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Immune Modulation for Treatment of Cancer

Author: Hamid Izadi

Affiliation: University of Waterloo
Date Published: Tuesday October 24th, 2006 @ 23:43:53 EST

Comments: No comments
From Category: Immunology

Abstract

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.

Natural Antibodies

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.

Purified Complement

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).


References

1. Boes M. Role of natural and immune IgM antibodies in immune responses.
Mol Immunol. 2000 Dec;37(18):1141-9.

2. Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J. A critical role of natural
immunoglobulin M in immediate defense against systemic bacterial infection.
J Exp Med. 1998 Dec 21;188(12):2381-6.

3. Tlaskalová-Hogenová, H., L. Mandel, R. Stepánková, J. Bártová, R. Barot, M.
Leclerc, F. Kováru, and I. Trebichavsky. 1992. Autoimmunity: from physiology to
pathology. Natural antibodies, mucosal immunity and development of B cell repertoire.
Folia Biol. (Praha). 38: 202-215

4. Bracy JL, Cretin N, Cooper DK, Iacomini J. Xenoreactive natural antibodies.
Cell Mol Life Sci. 1999 Dec;56(11-12):1001-7.

5. Tough DF, Chow DA. Natural antibody recognition of v-H-ras-induced 10T1/2
transformation. Nat Immun Cell Growth Regul. 1991;10(2):83-93.

6. Wang H, Chow DA. Protein kinase C expression links natural antibody binding with
surveillance of activated and preneoplastic cells. Scand J Immunol. 1999 Apr;49(4):381-
90.

7. Koda K, Nakajima N, Saito N, Yasutomi J, McKnight ME, Glassy MC. A human
natural antibody to adenocarcinoma that inhibits tumour cell migration. Br J Cancer.
1998 Nov;78(10):1313-22.

8. Gimmi CD, Morrison BW, Mainprice BA, Gribben JG, Boussiotis VA, Freeman GJ,
Park SY, Watanabe M, Gong J, Hayes DF, Kufe DW, Nadler LM. Breast cancerassociated
antigen, DF3/MUC1, induces apoptosis of activated human T cells. Nat Med.
1996 Dec;2(12):1367-70.

9. Rosenstein Y, Theelen M, Sanchez I, Celis E. Isolation, purification, and
characterization of a mouse plasmacytoma cell surface glycoprotein involved in the
resistance of the tumor cells to immune destruction. J Natl Cancer Inst. 1985
Mar;74(3):609-16.

10. Lu P, Sharom FJ. Immunosuppression by YAC-1 lymphoma: role of shed
gangliosides. Cell Immunol. 1996 Oct 10;173(1):22-32.

11. Tanaka F, Otake Y, Nakagawa T, Kawano Y, Miyahara R, Li M, Yanagihara K, Inui
K, Oyanagi H, Yamada T, Nakayama J, Fujimoto I, Ikenaka K, Wada H. Prognostic
significance of polysialic acid expression in resected non-small cell lung cancer. Cancer
Res. 2001 Feb 15;61(4):1666-70.

12. Morgan BP. Regulation of the complement membrane attack pathway.
Crit Rev Immunol. 1999;19(3):173-98.

13. Matsumoto M, Takeda J, Inoue N, Hara T, Hatanaka M, Takahashi K, Nagasawa S,
Akedo H, Seya T. A novel protein that participates in nonself discrimination of malignant
cells by homologous complement. Nat Med. 1997 Nov;3(11):1266-70.

14. Gorter A, Meri S. Immune evasion of tumor cells using membrane-bound
complement regulatory proteins. Immunol Today. 1999 Dec;20(12):576-82.

15. Leyland-Jones B, Smith I. Role of herceptin(®) in primary breast cancer: views
from north america and europe. Oncology. 2001 Oct;61 Suppl S2:83-91.

16. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications.
Br J Cancer. 2001 Nov;85(11):1619-1623.

17. Green MC, Murray JL, Hortobagyi GN. Monoclonal antibody therapy for solid
tumors.
Cancer Treat Rev. 2000 Aug;26(4):269-86.

