Cancer, Cryoablation, Naturopathic medicine, Botanicals, Saponins, Abscopal effect, Ovarian cancer/naturopathic protocol, PD-L-1 inhibitors, Autovaccination

Curmudgeon’s Corner

Autovaccination of Cancer

Jacob Schor ND, FABNO, with Tina Kaczor ND, FABNO

I recently had the opportunity to collaborate in the care of a cancer patient with my colleague Tina Kaczor and wish to summarize the treatment plan we created and explain the rationale behind it.

Dr. Kaczor is chief editor of the Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National College of Natural Medicine in Portland, Oregon, and completed a residency in naturopathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. Kaczor received dual undergraduate degrees in biochemistry and English from the State University of New York at Buffalo.

For many years she practiced in Eugene, Oregon, but has recently opened a practice in Portland called Round Table Cancer Care (http://www.roundtablecancercare.com) that focuses on providing advice and service to people with cancer who are in desperate straits and need good advice.

I met Dr. Kaczor when we served together on the board of the Oncology Association of Naturopathic Physicians (OncANP). We both have taken our turns as president of that association. Also, for nearly a decade we have worked together on The Natural Medicine Journal and, while we have separate areas of responsibility, have excuse for frequent interaction. She is on my short list of smart and inspiring colleagues.

Our mutual patient was treated for breast and ovarian cancer in close sequence nearly three years ago but was recently diagnosed with a recurrence of the later, a single detectable lesion tucked between liver and kidney. The word lesion is a euphemism of course; it is ovarian cancer that returned and she had another tumor. The tumor because of its location would have been challenging to reach surgically and radiation therapy would have caused considerable collateral damage to surrounding organs. Radiofrequency ablation was considered; but in the end, the medical oncologist and the patient opted to use cryoablation. Both Dr. Kaczor and I saw this as an opportunity we should try and take advantage of.

Cryotherapy is the use of extreme cold to destroy abnormal tissue. Cryosurgery can be used to treat both external and internal tumors. To treat internal tumors, liquid nitrogen or argon gas is circulated through a hollow instrument called a cryoprobe that is placed in contact with the tumor. Ultrasound or MRI is used to guide the probe’s placement. A ball of ice forms around the probe, freezing nearby cells, which die as they thaw.¹

Cryoablation presents an interesting opportunity to patients with cancer. While freezing provides a relatively benign way to destroy localized tumors, it offers something else; it releases relatively intact antigenic material derived from the cancer cells into circulation that, in turn, may trigger an immune reaction in which the body’s own defense system fights the cancer. The fragments of the tumor cells killed by freezing act as a self-made vaccine against the cancer, what, in the medical literature, is now being called auto-vaccination. In this way, cryoablation may lead to a spontaneous regression.² Dr. Kaczor and I asked ourselves if we could increase the likelihood of this happening?

Figuring out how to trigger a spontaneous tumor regression is kind of the Holy Grail in alternative cancer care.

Tumors that spontaneously regress are sometimes referred to as St. Peregrine’s tumor after Peregrine Laziozi (1265-1345), a young priest who healed from cancer as if by a miracle. Peregrine had a severe cancerous lesion in his leg, which became infected and then disappeared.³ St. Peregrine is, for good reason, considered the patron saint of cancer patients. His may be the earliest report of a spontaneous tumor regression, but it is far from the only one. Over the years, a substantial body of literature has been published in the medical journals, case reports of specific patients who for unclear reasons have had their tumors go away. Some of us read and collect these reports, (Dr. Kaczor is among that group), hoping to make sense of why this happens.

It seems that earlier in history such reports were more common than now, and virtually all of the reports note concomitant infections including diphtheria, gonorrhea, hepatitis, influenza, malaria, measles, smallpox, syphilis, and tuberculosis.² Could our modern decreased exposure to severe infectious disease be reducing these miraculous occurrences?

