Publications

Publications Related to OncoPherese
In 1989 a paper was published in the Journal of Molecular Biotherapy titled “The Phylogeny of Oncology.” In this paper, originally written in 1982, it was proposed that there were soluble inhibitors of normal immune function, based on a review of evolutionary biology, that exist in nature for the purpose of vertebrate type of reproduction where a seemingly intact, normal immune system must become tolerant of foreign tissue so that pregnancy can occur and be successful. The article proposed an immune similarity between the immunology of pregnancy and the immunology of cancer. (3)

It was discovered over 20 years ago that cancer cells are protected in cancer patients by their ability to produce and secrete decoy receptors/inhibitors. They accumulate in the microenvironment surrounding each cancer cell and protect it from the normal immune response of the patient. This important finding was first announced in a series of articles in prestigious scientific journals Cell, Lymphokine Research (now the Journal of Lymphatic Research and Biology) and the Proceedings of the National Academy of Sciences (5, 6, 8, 9). The discovery was officially announced at the Keystone symposium in Keystone Colorado in January, 1990.

In 1994 the British Journal of Cancer (15) confirmed these findings and published histologic proof that the cancer cells were blanketed by these inhibitors. Stromal cells that support the growth of certain cancers such as breast cancer were also seen to overproduce these inhibitors thus augmenting the necessary immune blockade essential for the tumor cells to survive.

Later in that same year the most distinguished medical journal of all, The Lancet, published findings demonstrating that the higher the level of these inhibitors in a patient the shorter was his survival, and conversely, the lower these inhibitors are in the patient the longer the survival

Similar findings were reported a few years later in the European Journal of Cancer. They concluded that these inhibitors represent a prognostic factor in cancer patients. “We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 (soluble TNF-R1 or -R2 inhibitor) in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (SICAM-1 / INTERCELLULAR ADHESION MOLECULE 1). Significantly raised sTNF-R1 levels were detected only in patients with metastatic melanoma compared with normal controls, whereas sTNF-R2 levels were increased both in primary and metastatic melanoma. A correlation between sTNF-Rs and SICAM-1 concentrations in patients’ sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumor progression.” (12)

A 2010 article in the journal Clinical Chemistry and Laboratory Medicine reported independent evidence that sTNF-R1 concentrations are a powerful predictor of outcome in breast cancer. The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer. The authors measured circulating cytokines and soluble cytokine receptors in breast cancer patients including interleukin 6, tumor necrosis factor-alpha, soluble tumor necrosis factor receptor type 1 and 2 (sTNF-R1, sTNF-R2), interleukin 1 receptor antagonist (IL- 1Ra), interleukin 10 (IL-10), macrophage colony stimulating factor (M-CSF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and followed them for ten years. Both sTNF-R levels were shown to be the most useful marker in predicting poor prognosis. The conclusion was: “a significant value of pre-treatment serum sTNF-Rs concentrations, next to stage and estrogen receptors expression, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer…. Serum sTNF-R1 may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.” The probable reason for poor survival in women with breast cancer who have elevation of these inhibitors is that their immune systems are more inhibited than women with low inhibitors and the cancer is more free to grow. (22)

The same phenomenon was documented in patients with metastatic sarcomas. The Journal of Surgical Oncology stated: “We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors specifically soluble tumor necrosis factor receptor 1 and 2 with clinicopathological features and survival of patients with bone sarcomas.” The conclusion was ”These cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.” (23)

A 2010 article published in the journal Tumor Biology found the same phenomenon in patients with colorectal cancer. Their conclusions were most striking: sTNF-R1 , IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF-R1 was found elevated in the greatest percentage of all CRC patients, in the greatest proportion of stage 1 patients and presented the best diagnostic sensitivity. In addition, the sTNF-R1 level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor. (24)

Another article published in the same journal concluded that this elevation of TNF inhibitors is similar in metastatic solid tumors in general:

“…for the soluble tumor necrosis factor (TNF) receptors type 1 (p55) and type 2 (p75) and IL-2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors, plasma levels of TNF receptor p75 and Il-2 receptor were not significantly different from the controls.” (13)

A study published about the same time in the journal Oncology made the same case for non-small cell lung cancer (NSCLC) along with an interesting comparison to the standard blood tumor markers: “…increases in IL-6, IL-8 and sTNF-R1 were noted in the greatest proportion of stage 1 patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers….” (25)

