Many malignant cells (such as those found in breast and stomach cancer) develop a tumor marker called the Thomsen-Friedenreich (T) antigen. This antigen is suppressed in normal healthy cells, much like a rock is covered over by water at high tide. T antigen only becomes 'unsuppressed' as a cell moves towards malignancy, much like the covered rock in our example becomes uncovered as the tide moves out. It is so rare to find the T antigen in healthy tissue, that we actually have antibodies against it. It is even more rare to find a Tn antigen on a healthy cell.
It has been estimated that in about 90% of all cancers and some leukemias, T and Tn antigens are expressed and uncovered. As a general rule, an orderly expression of T antigens on a cancer cell usually indicates a cancer with a relatively favorable outlook. However, a prevalence of Tn antigens (Note: Tn Antigen is actually a precursor to T antigen or a less well developed T antigen) on a cancer cell usually denotes a highly aggressive, metastatic cancer irrespective of organ or type of cancer.
Healthy cells do not normally express the T or Tn antigen, which are 'encrypted' or covered up by polysaccharides much the same way that a rock is covered by water at high tide. In malignant or pre-malignant cells, the ability to synthesize the polysaccharides which normally cover the T antigen is often lost, which causes T to be 'expressed' or uncovered, much like a falling tide will often uncover previously hidden rocks at a low tide.
Cancer cells differ radically from healthy cells in the fine architecture of their "cell surfaces". Think in terms of a healthy cell surface looking like a yard, with well-groomed bushes, shrubs, and flowers. A cancer cell looks like someone had taken a chain saw to the yard and leveled the bushes, shrubs, and flowers down to their stumps. So, in a very simplistic way, a cancer cell clearly looks like a different yard when observed by an outside observed (your immune system in this case).
In this example, the T and Tn antigens are the stumps found in cancer, while the well-groomed yard has bushes, shrubs, and flowers, that correspond to the ABO markers and other antigens found on healthy cells. The difference between the yards is largely because a cancer cell is unable to completely assemble a normal, healthy cell membrane structure like a blood type ABO antigen.
As a general rule, well-differentiated cancers usually have a preponderance of T antigens and less of the Tn antigens. However, as a cancer cell becomes poorly differentiated, Tn antigen expression predominates. One of the functions of these T and Tn antigens is to promote cancer cell adhesion----the ability for the cancer cell to stick to other cells including healthy cells. This process of adhesion is a critically important part of cancer cell invasion and metastasis. Everyone has preexisting anti-T and anti-Tn antibodies, or a built in immune system response against cells with these markers. These anti T and TN-antibodies are primarily induced by intestinal flora.
- Springer GF. T and Tn pancarcinoma markers: autoantigenic adhesion molecules in pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy. Crit Rev Oncog 1995;6(1):57-85
Anti T(Tn) Antibodies
All humans normally possess antibodies that react with the Thomsen-Friedenreich (T) and the Tn antigens.
Anti-Thomsen Freidenreich antibodies (TFA) are typically IgM class antibodies. The most common induction of TFA is through the gut; many gram negative organisms induce TFA.
T and Tn Antigens Structurally Similar to Blood Group A
The Thomsen-Friedenreich (T) antigen and Tn antigen show some structural similarity to the A antigen (even though it is derived from the M blood type antigen). Not surprisingly, blood type A individuals have the least aggressive antibody immune response against the T and probably Tn antigens. In fact, the T and Tn antigens, and blood type A antigens are actually immunologically considered to be quite similar because of their shared terminal sugar (N-acetylgalactosamine), and so might be readily confused by the immune system of blood type A individuals.
This finding has led researchers to conclude that the Tn antigen is an A-like antigen in a broad sense. So the hypothesis goes that because of the lower level of antibody against T and Tn antigens or stumps, and because of this tendency for the immune system of A's to be a bit confused or disinclined to attack Tn antigens, blood type A is at an immunologic disadvantage in attacking any cell bearing these T and Tn antigenic markers.
