Arizona Advanced Medicine Clinic

Metronomic Therapy

Another Option for Cancer Treatment

Tumors are a lot like parasites, and even a little bit like babies, in that they grow and develop in the human body, and are not rejected as foreign by the immune system. For some reason they are tolerated, and even welcomed, by the immune system as a “normal” inhabitant. In the scientific literature this is called “T-cell anergy,” and is caused by our bodies’ immune tolerance of foreign proteins, mediated by a part of our immune system called regulatory T cells (Treg).

Treg cells are those cells which enable us to recognize our own body tissues as belonging to us – and therefore not subject to attack. When a foreign protein invades (pollens, cat or dog dander, chemicals, etc) our bodies respond by mobilizing our immune systems to make antibodies against the foreign particles and destroy them.

When we make excessive antibodies against pollens, we call it “allergy” and treat it with antihistamines and decongestants.

When we make excessive antibodies against chemicals, we call it “multiple chemical sensitivity” (MCS) unless we don’t believe in the existence of MCS, in which case we call it a delusion, and treat it with antidepressant or antipsychotic medication. When we make excessive antibodies against our own body tissues, we call it “auto-immune disease”, “rheumatoid arthritis”, “Crohn’s disease”, “ulcerative colitis”, “Lupus” and treat it with immune suppressant medications like adalimubab (Humira®) or azathioprine (Imuran®) or infliximab (Remicade®).

How is it possible that our bodies, whose main drive is for survival, allow something which will eventually kill them, a tumor, to grow inside them without any kind of effective protest from our immune systems? Why do our immune systems apparently think that tumors are a normal part of our bodies and should not be rejected?

Two conditions are required for a tumor to grow:

  • Cancer cell proliferation – cancer cells have unchecked growth
  • Permissive environment – the environment of the cells allows them to have that unchecked growth

Tackling the permissive environment is a discussion for a different article. It starts with what we allow to come in to our bodies in the way of foods and chemicals and air and cosmetics and emotions.[i] Some of the things that we are exposed to can result in changes or mutation in our DNA. And some of these mutations can allow cells to grow and divide without regard to the rest of the body. This is what we call “cancer”.

Once cancer develops, it is a little late for prevention.

Chemotherapy, the mainstay of current cancer treatment, does not control the growth of new blood vessels (angiogenesis) or tumor-tolerant (tolerogenic) immunity. It only kills rapidly dividing cells – ALL rapidly dividing cells, including cells of the hair, the mouth, the intestinal tract, the skin...

A paper written in 1982 demonstrated that immune unresponsive (anergic) patients could be induced to developed delayed type hypersensitivity (DTH) to injected antigen if they were pre-treated with cyclophosphamide at low dose. “It appears that [cyclophosphamide] CY pretreatment resulted in the development of DTH responses in otherwise unreactive patients. Reversal of the T-cell anergy of advanced cancer could lead to augmentation of the immune response to tumor-associated antigens.”[ii] This was the first recorded demonstration that the treatment would enhance the antigenicity of tumors, and allow the innate immune system to “discover” the tumor and thus make effective antibodies to it.

Study of patients with “poor outcome” tumors (such as unresectable pancreatic cancer, NSCLC and prostate cancer) treated with an “induction” regimen consisting of a low dose of metronomic cyclophosphamide, a high dose of Cox-2 inhibitor, granulocyte colony-stimulating factor, a sulfhydryl (SH) donor, and a blood derivative that contained autologous (self) tumor antigens released from patient tumors into the blood showed improved survival in several different advanced malignancies.[iii] Standard chemotherapy was used along with the special induction regimen, so quality of life and toxicity of the therapy was no different between the two groups. But the survival was better.

If we can somehow break up the “immune tolerance” to cancer cells, then our own immune systems may begin to fight back. It appears that low dose cyclophosphamide can block the renewal of regulatory T cells (Tregs), at least in mice with multiple myeloma, thus enabling the restoration of an efficient immune response against those formerly immune-tolerated cancer cells.[iv]

Cyclophosphamide at low dose augments immune responses against tumors, acting on Tregs and inhibiting their suppressor function.3 Low dose cyclophosphamide (this study used 100 mg, which is four times the dose that is used with IPT chemotherapy) induced a selective reduction of Tregs, restored T-cell proliferation and NK cell killing activity. Cyclophosphamide inhibits Treg cells (CD4+CD25+) so that immunotherapy may be potentially curative.[v], [vi]

Cyclophosphamide is not the only chemotherapeutic agent that can be used in metronomic dosage. Metronomic doses of paclitaxel work in tandem with a cancer vaccine by depleting the Treg population and inhibiting the growth of new blood vessels into a tumor.[vii] This new growth of blood vessels supporting a tumor is called angiogenesis.