Writing in early 2017, D. Alan Potts from the University of Washington summed up a literature review on spontaneous remission:

The physiology of spontaneous remission remains unknown, although several proposed mechanisms exist. One leading hypothesis involves stimulation of an antitumor response from the host immune system, particularly immune activation secondary to infection or injury. Activation of antitumor immunity subsequent to local tissue injury and inflammation from a biopsy has been suggested previously in the literature…⁴

The reoccurring theme that we see in the reports is that spontaneous regressions of cancer are associated with infection or injury; sometimes just a biopsy of the tumor is enough to be the trigger. We are hoping that cryoablation may serve as the trauma that triggers the immune reaction. More importantly, the resultant dead cells may provide antigenic material so that the immune system learns to recognize the cancer.

The best-documented modern treatment instigated immune responses have come secondary to radiotherapy treatments used in palliative care. These reactions are often referred to be the term ‘abscopal effect.’

Knowledge of this abscopal effect goes back for over half a century; radiation oncologists have been well aware that localized radiotherapy can on rare occasion trigger “out-of-target tumor responses” so that tumors elsewhere in the body, areas that were not treated with radiation, shrink. This process is thought to be mediated “… by the immune system leading to immunogenic tumor cell death, a process which involves dendritic cells, T regulatory cells, and suppressor cells as critical mediators…. targeted radiotherapy in the proper setting can produce a consistent and robust abscopal effect, thus delivering clinically meaningful anti-tumor responses and disease control, if not eradicating distal disease in patients with metastatic cancer.”⁵ As well known as this is to radiation oncologists, we haven’t heard much talk about it in the natural medicine world. This sounds like a similar mechanism that is used to account for most, if not all, spontaneous remissions.

A 2007 case report of this abscopal effect leading to regression in ovarian cancer, was of particular interest to us as this is the type of cancer our patient has.⁶

Cryoablation is thought to be potentially more effective at triggering these immune stimulatory effects than radiation or radiofrequency ablation.⁷ Frozen cells after death may retain more antigenic potential. Heather Zwickey PhD, who teaches research and immunology at National University of Natural Medicine (NUNM) in Portland, confirmed this idea in an email: “We definitely saw more [antigenic] presentation with freezing than any other method of cell destruction.”⁸

The question then for Dr. Kaczor and myself was how could we increase the likelihood that such an immune reaction might occur in our patient?

One strategy that came to mind is through adjuvants. During the manufacture of vaccines, seemingly extraneous chemicals are frequently added to the mix. These specific chemicals, known as adjuvants, increase the likelihood that the immune system will learn to recognize and attack the disease antigens contained in the vaccine. Adjuvants are inexpensive compared to the actual bacterial or viral fragments in the vaccine, which are expensive to produce. Think of adjuvants as a trick to make a vaccine work better for less money. The phrase ‘kicking the hornets’ nest’ comes to mind in connection with adjuvants. These extra chemicals are selected because they arouse the immune system to respond to the disease antigen more vigorously.

A variety of substances are used as adjuvants. Many of the odd chemicals on the vaccine ingredient lists that cause us all sorts of consternation are included just because of their adjuvant action. Aluminum is probably the most widely used adjuvant. Not all adjuvants are nasty chemicals; there are a number of natural substances that can serve this purpose. One category of natural adjuvants, the saponins, have been singled out as being particularly effective at triggering immune responses, in particular when trying to create anti-tumor responses from the immune system’s dendritic cells. One paper we read reported that “…combining

saponin-based adjuvants with in situ tumor destruction leads to an extremely potent systemic anti-tumor response

.” In other words, giving a saponin adjuvant in conjunction with the destruction of a tumor is a potentially simple way to trigger an immune reaction.^9,10

Saponins, as many of you probably realize, are chemical components found in many plants. The two of particular interest to us are ginseng and astragalus. A third phyto-saponin also of interest, South American quillaja, has been developed into a drug (QS-21) and has been tested in a number of human clinical trials. As of 2002, this drug version of quillaja had been tested in more than 3000 patients in 60 clinical trials. At this time, though, we can’t find a legal source approved for human use. There was a concern that QS-21 may be risky in humans, though a 2016 meta-analysis of clinical trials did not confirm this worry and should eventually dispel most worries.¹¹ QS-21 is already used in veterinary medicine.