- Hirohashi S. Tumor-associated carbohydrate antigens related to blood group carbohydrates. Gan To Kagaku Ryoho 1986 Apr;13(4 Pt 2):1395-401
- Kurtenkov O, Klaamas K, Miljukhina L, et al. The lower level of natural anti-Thomsen-Friedenreich antigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype. Int J Cancer 1995 Mar 16;60(6):781-785
Blood-group-A cancer patients had the greatest and uniform suppression of the level of TFA agglutinins, irrespective of age, cancer stage or tumor morphology, and lower levels of anti-B isohemagglutinins. This is probably at least a part of the explanation for the poorer outcomes in many cancers among blood type A individuals.
This has been demonstrated in breast cancer, where a substantially greater amount of cancer patients (as compared with healthy non-cancer controls) have depressed levels of anti-T antibody.
- Springer GF, Desai PR, Scanlon EF. Blood group MN precursors as human breast carcinoma-associated antigens and "naturally" occurring human cytotoxins against them. Cancer 1976 Jan;37(1):169-76
T and Tn are exuberantly expressed in cells of the stomach which turn cancerous. Curiously, about 1/3 of all Japanese express some T antigen in apparently normal stomach tissue. (44) However, this may also help explain why stomach cancer rates in Japan are among the highest in the world. Since gastric juice is typically loaded with blood type antigens anyway, it is not unlikely that type A and AB would be at a disadvantage at recognizing the T antigens as cancer markers - and even if they do, would not likely mount much of an antibody response against them.
Neo Springerism: Typhoid Vaccine and T(Tn) Antigen
Georg F. Springer, MD, spent over 20 years harnessing the potential of the immune system to combat cancer. Although his treatments were outside of the mainstream, he was anything but (coming from a very traditional medical and research background). Originally, a pioneer in work with blood group antigens, Springer dedicated his life and his unique expertise to breast cancer after his wife died from this disease. His work eventually led him to the development of what is known as "Springer's Vaccine" and his reported five and ten-year survival rates for stage II, III, and IV breast cancer with this novel T (Thomson-Friedenreich) and Tn antigen therapy are nothing short of amazing when compared against standard treatments.
Springer's work capitalized on this difference between healthy and cancerous cells and his knowledge of the immune system to create a vaccine, which specifically stimulated the immune system to fight cells with these stumps (T and Tn antigens). His vaccine consisted of three parts: 1) chemically degraded O-group blood cells (providing T and Tn antigens), 2) the Salmonella typhii vaccine or typhoid vaccine (which contains T and Tn antigens), and 3) calcium phosphate (he believed the T and Tn antigens could stick to this).
His protocol entailed giving his vaccine to patients subcutaneous (under the skin), initially at 6-week intervals, eventually extending the gap to 12 weeks. For people receiving chemotherapy, he would wait 3 to 4 weeks after cessation of the last round of chemotherapy prior to beginning his treatment. In the case of radiation, he would wait 1 to 3 months after the last dose of radiation prior to initiating treatment. He recommended that his patients receive this vaccine "ad infinitum".
Springer passed away in the spring of 1998 and the vaccine he used with such great results is, as far as we know, currently unavailable. The S. typhii vaccine, a component of his vaccine, however, is readily available.
As a public health measure, the typhoid vaccine is readily available. Dosing schedule is usually 2 injections, 1 month apart. A booster is usually recommended every 3 years. The vaccine should never be given during pregnancy and during an active infection. It should also not be until about 1 month after the last dose of chemotherapy, or 1-3 months after the last dose of radiation (for people using these interventions).
This vaccine is generally very well tolerated; however, occasionally some flu-like symptoms will occur and persist for 1-2 days following the vaccination. Localized redness, swelling, and discomfort can occur at the injection site (this is probably more likely to occur in people with an active cancer) and may last 1-2 days.
While this vaccine cannot be expected to produce the outcomes Springer appeared to be achieving, it is one of the only options possibly promoting increased amounts of T and Tn antibodies. As such it offers a potential to work in an area that is ignored in most cancer protocols. This vaccine is safe for all blood types.
