Prof. Ernst Freund, M.D. (1863-1946) of the University of Vienna is the first researcher to postulate the existence of “blocking factors” in the serum of cancer patients. While still a student at the University of Vienna, Freund suggests the existence of “carcinolytic” (i.e., cancer-dissolving) factors in normal serum that routinely destroy cancer cells.
William Coley, a surgical oncologist, publishes evidence of the apparent relationship between infection and cancer regression. Two years later he develops Coley’s Toxins, a mixture consisting of killed bacteria of species Streptococcus pyogenes and Serratia marcescens, as a treatment for cancer. His initial attempts at deliberate infection are mixed. Coley’s Toxins are used against different types of cancer from the year 1893 through the year 1963.
Edinburgh embryologist John Beard (1858-1924) outlines his “trophoblastic theory of cancer” in his book The Enzyme Treatment of Cancer. Beard’s theory that tumors mimic many of the behaviors of the developing embryo foreshadows Dr. Lentz’ seminal 1990 paper “The Phylogeny of Oncology,” which makes a similar observation and also proposes an evolutionary basis (Dr. Lentz was not aware of Beard’s work at the time his paper was published).
Georg Haas (1886-1971) of Giessen, Germany carries out the first blood dialysis procedure. “From the initial idea to the actual realization of the dialysis method, it was a very long way. I would have to say,” he added ruefully, “it was the way of the Cross.”’
“Because of lack of support by the medical community, Haas was forced to discontinue his promising work in the field of dialysis,” wrote his biographer, Dobrin N. Paskalev, M.D., Ph.D. It was only resumed after World War II.
Swedish scientist Lars Odin notes the presence of high levels of sialic acid in the blood serum of cancer patients.
Two medical pioneers, the Australian Macfarlane Burnet and the American Lewis Thomas, independently propose the “immune surveillance theory of cancer.” This holds that the immune system’s role is to knock out aberrant cells, including cancer cells. This system functions with a high degree of efficiency so that the majority of people, although they might develop cancer cells on a routine basis, do not generally develop malignant tumors. The emergence of malignant tumors therefore represents a failure of immune surveillance.
The husband-and-wife team of Gabriel and Tatiana Gasic propose the use of receptor-destroying enzyme (RDE) to remove the sialic acid coating, and thereby reduce the ability of a tumor cell to metastasize.
“We believe,” they write, “that the anti-metastatic effect of this enzyme is a phenomenon connected with the removal of sialic acid….”
The National Cancer Institute announces the first in a series of automated Continuous Flow Blood Cell Separators, developed jointly with IBM. This technology enables the entire field of therapeutic apheresis, including both dialysis and OncoPherese.
Gale A. Granger, M.D. of the University of California, Irvine Medical Center first describes TNF-beta. He isolates what he calls “non-specific toxic materials… released when the cells are cultured in the presence of specific antigen” and names this resulting chemical lymphotoxin.
A husband-and-wife team of European researchers, Karl Erik and Ingegerd Hellström, trained at the Karolinska Institute Medical School, Stockholm as colleagues of the famed oncologist, Georg Klein, come to America to work at the University of Washington in Seattle. They find that adding “tumor fluids” from cancer patients’ blood to immune cells will “specifically block the ability of human lymphocytes to kill… tumor cells.” When these still-undefined factors are removed, immune cells are once again able to attack cancer cells. The Hellströms write:
“Sera from mice carrying progressively growing sarcomas… can block the cytotoxic effect of lymphocytes immune to the tumor-specific antigens of the respective neoplasms [i.e., cancers]. The blocking effect can be specifically removed by absorbing sera with the respective types of tumor cells.”
Also in 1971, plasmapheresis becomes practicable after Jack Latham starts manufacturing disposable plastic parts for plasmapheresis machines.
In his second year at Georgetown Medical School, Dr. Lentz attends a lecture by the famed immunologist Joseph Bellanti, M.D., soon to become President of the American College of Allergy and Immunology. Dr. Bellanti explains that T-cells are the primary actors in dealing with viral infections, transplantation and immune surveillance. Dr. Lentz becomes convinced that there must be an immunological explanation for clinical cancers – i.e. that cancer cannot be understood solely based on genetically determined cellular transformation. There must be a significant alteration in immune surveillance for an otherwise healthy person to develop cancer. This realization establishes the trajectory of Dr. Lentz’s entire medical career.
