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War on cancer.

Scientists at Duke University have come up with an ingenious new treatment for one of the deadliest of all cancers, glioblastoma multiforme (GBM) of the brain. It consists of a dendritic cell (DC) vaccine, which is conditioned not with cancer cells but with a modified form of the ordinary tetanus vaccine.

This "double vaccine" study was the subject of a 16page report in Nature (Mitchell 2015) and many laudatory articles in the news.

"Patients with glioblastoma usually survive for little more than one year. However, in patients who received the immunotherapy, half lived nearly five years or longer from their diagnosis," said John Sampson, MD, of Duke University Medical Center, who oversaw the study, according to NBC News.

Typically, to make a DC vaccine, scientists remove a bit of the tumor, then "pulse" it with white blood cells, to create a plethora of dendritic cells, which are then injected back into the body. This is a standard treatment for prostate cancer (Provenge) and is available experimentally for other cancers in clinical trials or at foreign CAM clinics.

Dendritic cells are also known as "antigen-presenting cells." They hold up examples of a desired target to the killer portion of the immune system. They especially occur in parts of the body that are in contact with the external world, such as the skin, nose, lungs, stomach, and intestines. Although part of the more primitive innate immune system, they also serve as a link to the more evolved adaptive immune system. They are called dendritic cells because they resemble the branching structure of dendrites, or nerve cells. (The word dendron in Greek means "tree.") But, to avoid confusion, we should point out that they have no particular relationship to the nervous system.

Dendritic cells were first discovered and described in the 19th century by Paul Langerhans, who also discovered the "Isles of Langerhans" that produce insulin in the pancreas. Because of their appearance, he thought that they were nerve cells. It was only a century later that Ralph Steinman, MD, of Rockefeller University, New York, described the true function of the dendritic cells in immunity. He was awarded the William B. Coley Prize in 1998 (linking his name to that of the American founder of cancer immunotherapy). He won the Nobel Prize in 2011 for "his discovery of the dendritic cell and its role in adaptive immunity." In an odd twist of fate, Steinman died of pancreatic cancer just three days before the Nobel Committee announced the award. The Nobel Prizes cannot be awarded posthumously. But since the committee did not know about his death, it agreed to give the prize (and prize money) to his widow.

Using this combination of DCs and the tetanus vaccine, Duke researchers were able to bring about long-term progression-free survival in 3 out

of 6 of the patients who received the tetanus-treated DC. None of the patients who received the ordinary, or "unpulsed," DC survived to the 40-month mark. Obviously, the great weakness of this study is the small number of patients. It will have to be repeated in a much larger group in order to be widely accepted. But there are some tentative conclusions that can be drawn from this, with implications for the field of complementary and alternative medicine (CAM).

Glioblastoma is somewhat different from other cancers. It often contains large amounts of cytomegalovirus (CMV). This is a virus that is present in many individuals, without causing symptoms. It is not clear if CMV causes the cancer or is merely a hitchhiker. In either case, scientists can use CMV as a target, a way of homing in on infected cells. The Duke team has been using anti-CMV antibodies to target these cancer cells, and it has worked somewhat. They extended average survival from 12 to 18 months. Duke scientists decided to add a tetanus shot to the treatment, in order to generally boost the patient's immunity. After receiving standard surgery, radiation, and chemotherapy, the patients also got this combination of DCs and tetanus. The tetanus was the same one that anyone would receive after stepping on a rusty nail.

This general stimulation of the immune system significantly improved the outcome of the treatment. Patients who received the tetanus booster lived more than 26 months on average. One patient has lived 8 years now after being told that she had about 3 months to live.

"What we think is going on is that this tetanus booster vaccine does such a good job at putting the immune system at high alert ... acting like a siren to the rest of the cells," said Kristen Batich, MD, of Duke University, lead author on the study. "And so the immune system knows to look for the next incoming danger signal. In this scenario it would be our immunotherapy vaccine that's specific for the brain tumors in these patients."

DCs are both very promising and very frustrating. Sometimes they seem to have major positive effects in cancer patients. Steinman reputedly kept himself alive for 5 years with pancreatic cancer using DCs as a major part of his treatment. However, DCs, as usually produced, "have shown limited promise" in advanced cancer, including in GBM (Palucka 2012; Liau 2005; Yu 2004).

The reader may notice that conventional cancer treatment is in some ways edging closer and closer to the holistic philosophy preached and practiced at CAM clinics for decades. Thus, glioblastoma patients in the current trial are receiving a judicious combination of surgery, radiation, chemotherapy, dendritic cell immunotherapy, and now a nonspecific immune stimulation with tetanus vaccine. We have also seen increased interest in such things as the Novocure electrical device and a ketogenic diet. All of these can help. Thus, on both sides of the CAM divide, we are moving "beyond the magic bullet" (to use Dr. Raymond Chang's book title) and seeking a synergistic suite of treatments, individualized for the particular patient, that can bring about a better outcome than any single treatment alone.

CAM clinics in Europe and Mexico have been using DCs for over a decade. Not one of these would think of giving DCs alone, without also doing everything in its power to enhance the general immune response. This would include local-regional as well as whole-body heat therapy, and various stimulatory substances, such as medicinal mushrooms, mistletoe products, and low doses of interleukin-2 (IL-2).