Ginseng and astragalus, on the other hand, are quite available, have a long and safe record of use and most importantly, are effective saponin adjuvants.^12-15 Viewing these herbs as adjuvants that stimulate immune reactivity to antigens may provide us with a new way to understand the mechanism of action these herbs may have in cancer that was previously unclear. We should probably re-examine some of the classic herbal cancer formulas and evaluate their saponin content; they may be acting as adjuvants increasing the possibility of auto-vaccination. Such formulas may have been unfairly discounted because they have no in vitro cytotoxic action; the benefit may only become apparent ex vivo and in combination with a procedure that caused tumor injury.

Thus, Dr. Kaczor and I suggested to our patient that she promptly start taking significant doses of both astragalus and ginseng, after determining that we could not easily acquire either quillaja or the drug made from it.

Standard vaccinations offer us another way to stimulate the immune system to elicit an immune response. Vaccines contain both antigenic material against the target disease plus adjuvants. There are reported cases of spontaneous remission of cancer following vaccination and a number of clinical trials in progress administering vaccines to treat cancer.

A case of metastatic melanoma was reported in 2013 to have disappeared in a patient after receiving DPT vaccine. DPT had been reported in 2011 to have an in vitro effect against melanoma.^16,17 Rabies vaccine has been linked with regression of melanoma, cervical cancer, and glioma. Dr. Zwickey suggested we try Yellow Fever vaccine. Dr. Kruzel has long used diptheria vaccinations in his cancer patients.¹⁸ Tuberculosis, of course, is another possibility; and BCG, tuberculosis, has long been used to treat bladder cancer.¹⁸

The other angle that comes to mind in order to elicit an immune response targeting tumor cells is through PD-F-1 inhibition. Check point inhibitor drugs that are being researched to treat cancer are now being used in combination with radiation in the hope of triggering abscopal effects more reliably.¹⁹ Yet the chance of we naturopathic doctors getting such drugs prescribed easily is a challenge as this strategy is still thought to be outside of a standard of care.

It is worth noting that a few minutes after writing the preceding paragraph, a patient relayed a conversation with their medical oncologist at Dana-Farber Cancer Institute in Boston. The doctor described the possibility of enrolling in a clinical trial that combined targeted radiation therapy of a single tumor lesion along with administration of the immunotherapy drug Keytruda (Pembrolizumab). There are quite a few clinical trials of this sort in progress. That is something of an understatement: a May 2017 review of these trials listed 18 trials using radiation in combination with CTLA-4 inhibitors, 51 trials combining radiation with PD-L-1 inhibitors, and five more that combine radiation with either a TGF-β blockade or GM-CSF.²⁰ There is a degree of excitement about this. Those counts may be conservative. Searching ClinicalTrials.gov today just for “pembrolizumab and radiation” yields 81 current clinical trials.²¹ The patient, well actually the patient’s sister, summed up the Dana-Farber doctor’s description of the trial for me:

They know that if they give pembrolizumab on its own for people who have estrogen positive breast cancer, it works less than 5% of the time. It’s not a very good drug. The theory is that if you break up the tumor with radiation and then give immunotherapy, it’s like giving your body a vaccine. You break up the cancer with radiation, like in a blender, then boost immune system, and because you zapped the tumor, the immune system can see the tumor better. The theory is that if your body learns how to recognize the caner that got radiated, then it should recognize the other cancer in your body because it’s an immune reaction.²² END QUOTE

There are two natural substances we know of that inhibit PD-1 or PD-L-1, the mushroom Coriolus versicolor²³ and the yeast extracts beta glucan.²⁴ With this thought in mind, we added both to our proposed protocol for our patient who underwent cryoablation. We also added curcumin based on a 2015 paper that combined liposomal curcumin with cryotherapy in treating mice who had been given triple negative breast cancer. That combination proved to be significantly more effective at reducing cancer metastasis than either approach alone.²⁵ There are other published examples of curcumin enhancing anti-cancer immune responses to vaccines, including BCG against bladder cancer²⁶ and mage-b vaccine against TNBC.²⁷