Springer's work was truly ahead of its time. Perhaps someday it will be widely embraced and used, until that day we are left with the typhoid vaccine (as a poor man's/woman's substitute) and a legacy giving us a new insight into immunity, cancer, and the elegant architecture of a breast cancer cell.
The injectable vaccine should not be administered to:
- Persons with a history of hypersensitivity to any component of the vaccine (Vi antigen, isotonic buffer or phenol).
- Immunization should not be given in the event of a fever or severe infection.
- The vaccine should not be given to children under the age of 2 years.
Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy.
Springer GF. J Mol Med 1997 Aug;75(8):594-602
Aberrant glycosylation is a hallmark of cancer cells. The blood group precursors T (Thomsen-Friedenreich) and Tn epitopes are shielded in healthy and benign-diseased tissues but uncovered in approx. 90% of carcinomas. T and Tn glycoproteins are specific, autoimmunogenic pancarcinoma antigens. These antigens may also be found in neoplastic blood cells (and on LTV-II infected T lymphocytes).
Fundamental chemical and physical aspects of these glycoproteins of primary carcinomas are discussed first. Tn and T epitopes are cell and tissue adhesion molecules, essential in invasion by and metastasis of carcinoma which includes adherent and proliferative phases. These properties are then delineated next, followed by consideration of pathophysiological and clinical aspects of these antigens. Immunohistochemical studies of the extent of Tn antigen expression in primary breast carcinoma demonstrate it highly significant correlation with clinicopathological tumor stages, and hence its value as a reliable prognosticator. On the other hand, there is no significant, prognostically useful association between T antigen expression and clinical disease course. Everyone has "preexisting" anticarcinoma anti-Tn and anti-T antibodies, induced predominantly by the intestinal flora, while cellular immune responses to T and Tn epitopes are evoked only by carcinomas and some lymphomas. Carcinoma dedifferentiation leading to predominance of Tn over T epitopes is described, as is the role of Tn and T epitopes in very early, including preclinical, carcinoma detection. The highest sensitivities in carcinoma detection are for preclinical and the earliest clinical stages.
Obviously, preclinical carcinoma detection is of practical importance. T/anti-T tests detected preclinical carcinoma in 77% of 48 patients long (mean 6 years) before their biopsy/X-ray results became positive. There were no false predictions of carcinoma in 38 control persons with benign diseases (observation average 4.8 years). These findings open a novel window for both curative approaches and pathophysiological studies. The autoimmunogenicity of carcinoma T/Tn antigen led us more than two decades ago to begin intradermal vaccination of patients with advanced breast carcinoma of stages IV-IIb, predominately after modified radical mastectomy and sometimes lumpectomy plus axillary dissection always followed by adjuvant radio/chemotherapy.
The vaccine consists of human group O red blood cell membrane derived, HLA-free T/Tn antigen containing as adjuvant Ca3(PO4)2 plus a trace of phosphoglycolipid A hyperantigen, i.e., S typhi vaccine (USP), which itself has T and Tn specificities. Our efforts have now for up to 20 years remained successful in a large majority of the 32 patients. All 32 patients survived at least 5 years; 10-year survival was statistically highly significantly improved (5-year survival: P < 1 x 10(-7); 10-year survival: P < 1 x 10(-5)) compared to statistics of the United States National Cancer Institute. Because these vaccinations are successful, their extension to large populations with major types of carcinomas should be considered, and even immunological carcinoma prevention may be contemplated.
Thomsen-Friedenreich-related carbohydrate antigens in normal adult human tissues: a systematic and comparative study.
Cao Y, Stosiek P, Springer GF, Karsten U. Max Delbruck Centre for Molecular Medicine, Berlin-Buch, Germany.