There are some advantages of getting involved in a clinical trial, such as the one at Duke. They are less expensive for the patient and often easier to get to. However, if you go to clinicaltrials.gov and enter the words dendritic cells and tetanus, you come up with only one open study whose status is known, and that is the Duke study. But there are drawbacks. First of all, at this writing, "This study is not yet open for participant recruitment." But GBM is not a disease that allows for any delays in treatment.

Second, although this is a phase II study, patients will in fact be randomized to receive either the ordinary DCs or the new tetanus-enhanced treatment. This randomization is understandable from a scientific point of view, but it leaves up to half the patients with what almost certainly will be an inadequate treatment. Treatment at a clinic that can give a combination of DCs and immune stimulants might be a better option for many people, especially those who cannot get into desirable clinical trials.

Exercise and Cancer Survival

A few years ago, I published an article on the value of exercise in survival from brain cancer. Research in the authoritative Journal of Clinical Oncology showed that working out on an exercise bike for 30 minutes per day prolonged survival, even in those with aggressive forms of brain cancer such as gliomas (Ruden 2011). The study in question looked at 243 patients who had advanced recurrent malignant brain tumors. Those who exercised briskly and regularly lived on average about 22 months compared with just 13 months for those who were less active. This level of activity was equivalent to walking briskly for 30 minutes 5 days per week. The authors concluded: "Exercise behavior was an independent predictor of survival" (Ruden 2011).

This is no small claim!

"Numerous studies show exercise lowers fatigue and enhances physical function for cancer patients, but we wanted to look at whether exercise fundamentally is associated with the risk of cancer progressing or coming back," said Lee W. Jones, PhD, senior author on the study (Ruden 2011). And indeed it did.

At the time, Jones was an exercise scientist and associate professor at Duke Cancer Institute in Durham, NC. (He is now at Memorial Sloan Kettering Cancer Center, New York.) It would be a good bet for patients to contact a physical therapist who can help them strengthen their muscles and launch an exercise program, where appropriate. The American Physical Therapy Association (APTA.org) is a good first place to begin looking. Health insurance often pays for physical rehabilitation.

A 2013 study at Dana-Farber Cancer Institute, Boston, has extended these findings to another common cancer. The study looked at 237 colon cancer patients who first had a resection of their stage III disease. The authors then measured physical activity 6 or so months after the completion of therapy and 14 months after surgical resection, but before any recurrent disease was detected. The primary end point of the study was these patients' survival time after recurrence (Jeon 2013).

Patients who engaged in more intensive physical activity (measured in what are called metabolic equivalent task, or MET, time per week) showed a statistically significant trend for increased survival after recurrence. There was a 29% reduction of death in this group. Interestingly, survival "was not significantly modified by sex, body mass index (BMI), number of positive lymph nodes, age, baseline performance status, adjuvant chemotherapy regimen, or recurrence-free survival period" Oeon 2013). In other words, it appears to be a result of the increased level of activity. In 2012, scientists at the National Cancer Institute surveyed the cancer literature, looking for an association between exercise and survival in cancer. They concluded:

There was consistent evidence from 27 observational studies that physical activity is associated with reduced all-cause, breast cancer-specific, and colon cancer-specific mortality. There is currently insufficient evidence regarding the association between physical activity and mortality for survivors of other cancers. Randomized controlled trials of exercise that included biomarker endpoints suggest that exercise may result in beneficial changes in the circulating level of insulin, insulin-related pathways, inflammation, and, possibly, immunity; however, the evidence is still preliminary (Ballard-Barbash 2012).

Exercise is of course very important in diabetes, prediabetes, and metabolic syndrome. So once again we see the link between these conditions and cancer.

It's a cliche to say so, but patients should talk to their physicians before beginning any exercise regimen. That is especially important in this case since, particularly if one already has had heart problems, aerobic exercise might make things worse. Anecdotally, many of us know people who had heart attacks or even died after suddenly starting a vigorous exercise program after being sedentary for a long time. A study by Jones (2014) showed an increase in all-cause mortality or hospitalization at 2 years in some cancer patients who were doing aerobic exercise. But, with that caveat in mind, it is a fair bet that exercise and general physical activity would benefit most people with various kinds of cancer.

References

Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(11):815-840. doi:10.1093/jnci/djs207.

Jeon J, Sato K, Niedzwiecki D, et al. Impact of physical activity after cancer diagnosis on survival in patients with recurrent colon cancer: Findings from CALGB 89803/Alliance. Clin Colorectal Cancer. 2013;12(4):233-238. doi:10.1016/j.clcc.2013.06.005.

Jones LW, Douglas PS, Khouri MG, et al. Safety and efficacy of aerobic training in patients with cancer who have heart failure: an analysis of the HF-ACTION randomized trial. J Clin Oncol. 2014;32(23):2496-2502. doi: 10.1200/JC0.2013.53.5724.

Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015. doi:10.1038/nature14320.

Liau LM et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005; 11:5515-5525.

Ruden E, Reardon DA, Coan AD, et al. Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma. J Clin Oncol. 2011 ;29(21):2918-2923. doi:10.1200/ JCO.2011.34.9852.

Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nature Rev Cancer. 2012;12:265-2 77.

Yu JS et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64:4973-4979.

by Ralph Moss, PhD

www.cancerdecisions.com

2015 Ralph W. Moss, PhD

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.
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Date:Jun 1, 2015
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