Topotecan has also been used. In a mouse model of ovarian cancer, pazopanib (Votrient®) plus metronomic topotecan caused tumor size to regress by 80%, and the mice lived longer.[viii] They were not cured, but they did live longer with their tumors. Pazopanib is a tyrosine kinase inhibitor which makes it anti-angiogenic, like cyclophosphamide. Topotecan is an inhibitor of DNA topoisomerase which helps to repair broken strands of DNA.

A paper written in 2000 describes the use of vinblastine and a vascular endothelial receptor blocker (blood vessel inhibitor) to induce sustained tumor regression, without major toxicity.[ix] This study did not mention the Treg cell issue, only the growth of new blood vessels, and was a study done in tissue culture, not in humans. Other angiogenesis inhibitors include drugs such as thalidomide – which could explain why the limb buds failed to progress to regular arms and legs in the tragic case of the thalidomide babies in the 1950s. An interesting side-note in this paper: “most human cancers are intrinsically resistant to chemotherapy”.

A paper written in 2002 describes the same angiogenesis inhibition effect, this time in treatment-resistant breast cancer patients, using methotrexate and cyclophosphamide in metronomic dose.[x]

As early as 2006 the information was published by the National Cancer Institute, describing the effect of very low dose chemotherapy on the linings (endothelial cells) of the blood vessels supplying solid tumors.[xi] Published papers appeared in other journals as well, occasionally in human trials.[xii] There is still no mention of tumor antigenicity, or of the ability of the body to “discover” tumors as foreign objects, just of disruption of growth of blood vessels.

In a preliminary study of patients with solid tumors refractory to chemotherapy (patients whose tumors continued to grow despite conventional chemotherapy), low dose cyclophosphamide given in a single dose at the same time as injection of an oncolytic (tumor-destroying) adenovirus into the tumor resulted in 53% progression free survival for the group given oral cyclophosphamide, and 42% for the group given oral plus intravenous.[xiii] It is interesting that the lower dose oral group did better than the higher dose oral plus intravenous group.

Regulatory T cells (Treg) are co-opted by tumors, resulting in loss of their guardian function. The Treg cells begin to accept the tumor cells as a “normal” part of the body – much like a “mole” infiltrating an organization with the ultimate goal of taking over that organization.[xiv] Progressive tumor growth promotes growth of tumor suppressor T cells. Treg cells are actively recruited by tumor cells with the ultimate goal of promoting immune tolerance to the tumor, so that the tumor suppressor cells can no longer see anything to suppress.

A similar effect is evoked using beta hyaluronidase in a little-known allergy therapy called LDA, low dose enzyme potentiated antigen therapy.

A single injection of cyclophosphamide depletes the Treg cells in tumor-bearing mice, delays the growth of their tumors, and cures rats bearing established prostate cancer tumors, when followed by an immunotherapy that has no effect when administered by itself.7

In vivo (in living animals), inhibition of inflammatory enzymes (COX-2) reduced Treg cell numbers and activity, and decreased tumor burden, providing evidence that inhibition of inflammation suppresses Treg cell activity and enhances antitumor responses.[xv]

It appears that, while depletion of Treg cells is insufficient in and of itself to destroy a tumor completely, such depletion does enhance anti-tumor immunity by augmenting the sensitization of immune T cells in the draining lymph nodes.[xvi]

IL2 induced anti-tumor immunity is augmented by Treg depletion, and results from tumor infiltration by CD8+ cytotoxic T cells. “Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.”[xvii]

Cancer cells may comprise as little as 30% of the bulk of a tumor.[xviii] The rest is called the tumor environment, or stroma – those tissues which sustain the tumor growth.

There may be a way to predict which patients are going to relapse, based on the proportion of specific immune cells within and around the tumor.[xix] Five-year survival of patients with high densities of CD8+ and CD45RO+ cell was 86%, where there was tumor recurrence in 75% of patients with low densities of these cells, and only 27.5% 5-year survival. The big question is how to measure those levels. Measurement would have to be performed at the time of surgery, on the tissue removed. Identification of patients with high risk of recurrence is important and could be extremely helpful. This method would be less helpful if a new specimen of tissue were required for each measurement of Treg cells.