A very important study published in the journal Cellular Immunology summarized the science behind immune unblocking. In this study the investigators blocked the decoy effect of soluble tumor necrosis factor receptor type 1 (sTNF-R1) with neutralizing antibodies and observed tumor resolution. Their data led them to this conclusion – “These data demonstrate that sTNF-R1 directly influences tumor formation and persistence in vivo and suggests that the selective removal and /or inactivation of sTNF-R1 is a promising new avenue for cancer immunotherapy.” (18)

Clinical Application & Clinical Experience

It is very clear that a logical clinical strategy is to remove these shed receptor inhibitors (sTNF-Rs) so that the immune system can effectively attack cancer cells. Methods and systems have been evolving since the late 1980’s to accomplish this clinical goal. This has been a journey of technical discovery and invention. There have today been more than 15 generations of the medical technology, each an improvement on its predecessor.

Pre-clinical work was published in the Proc. Nat. Acad. Sci. and documented that the inhibitors could be successfully filtered out of the patient’s blood by a newly invented medical technology termed “Ultrapheresis™”. “Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro.”

The investigators proceeded to show that the blocking factor is derived from malignant cell membrane TNF receptors. They further observed that: “Purified BF blocks the lytic (malignant cell destroying) activity of recombinant human and mouse TNF-alpha…. The BF has an important role in interactions between the tumor and the host antitumor mechanisms….” (9)

The first human application of the Ultrapheresis™ – a blood filtration technique that targets proteins in blood based on their molecular size – was conducted in 1987 and published in the Journal of Biologic Response Modifiers in 1989. The name of this journal was later changed to Journal of Immunotherapy. (2)

In this classical Phase I study, 16 patients with metastatic cancers of various types were treated with repetitive Ultrapheresis™. The procedure provoked a low-grade fever and general flu-like feeling. Evidence of tumor-specific inflammation was observed: redness, swelling and inflammatory pain. There was objective tumor regression in 50% of these patients and 3 suffered very rapid tumor breakdown. Subjective improvement in general physical condition and sense of well-being was reported in the majority of cases (65%). Although survival was not a study parameter, 9 of the 16 survived for more than a year and 6 of the 16 for more than two years. This was considered clinically significant in that an inclusion criterion at study entry was that patients had previously failed all other standard therapies and in the opinion of their referring physicians had a life expectancy of less than 6 months.

Multiple technical improvements were subsequently made to the Ultrapheresis™ technology, leading to improved clinical outcomes.

A paper by Lentz et al published in 1997 in Japanese Journal Apheresis found that the best clinical responses where achieved in those patients who attained the lowest post-treatment inhibitor levels. This article concluded “finding… a circulating inhibitor to TNF and LT that is significantly elevated in patients with cancer, suggests a paradigm for cytokine regulation. It strongly suggests that the immune response is dynamic, and as such, the quantity of a particular cytokine in the patient may not be as important to influencing a cancer at the regulatory stage upon which cytokines and inflammatory cells act. It suggests further that the immune mediated inflammatory response is homeostatically regulated in nature, and that future therapeutic strategies in tumor immunology must respect the balance between cytokines, cells and their respective inhibitors/receptors.” These data and others led to the development of another technological improvement: immune adsorption. (17)

The development of selective adsorption of immune inhibitors produced far greater reduction of the levels of these inhibitors and obviated the need for replacement fluid for the patients. This improvement made the clinical treatment safer and more effective.

Another paper published by Lentz et al in 1999 in Therapeutic Apheresis and Dialysis documented the emerging insights and outstanding outcomes with a variety of cancer patients that were already being accomplished: “Immunosuppression is a hallmark of advanced malignancies in man. Over the past 40 years, many investigators have identified soluble immunosuppressive factors in blood, serum, ascitic fluid, and pleural fluid from cancers in man and other species. Suppressive factors have also been identified that are specifically produced by tumors…[Following removal of these factors via Ultrapheresis™] an improvement in patient performance status, clinical symptoms and reduction of tumor size has been observed.”

In 2008, further advances in clinical outcomes were reported by Lentz et al in Therapeutic Apheresis and Dialysis. (19):

“Mean reduction in sTNF-R1 (48%), sTNF-R (55%), and sIL-2R levels (72%) were observed in patients from before to after [OncoPherese]….”

