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