Townsend Letter readers will recall that I typically encourage patients to either fast or practice fairly significant caloric restriction to enhance the benefit of chemotherapy. But in situations where we are hoping to trigger an auto-vaccination response we are not suggesting this; in fact, we may want to do the opposite. While the evidence isn’t clear, there are hints from animal studies that high protein diets will enhance the kind of immune response we want to occur while low protein diets, which lower IGF-1, may inhibit the desired response.^28-30 Thus, rather than caloric restriction for this patient, we encouraged a significant increase in animal protein and a caloric intake aimed at maintaining current body weight.

Thus, we ended up with a relatively simple natural protocol to consider in patients with cancer tumors who are being treated with radiotherapy, radiofrequency, or especially cryoablation. In these situations, we suggest a combination of astragalus, ginseng, coriolus, beta glucan, liposomal curcumin, along with a wide range of vaccinations in particular diphtheria, yellow fever, Tb, and even possibly rabies. If the patient has been practicing caloric restriction prior to this, we specifically encourage a diet that is high in protein and of adequate calories.

A Few Other Things

Heather Zwickey reminded us that hydrotherapy may aid in triggering an immune response. Gurdev Parmar, ND, reminded us that hyperthermia treatments can be very effective at activating immune responses (and which our patient is currently doing).³¹ Both Drs. Zwickey and Kaczor think that Coley’s Toxins could be helpful, though Dr. Schor pointed out that this would change the protocol from easy and accessible to both esoteric and risky. Might a protocol like this also be helpful after biopsy of solid tumors? Should we consider these ideas during any adjuvant radiation? We cannot offer answers to these and other basic answers yet.

The bottom line: Multiple lines of information, from case histories of spontaneous remission, to knowledge of vaccination biology, to the abscopal effect of radiation therapy, and to modern PD-L1 drug development have led us to a view that offers exciting possibilities. Our view of localized tumor treatment has taken a dramatic shift; it is an opportunity to take advantage of.

References

1. https://www.cancer.gov/about-cancer/treatment/types/surgery/cryosurgery-fact-sheet. Accessed May 24, 2017

2. Jessy T. Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med. 2011 Jan;2(1):43-9.

3. Pakhmode VK. Understanding the possible mechanisms of spontaneous regression of oral cancer. J Oral and Maxillofac Pathol. 2007;11:2–4.

4. Potts DA, et al. Spontaneous Remission of an Untreated, MYC and BCL2 Coexpressing, High-Grade B-Cell Lymphoma: A Case Report and Literature Review. Case Rep Hematol. 2017;2017:2676254.

5. Ng J, Dai T. Radiation therapy and the abscopal effect: a concept comes of age. Ann Transl Med. 2016 Mar; 4(6): 118.

6. Fujiwaki R, Sawada K. Spontaneous regression in recurrent epithelial ovarian cancer. Arch Gynecol Obstet. 2007 May;275(5):389-91. Epub 2006 Dec 20.

7. Karpan BM. [Clinical picture and complex treatment of primary and metastatic hepatic cancer]. [Article in Ukrainian] Lik Sprava. 2006 Apr-May;(3):3-10.

8. Email, 5-1-2017

9. den Brok MH, et al. Saponin-based adjuvants create a highly effective anti-tumor vaccine when combined with in situ tumor destruction. Vaccine. 2012 Jan 17;30(4):737-44.

10. Skene CD, Sutton P. Saponin-adjuvanted particulate vaccines for clinical use. Methods. 2006 Sep;40(1):53-9.

11. Bigaeva E, et al. Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability. PLoS One. 2016 May 5;11(5):e0154757.

12. Abdullahi AY, et al. Vaccination with Astragalus and Ginseng Polysaccharides Improves Immune Response of Chickens against H5N1 Avian Influenza Virus. Biomed Res Int. 2016;2016:1510264.

13. Li R, et al. Enhanced immune response to foot-and-mouth disease vaccine by oral administration of ginseng stem-leaf saponins. Immunopharmacol Immunotoxicol. 2016 Aug;38(4):257-63.