Clinical findings indicated tumor inflammation and necrosis in most patients. Treatment effects included low-grade fever, transient flu-like symptoms, tumor pain along with tumor redness, warmth, tenderness and edema. All such effects are evidence of tumor-specific immune attack. The OncoPherese immune adsorbent column demonstrated increased efficacy in terms of improved reduction of plasma sTNF-R1, sTNF-R2, and sIL-2R levels compared with the previous Ultrapheresis™ treatment.

Clinical experience to date has demonstrated significant responses in a variety of metastatic cancers. Major responses, defined as more than 50% tumor reduction by standardized criteria, have been documented in metastatic cancers including breast, non-small cell lung, melanoma, colon, prostate, soft tissue sarcoma, pancreatic, renal and ovarian, as well as primary tumors of the brain.

The best responses have been observed in patients who appear to have the least compromised immune systems – i.e. least amount of prior chemotherapy – as well as the best nutritional status and least amount of weight loss.

The fact that anti-tumor activity is seen in such a diverse group of tumors following OncoPherese supports the idea of a common immune inhibitory mechanism active in all solid-tumor cancers.

We must now await prospective clinical trials at multiple clinical sites focused on multiple cancer types to determine the true response rates in individual tumor types, duration of response and true impact on survival. Additionally, we must continue to research the underlying causal factors triggering emergence of malignancies in the first place and promoting their recurrence.

The papers cited above are selected from a much larger body of literature. The following is the relevant bibliography (note that some papers have download links):

