Described is a method of immunomodulation cancer patients, according to some ideas
proposed in the 1960s which I have tried to bring up to date. According to this novel
treatment method the patient is treated with individualized doses of three biological
solutions: 1) Natural Antibody, 2) Purified Complement, and 3) Alpha-2 macroglobulin.
Natural antibodies are obtained from healthy volunteers and a portion of these antibodies
are postulated to possess anti-tumor activity. Purified complement will increase the
efficacy of the natural antibodies in destruction of tumors. Alpha 2-macroglobulin will
neutralize the immune suppressive effects of the cancer in order for the natural antibody
to effectively destroy its target.
This type of antibody is an innate form of immune response, which is produced by a
specialized type of B cell called the B-1 cell (1). These antibodies recognize molecular
targets that evolutionarily been a “danger” to the host such as bacterial antigens (2,3). In
addition, it is natural antibodies which cause hyperacute rejection of xenotransplants (4).
Such antibodies have been described against cells expressing mutated oncogenes such as
ras (5), against activated protein kinase C (6) and against human adenocarcinoma cells
(7). If naturally occurring antitumor antibodies exist then why do people still get cancer?
The problem lies in part on the ability of the cancer cells to mutate and alter their surface
molecule at a rate higher than that which immune cells can recognize and kill. Several
molecules are upregulated on cancer cells in order to protect them from antibody
responses these include, mucins (8), sialic acids (9) and gangliosides (10). In many
cases, altered expression of these molecules correlates with poor prognosis (11).
Therefore a therapeutic intervention would focus on not only administration of anti-tumor
antibody but also a cofactor to increase efficacy. The cofactor in this case is purified
Complement proteins are a family of zymogens which are activated in a cascade type
manner after binding of antibody to antigen. Antibody mediated destruction of target
cells occurs with the final step of the complement cascade in which a pore is made into
the membrane of the target cell by the assembled proteins. The pore forming aggregation
of complement proteins, called the membrane attack complex, lyse the cell by creating
osmotic disbalance (12). Additionally, the complement cascade can be activated by
tumor cells directly, in absence of antibody (13). Some tumor cells try to block
formation of the membrane attack complex by expressing membrane-bound complement
regulatory proteins which accelerate the rate of complement degradation (14). Therefore
administration of complement proteins, may be useful alone, or in combination with
antibodies to the tumor.
The question here is what portions of the complement cascade should be added to this
combination therapy so to increase therapeutic benefit without causing systemic toxicity.
Once a standard cocktail of purified complement proteins is established, this combination
will be useful in together with currently used antibody mediated treatments, such as
Herceptin for breast cancer (15) or rituximab for lymphoma (16). Presently researchers
are searching for novel means to increase efficacy of these two drugs (17).
Alpha-2 Macroglobulin for Blocking the Blockers
Tumor secreted immune blocking factors have been well described in the literature. The
pioneers of this field were Karl and Ingrid Hellstrom who demonstrated that natural
inhibitory ability of immune cells to block cancer cell proliferation was block by factors
in the serum of patients with cancer (18). Such blocking factors have also been
demonstrated in the sera of rodent transplant recipients which are tolerant to their
allografts (19) as well as in the sera of pregnant women (20). Depending on the situation,
several such blocking factors have been identified at a molecular level. These include
non-complement fixing assymetrical antibodies (21), antigen-antibody complexes (22),
soluble tumor necrosis factor receptor (23), and soluble fas ligand (24). The importance
of tumor secreted blocking factors in demonstrated by association between such factors
and poor prognosis (25-29). Removal of blocking factors by ultrapheresis was
demonstrated to induce a more than 50% reduction in tumor size in 3/16 patients with
metastatic cancer (30).
Removal of blocking factors from the blood of cancer patients is very important in any
cancer therapy. Although very little is known about naturally occurring de-blocking
factors, a possible de-blocking factor is alpha 2-macroglobulin. This molecule is found
in human serum and is responsible for binding activated proteases and recycling them to
the liver where they are degraded (31). In 1998, Harthun et al demonstrated alpha 2-
macroglobulin can block the immune suppressive effects of proteins secreted by breast
cancer cells (32). Transforming growth factor beta, an immune suppressive cytokine
made by cancer cells, is also inactivated by alpha 2-macroglobulin (33). Interestingly
alpha 2-macroglobulin also seems to inhibit activity of basic fibroblast growth factor, a
protein which stimulates cancer cell proliferation and angiogenesis (34).
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