Histochem Cell Biol 1996 Aug;106(2):197-207
A broad variety of normal human tissues were examined for the expression of Thomsen-Friedenreich (TF)-related histo-blood group antigens, TF (Gal beta 1-3GalNAc alpha 1-R), Tn (TF precursor, GalNAc alpha 1-R), sialosyl-Tn (NeuAc alpha 2-6GalNAc alpha 1-R), considered to be useful in cancer diagnosis and immunotherapy, and sialosyl-TF, the cryptic form of TF. These antigens or, more correctly, glycotopes, were determined by immunohistochemistry with at least two monoclonal antibodies (mAbs) each (except sialosyl-TF) as well as by lectin histochemistry. For a better dissection of sialosyl-TF and TF glycotopes, tissue sections were pretreated with galactose oxidase or the galactose oxidase-Schiff sequence. Staining with mAbs appeared to be more restricted than with the lectins used. Distribution patterns among normal epithelia were different for all four antigens. These antigens were also detected in some non-epithelial tissues. They can be classified in the following sequence according to the frequency of their occurrence in normal tissues: sialosyl-TF > > sialosyl-Tn > Tn > TF. Most of the positively staining sites for TF, Tn, and sialosyl-Tn are located in immunologically privileged areas. The complex results obtained with anti-TF mAbs (after treatment of the tissue sections with sialidase from Vibrio cholerae) and the lectins amaranthin and jacalin revealed a differential distribution of the subtypes of sialosyl-TF [NeuAc alpha 2-3Gal beta 1-3GalNAc alpha 1-R and Gal beta 1-3 (NeuAc alpha 2-6)GalNAc alpha 1-R] in normal human tissues. From our data it can be inferred that TF, Tn, and sialosyl-Tn are promising targets for a cancer vaccine.
T and Tn pancarcinoma markers: autoantigenic adhesion molecules in pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy.
Springer GF. Heather M. Bligh Cancer Research Laboratories, Department of Microbiology-Immunology, Chicago Medical School, IL 60064, USA. Crit Rev Oncog 1995;6(1):57-85
Physical and chemical nature of the T and Tn pancarcinoma [CA] glycopeptide epitopes [EPs], which are immediate precursors of the blood group MN EPs, and their role in CA pathogenesis and in clinical disease are discussed. T/Tn are immuno-occluded in non-CA diseased and in healthy tissues. Well-differentiated CAs usually express a higher proportion of T than Tn EPs, while Tn predominates in poorly differentiated primary CAs. Measurement of density of T and Tn EP expression on primary breast CA permits disease prognostication. CA-T and -Tn are cell adhesion molecules involved not only in invasion but also in metastasis. Immunological methods readily detect in vivo autoimmune responses to CA-T and -Tn EPs in about 90% of all CA patients from incipience and throughout. Everyone has preexisting anti-T and anti-Tn antibodies [Abs] induced by the intestinal flora. T/anti-T immunoassays are highly efficient in detection of incipient and clinically overt CAs and, importantly, predicted CA in 77% of the patients, months to many years before their biopsy/X-ray turned positive; there were no false immune predictions of CA. Since 1974, we use human O MN red cell-derived T/Tn glycoprotein vaccine plus adjuvants successfully in safe, specific, effective, long-term, active immunotherapy against recurrence of advanced breast CA pTNM Stages IV, III, and II.
T/Tn antigen vaccine is effective and safe in preventing recurrence of advanced breast carcinoma.
Springer GF, Desai PR, Spencer BD, Tegtmeyer H, Carlstedt SC, Scanlon EF. Cancer Detect Prev 1995;19(4):374-80 Heather M. Bligh Cancer Research Laboratories, Chicago Medical School, IL 60064, USA.