1. Israel, L., Edelstein, R.: In vivo and in vitro studies on nonspecific blocking factors of host origin in cancer patients. Role of plasma exchange as an immunotherapeutic modality. Isr J Med Sci 1978; 14:105-30
2. Lentz, M. R.: Continuous Whole Blood UltraPheresis Procedure in Patients with Metastatic Cancer. Journal Biologic Response Modifiers, 8:511-527, 1989. PDF-Download 3.34 MB
3. Lentz, M. R.: Phylogeny of oncology, Molecular Biotherapy, 2:137-144, Sep 1990. PDF-Download 1.95 MB
4. Lentz, M .R., Saltonstahl, W.P.: Apheresis of low molecular weight protein fraction and the onset of labor. Journal of Clinical Apheresis, 5:62-67, 1990.
5. Lentz, M.R.: Description and identification of a new inhibitor to NK-cell function and to TNF mediated killing in the serum and ultrafiltration of sera from cancer patients. Proceedings Keystone Symposium, UCLA, Feb 1990.
6. Gatanaga, T., Lentz, M.R., Masunaka, I., Tomich, J., et al.: Identification of TNF – LT blocking factors in the serum and ultrafiltrates of human cancer patients. Lymphokine Research, 9:225-229, 1990. PDF-Download 2.21 MB
7. Brocklous M, Schoenfield HJ, Laetscher H: Identification of two types of tumour necrosis factor receptors on human cells lines by monoclonal antibodies. Proc Natl Acad Sci 1990; 87: 31271131.
8. Schall, T. J., Lewis, M., Gatanaga, T., Granger, G.A., Lentz, M.R., et al.: Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell, 61:361 – 370, April 20, 1990. PDF-Download 759 KB
9. Gatanaga,T., Lentz, M.R., Tomich, J.: Purification and characterization of an inhibitor (soluble Tumor necrosis factor receptor ) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proceedings National Academy of Science USA, 87:8781 – 8784, November, 1990. PDF-Download 920 KB
10. Aderka D., Engelmann H., Hornik V, Skornick Y., Levo Y., Wallach D., Kushtai G.: Increased serum levels of soluble receptors for tumor necrosis factor in cancer. Cancer Res 1991 751 :5602-5607. PDF-Download 349 KB
11. Olssoon, I., Gatanaga,T., Gulberg, U., Lentz, M.R., Granger, G.A.: Tumor necrosis factor (TNF) binding proteins (soluble TNF receptor forms) with possible roles in inflammation and malignancy. Euro Cytokine Network, 4:169-180, 1993.
12. Denz H, Orth D, Fuchs D: Serum soluble tumor necrosis factor receptor 55 is increased in patients with haematological neoplasms and is associated with immune activation and weight loss (soluble tumor necrosis factor 55 is sTNF-R1). Eur J Cancer 1993; 29A:2232-2235.
13. Elsasser-Beile, U., Gallati, H., Weber, W., Wild, ED, Schulte Monting, J. , von Kleis, S.: Increased plasma concentrations for type I and II tumor necrosis factor receptors and IL-2-receptors in cancer patients. Tumour Biol 1994; 15:17-24
14. Langkopf, F., Atzpodien, J.: Soluble tumour necrosis factor receptors as prognostic factors in cancer patients. Lancet 1994; 344:57-8. PDF-Download 96 KB
15. Pusztai L., Clover L.M., Cooper K., Starkey P.M., Lewis C.E., McGee J.O.: Expression of tumor necrosis factor a and its receptors in carcinoma of the breast. Br. J. Cancer 1994;70:289-292. PDF-Download 343 KB
16. Lentz, M. R., Hubbard, W.J., Fischer, C.: Low molecular weight protein apheresis and regression of breast cancer. Japanese Journal Apheresis Vol 16. No I, 1997. PDF-Download 1.42 MB
17. Lentz, M.R.: The Role of Therapeutic Apheresis in the Treatment of Cancer: A Review. Therapeutic Apheresis 1999 3 (I):40-49. PDF-Download 1.75 MB
18. Selinsky, CL, Howell, MD: Soluble tumor necrosis factor receptor type I enhances tumor development and persistence in vivo. Cell Immunology 2000; 200:81-7. PDF-Download 111 KB
19. Lentz, M.R., Kumar, K.: Reduction of Plasma Levels of Soluble Tumor Necrosis Factor and Interleukin-2 Receptors by Means of a Novel Immunoadsorption Column. Therapeutic Apheresis and Dialysis 12(6), 2008:491-499. PDF-Download 349 KB NOTE: This publication contains errors in the formatting of radiographic imagery pre- and post-treatment. A supplement containing correctly formatted imagery is being prepared and will be posted to this website upon completion.
20. Bambauer, R., Latza R., Lentz, M.R.: Therapeutic Plasma Exchange and Selective Plasma Separation Methods, Dustri Verlag, 2009.
21. Kotowicz, Beata Ph.D.; Kaminska, Janina Ph.D.; Fuksiewicz, Malgorzata Ph.D.; Kowalska, Maria Ph.D.; Jonska-Gmyrek, Joanna Ph.D.; Gawrychowski, Krzysztof Ph.D.; Sobotkowski, Janusz Ph.D.; Skrzypczak, Maciej Ph.D.; Starzewski, Jozef M.D., Ph.D.; Bidzinski, Mariusz M.D., Ph.D.: Clinical Significance of Serum CA-125 and Soluble Tumor Necrosis Factor Receptor Type I in Cervical Adenocarcinoma Patients, International Journal of Gynecological Cancer: May 2010-Volume 20 – Issue 4 – pp 588-592, doi: 10.1111/IGC.0b013e3181d5c27
22. Łukaszewicz-Zajac M, Mroczko B, Kozłowski M, Nikliński J, Laudański J, Szmitkowski M.; Clinical significance of serum macrophage-colony stimulating factor (M-CSF) in esophageal cancer patients and its comparison with classical tumor markers. Clin Chem Lab Med. 2010 Oct; 48(10):1467-73
23. Department of Soft Tissue/Bone Sarcomas, M Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Cytokine and cytokine receptor serum levels in adult bone sarcoma patients: correlations with local tumor extent and prognosis. Journal of Surgical Oncology (Impact Factor: 2.64). 11/2003; 84(3):151-9.
24. Kaminska J. · Nowacki M.P. · Kowalska M. · Rysinska A. · Chwalinski M. · Fuksiewicz M. · Michalski W. · Chechlinska M.; Clinical Significance of Serum Cytokine Measurements in Untreated Colorectal Cancer Patients: Soluble Tumor Necrosis Factor Receptor Type I – An Independent Prognostic Factor. Tumor Biol 2005;26:186–194
25. Kaminska J. · Kowalska M. · Kotowicz B. · Fuksiewicz M. · Glogowski M. · Wojcik E. · Chechlinska M. · Steffen J.; Pretreatment Serum Levels of Cytokines and Cytokine Receptors in Patients with Non-Small Cell Lung Cancer, and Correlations with Clinicopathological Features and Prognosis. Oncology 2006;70:115–125
26. Bellanti J.; Immunology IV, Clinical Applications in Health and Disease (Extract from chapter 20), 2012. PDF-Download 993 KB