs that much stronger, give you that youthful look you have always wanted, what is not to like?