18. Hellstrom I, Hellstrom KE, Evans CA, Heppner GH, Pierce GE, Yang JP. Serummediated
protection of neoplastic cells from inhibition by lymphocytes immune to their
tumor-specific antigens. Proc Natl Acad Sci U S A. 1969 Feb;62(2):362-8.

19. Bansal SC, Hellstrom KE, Hellstrom I, Sjogren HO. Cell-mediated immunity and
blocking serum activity to tolerated allografts in rats. J Exp Med. 1973 Mar
1;137(3):590-602.

20. Tamura M, Takakuwa K, Arakawa M, Yasuda M, Kazama Y, Tanaka K.
Relationship between MLR blocking antibodies and the outcome of the third pregnancy
in patients with two consecutive spontaneous abortions.
J Perinat Med. 1998;26(1):49-53.

21. Gentile T, Margni RA. IgG asymmetric anti-ovalbumin antibodies synthesized by
virgin and pregnant rats. J Reprod Immunol. 1995 Jan;28(1):1-13.

22. Bansal SC, Bansal BR, Boland JP. Blocking and unblocking serum factors in
neoplasia.
Curr Top Microbiol Immunol. 1976;75:45-76.

23. Grosen EA, Yamamoto RS, Ioli G, Ininns EK, Gatanaga M, Gatanaga T, DiSaia PJ,
Berman M, Manetta A, Granger GA. Blocking factors (soluble membrane receptors) for
tumor necrosis factor and lymphotoxin detected in ascites and released in short-term
cultures obtained from ascites and solid tumors in women with gynecologic malignancy.
Lymphokine Cytokine Res. 1992 Dec;11(6):347-53.

24. Song E, Chen J, Ouyang N, Su F, Wang M, Heemann U. Soluble Fas ligand released
by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of
immune evasion in colon cancer. Br J Cancer. 2001 Sep;85(7):1047-54.

25. Mizutani Y, Hongo F, Sato N, Ogawa O, Yoshida O, Miki T. Significance of serum
soluble Fas ligand in patients with bladder carcinoma. Cancer. 2001 Jul 15;92(2):287-93.

26. Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased soluble CD95 (sFas/CD95)
serum level correlates with poor prognosis in melanoma patients. Clin Cancer Res. 2001
May;7(5):1282-6.

27. Ocvirk J, Stabuc B, Rudolf Z, Galvani V, Curin-Serbec V. Serum values of tumour
necrosis factor-alpha and of soluble tumour necrosis factor-R55 in melanoma patients.
Melanoma Res. 2000 Jun;10(3):253-8.

28. Sinha R, Gupta SC, Naithani YP. Cellular immune profile and T-lymphocyte
blocking factors in cancer of the head and neck and their prognostic significance.
Indian J Cancer. 1985 Mar;22(1):8-16.

29. Loni C, Ricci S, Azzara A, Bertoncini G. Circulating immune complexes in patients
with lymphoproliferative and myeloproliferative diseases Quad Sclavo Diagn. 1984
Jun;20(2):193-202.

30. Lentz MR. Continuous whole blood UltraPheresis procedure in patients with
metastatic cancer. J Biol Response Mod. 1989 Oct;8(5):511-27.

31. Chu CT, Pizzo SV. Alpha 2-Macroglobulin, complement, and biologic defense:
antigens, growth factors, microbial proteases, and receptor ligation.
Lab Invest. 1994 Dec;71(6):792-812. Review

32. Harthun NL, Weaver AM, Brinckerhoff LH, Deacon DH, Gonias SL, Slingluff CL
Jr. Activated alpha 2-macroglobulin reverses the immunosuppressive activity in human
breast cancer cell-conditioned medium by selectively neutralizing transforming growth
factor-beta in the presence of interleukin-2.
J Immunother. 1998 Mar;21(2):85-94.

33. Lauer D, Muller R, Cott C, Otto A, Naumann M, Birkenmeier G. Modulation of
growth factor binding properties of alpha2-macroglobulin by enzyme therapy. Cancer
Chemother Pharmacol. 2001 Jul;47 Suppl:S4-9.

34. Asplin IR, Wu SM, Mathew S, Bhattacharjee G, Pizzo SV. Differential regulation of
the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for
selective modulation of FGF-2-induced angiogenesis.



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