14. Yuan D, et al. Vaccine adjuvant ginsenoside Rg1 enhances immune responses against hepatitis B surface antigen in mice. Can J Physiol Pharmacol. 2016 Jun;94(6):676-81.

15. Su X, et al. Ginsenoside Re as an adjuvant to enhance the immune response to the inactivated rabies virus vaccine in mice. Int Immunopharmacol. 2014 Jun;20(2):283-9.

16. Tran T, et al. Spontaneous regression of metastatic melanoma after inoculation with tetanus-diphtheria-pertussis vaccine. Curr Oncol. 2013 Jun;20(3):e270-3.

17. Lee JS, et al. Deoxypodophyllotoxin Induces a Th1 Response and Enhances the Antitumor Efficacy of a Dendritic Cell-based Vaccine. Immune Netw. 2011 Feb;11(1):79-94.

18. Kucerova P, Cervinkova M. Spontaneous regression of tumour and the role of microbial infection–possibilities for cancer treatment. Anticancer Drugs. 2016 Apr;27(4):269-77.

19. Sindoni A, et al. Combination of immune checkpoint inhibitors and radiotherapy: Review of the literature. Crit Rev Oncol Hematol. 2017 May;113:63-70.

20. Kang, J, et al. Current clinical trials testing the combination of immunotherapy with radiotherapy. Journal for ImmunoTherapy of Cancer. 2016;4:51.

21. https://clinicaltrials.gov/ct2/results?term=radiation+and+keytruda&Search=Search

22. Private communication May 27, 2017 with patient AC

23. Huang R, et al. Immunomodulatory effects of polysaccharopeptide in immunosuppressed mice induced by cyclophosphamide. Mol Med Rep. 2013 Aug;8(2):669-75.

24. Hunter KW, et al. Microparticulate beta-glucan upregulates the expression of B7.1, B7.2, B7-H1, but not B7-DC on cultured murine peritoneal macrophages. Immunol Lett. 2004 Apr 30;93(1):71-8.

25. Chandra D, et al. Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer. Oncoimmunology. 2015 May 29;5(1):e1049802.

26. Kamat AM, et al. Curcumin potentiates the antitumor effects of Bacillus Calmette-Guerin against bladder cancer through the downregulation of NF-kappaB and upregulation of TRAIL receptors. Cancer Res. 2009 Dec 1;69(23):8958-66.

27. Singh M, et al. Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1.C ancer Med. 2013 Aug;2(4):571-82.

28. Matsumura K, et al. [Antitumor immunity in the relatively early period after cryosurgery. Experimental study using rat’s metastasizing mammary tumor]. [Article in Japanese] Nihon Geka Gakkai Zasshi. 1983 Nov;84(11):1130-7.

29. Artioli LF, et al. Decreasing the frequency of energy supplementation from daily to three times weekly impairs growth and humoral immune response of preconditioning beef steers. J Anim Sci. 2015 Nov;93(11):5430-41. doi: 10.2527/jas.2015-9457.

30. Moriel P, Arthington JD. Metabolizable protein supply modulated the acute-phase response following vaccination of beef steers. J Anim Sci. 2013 Dec;91(12):5838-47.

31. Mukhopadhaya A, et al. Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity. Cancer Res. 2007 Aug 15;67(16):7798-806.

Authors

• 
  Jacob Schor, ND, FABNO

  Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies,  nutrition, and cancer (https://drjacobschor.wordpress.com/). He was a board member of CoAND and past president of OncANP, and is someone who is happier outdoors than inside.

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• 
  Tina Kaczor, ND

  Tina Kaczor, ND, FABNO, is editor in-chief of Natural Medicine Journal and the creator of Round Table Cancer Care. Kaczor is a naturopathic physician board certified in naturopathic oncology. She received her naturopathic doctorate from the National University of Natural Medicine and completed her residency at Cancer Treatment Centers of America. She is also the editor of the Textbook of Naturopathic Oncology and cofounder of The Cancer Pod, a podcast for cancer patients, survivors, caregivers, and everyone in between.

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