Recent data demonstrate that tumors actively prevent the induction of tumor-associated antigen-specific immunity through an increase in circulating numbers of of Treg cells.[xx] An elevated number of Tregs in peripheral blood has been demonstrated in several tumor types.[xxi], [xxii] Therapy aimed at decreasing the number of Tregs in the system has been shown to improve survival in melanoma patients.[xxiii] This is the mechanism by which the human monoclonal antibody ipilimumab has its effect.[xxiv]

It is possible through standard laboratory measurements to test a patient’s Treg cells in peripheral blood. A panel of lymphocytes expressing the following markers: CD4+ CD25+Cd127low/- is required.[xxv]

Is metronomic chemotherapy the final answer to eradication of cancer in the body? That would be ideal, but remember that tumor cells mutate constantly – that’s what cancer is all about, mutation of genes to allow the cancer cells to survive. Remember the mice? They survived longer, even if the cancers were metastatic, but they did eventually die of their tumors.

One study on resistant prostate cancer (for which there is no standard chemotherapy) showed a PSA-lowering response, decrease in bone pain (presumably from metastatic disease) and an increase in survival time, without toxicity, using metronomic cyclophosphamide.[xxvi] Another study involving patients with metastatic breast cancer showed one complete response only, but there was partial response in 50% of the patients. Twenty out of twenty-five patients were stable or improved, and only five patients had progression of disease during the period of the study, using a regimen of cyclophosphamide (Cytoxan®), capecitabine (Xeloda®) and bevacizumab (Avastin®).[xxvii] This study found that the number of baseline circulating endothelial cells (CECs – also called Circulating Tumor Cells) was a predictive biomarker for selection of those whom metronomic chemotherapy would help. High CEC count indicates good candidate for therapy.

In conclusion, it appears that metronomic therapy for cancer using continuous low dose cyclophosphamide can be extremely helpful in prolonging tumor-stable (or even tumor-free) life, without any significant toxicity. Why would one not want to use this therapy for all patients with solid tumors? We know that the tumors recur, even if they appear to have been successfully treated in the beginning. Why is this form of therapy not more widely used in conventional oncology?

Call us if you have cancer, and are interested in exploring this form of therapy. We can be reached at 480-240-2600 to schedule a free 15-minute phone consultation to explore your options.

[ii] Berd D, Mastrangelo MK et al. Augmentation of the Human Immune Response by Cyclophosphamide. Cancer Research (November 1982) 42;11:4862-4866.

[viii] Merritt WM, Nick AM et al. Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer. Mol Cancer Ther. 2010 Apr;9(4):985-95. doi: 10.1158/1535-7163.MCT-09-0967

[xi] NCI Cancer Bulletin (June 27, 2006) 3;26

[xiii] Cerullo V, Diaconu I et al. Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus. Mol Ther. 2011 September; 19(9): 1737–1746.

[xiv] Ha T-Y. The Role of Regulatory T Cells in Cancer. Immune Netw. 2009 Dec; 9(6): 209–235. doi: 10.4110/in.2009.9.6.209

[xv] Ibid

[xvi] Tanaka H1, Tanaka J, Kjaergaard J, Shu S. Depletion of CD4+ CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother. 2002 May-Jun;25(3):207-17.

[xviii] Hadrup S, Donia M and Straten PT. Effector CD4 and CD8 T Cells and Their Role in the Tumor Microenvironment. Cancer Microenviron. 2013 Aug; 6(2): 123–133.

[xix] Pagès F, Kirilovsky A et al. In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer. JCO (December 10,2009) 27;35:5944-51. doi: 10.1200/JCO.2008.19.6147

[xx] Cerullo V, Diaconu I et al. Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus. Mol Ther. 2011 September; 19(9): 1737–1746.

[xxii] Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005 Mar 15;65(6):2457-64.

[xxiii] Hodi FD, O’Day S et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010; 363:711-723 (August 19, 2010) DOI: 10.1056/NEJMoa1003466

[xxiv] Romano E, Kusio-Kobialk M et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A. 2015 May 12; 112(19): 6140–6145.

[xxv] Yu N, Li X, Song W, Li D, Yu D, Zeng X, Li M, Leng X, Li X. CD4(+)CD25 (+)CD127 (low/-) T cells: a more specific Treg population in human peripheral blood. Inflammation. 2012 Dec;35(6):1773-80. doi: 10.1007/s10753-012-9496-8.

[xxvii] Dellapasqua S, Bertolini F, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol. 2008 Oct 20;26(30):4899-905. doi: 10.1200/JCO.2008.17.4789.