Since 1974, and as of March, 1993, we have used T/Tn antigen vaccine in safe, specific, effective, long-term intradermal vaccination against recurrence of advanced breast carcinoma (CA). Staging is by the pathologic TNM system. Treatment is ad infinitum. Of 19 consecutive breast carcinoma patients vaccinated, six Stage IV, six Stage III, and seven Stage II all survived > 5 years postoperatively. Three Stage III, three Stage IV, and five Stage II patients (i.e.,
11) survived > 10 to > 18 years. Five others are alive but have not reached 10 years; three of them have no evidence of disease (NED). Three patients died of CA before reaching 10 years. An additional three breast CA patients are being treated for > 2 years, but, < 5 years postoperatively, they are NED. The vaccination are presented as a delayed-type hypersensitivity reaction with significant inflammation with increase of helper T lymphocytes and decrease of T suppressor/cytotoxic cell ratio.
Pancarcinoma T/Tn antigen detects human carcinoma long before biopsy does and its vaccine prevents breast carcinoma recurrence.
Springer GF, Desai PR, Tegtmeyer H, Spencer BD, Scanlon EF. H. M. Bligh Cancer Research Laboratories, Chicago Medical School, Illinois 60064.
Ann N Y Acad Sci 1993 Aug 12;690:355-7
Precursors of the blood group MN antigens as human carcinoma-associated antigens.
Springer GF, Desai PR, Murthy MS, Yang HJ, Scanlon EF. Transfusion 1979 May-Jun;19(3):233-49
The lower level of natural anti-Thomsen-Friedenreich antigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype.
Int J Cancer 1995 Mar 16;60(6):781-785 Kurtenkov O, Klaamas K, Miljukhina L, Department of Experimental Oncology, Institute of Experimental and Clinical Medicine, Tallinn, Estonia.
- The TFA is a tumor-associated, blood-group-related glycosidic precursor structure [Gal(beta 1-3)GalNAc]. Its expression in carcinomas is accompanied by a decrease of natural TFA antibodies in serum. The relationship between the ABO(H)-blood-group phenotype and natural anti-TFA immune response in patients with gastric cancer was studied. The level of TFA agglutinins in the sera of patients with gastric cancer and of healthy controls was examined by the hemagglutination of neuraminidase-treated blood-group-O donor erythrocytes. Individuals were classified as weak or strong TFA responders. They were also classified by ABO(H)-blood-group status, age, cancer stage, tumor morphology and level of isohemagglutinins. The proportion of weak TFA responders (WR) in cancer patients was 33, 50, 50 and 20% (for O, A, B and AB blood groups respectively), as compared with 11.7, 14.5, 13.9 and 26.1% for blood-group-related controls. Further analysis showed age-dependence in blood-group-O and -B controls, with a high level of WR in the older group. Blood-group-A cancer patients had the greatest and uniform suppression of the level of TFA agglutinins, irrespective of age, cancer stage or tumor morphology, and lower levels of anti-B isohemagglutinins.
- Baptisia tinctoralis is known to possess Tn like antigenic attributes (Glycoconj J 1995 Feb;12(1):55-62) Interestingly, Baptisia tinctoralis raises anti-typhoid agglutinins. “Baptisia tinctoralis in low dilutions produces a form of antibodies to the bacillus typhosus, i.e. the agglutinins. Thus it raises the natural bodily resistance to the invasion of the bacillary intoxication, which produces the typhoid syndrome.” (Boericke , Pocket Materia Medica)
- Lamium, Salvia and Marrubium species are also known to induce anti-Tn, due to the possessing of anti-Tn specific lectins. (Clin Lab Haematol. 1982;4(4):403-4.) Many colon cancer lines are agglutinated by lectin-producing Salvia species (Tn specific lectins) (Eur J Biochem 2000 Mar;267(5):1434-40)
- Marrubium species tested seem to have anti-tn lectins
- Jacalin binds IgA and Thomsen Friedenreich. Its TF binding inhibits several glycoproteins elaborated by endometrial tissue undergoing disease processes. Major lectin in the seeds and pulp is Jacalin. Jacalin binds IgA and Thomsen Friedenreich. Jacalin produced dose-dependent and non-cytotoxic inhibition of proliferation in human colon cancer cells. (J Cell Physiol 2001 Feb;186(2):282-7)
Lecster: Lectins and other adhesion molecules with Thomsen-Friedenreich specificity