Also in 1972, President Richard Nixon signs amendments to the Social Security Act, which establishes end-stage renal disease (ESRD) as a reimbursable health condition under Medicare. 48 years after it was first used successfully, dialysis is now accepted by the medical profession and by governmental insurance plans as a practical means of keeping kidney failure patients alive.
Lucien Israël, M.D. uses the NCI-IBM Continuous Flow Blood Cell Separator to exchange 4 to 5 liters of plasma from healthy individuals to cancer patients every 48 hours. These patients, all of whom had disseminated and rapidly progressing disease, receive between 3 and 12 such sessions, conducted twice weekly.
“To our surprise,” he writes, “some of these early patients had objective reduction in tumor size. Subsequently,” he adds, “plasma exchange assumed considerable clinical importance.”
Lloyd J. Old, M.D. of Sloan-Kettering Institute in New York is senior scientist on the discovery of TNF (now called TNF-alpha). This epochal discovery comes in the course of Old’s prolonged investigation of endotoxin, a substance he believes is responsible for the clinical effectiveness of Coley’s Toxins. Old et al’s identification of TNF appears in the Proceedings of the National Academy of Sciences (PNAS). In this article they describe TNF as “an endotoxin-induced serum factor that causes necrosis of tumors.”
Peter Hersey et al. of the Melanoma Unit at the Kanematsu Institute, Sydney Hospital, publish the earliest report of the use of plasmapheresis to treat cancer, which appears in The Lancet. Hersey et al. treat patients with advanced melanoma and find that it “result[s] in removal of serum blocking activity” and also report that the procedure is well tolerated; these preliminary results indicate “that this form of therapy could act as an adjunct to other forms of treatment of advanced melanoma.”
Lucien Israël, M.D. and his colleague, Richard Edelstein, M.D. examine the role of blocking factors, trying to remove them from the plasma of cancer patients. Israël’s focus is that the existence of “nonspecific blocking factors of host origin in cancer patients” are not found in the blood of people without cancer. Like others, Israël observes that swapping plasma has a therapeutic effect in some patients, but he’s uncertain of the cause. In an article in Cancer, Israël reports the first results in 23 patients:
“Eight patients (35 percent) had an objective partial response demonstrable 2 to 3 weeks after onset of plasmapheresis and before any other therapy had been undertaken, 3 showed no change followed by an objective response on subsequent chemotherapy and/or immunotherapy and 12 had unmodified progression of disease or no change followed by progression and were considered ‘progressors.’”
In this same Cancer article, Israël hypothesizes that the blocking factors might be produced by the tumor itself as a self-defense mechanism: “Nonspecific factors produced by the tumor itself may afford self-protection against attack by the host’s immune mechanisms.”
Publication: 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
Fanned by the media, as well as some self-promoting researchers, the public develops unrealistic expectations for a new generation of “biological response modifiers,” which in practice consist of high doses of isolated cytokines. Interferon-alfa is famously extolled in an 11-page cover story in Time (March 31, 1980). The magazine writes of a “growing and barely suppressed sense of excitement among medical specialists” concerning interferon. This is followed by a similar publicity blitz for another “cancer breakthrough,” interleukin-2 (IL-2) and a somewhat smaller flurry around tumor necrosis factor itself. After these “ideal cancer drugs” fail to perform as expected, the immunotherapy bubble bursts.
Lucien Israël updates his prior plasmapheresis results and shows an objective and measurable tumor response in 14 out of 45 evaluable patients, or 31 percent, with a symptomatic or subjective response in some others. A partial response is defined as shrinkage of measurable tumors by more than 50 percent. Such regression of tumors in over 30 percent of very advanced cancer patients simply by swapping some of their plasma with that of non-cancer patients is indeed of “considerable interest,” as Israël himself notes.
Also in 1981, Spyros Retsas, M.D. of Westminster Hospital, London reports on four advanced renal cell carcinoma (RCC) patients treated with plasmapheresis. It isn’t a fair test of the method, he suggests, because these patients had an “enormous tumor load, measurable in kilograms.” When plasmapheresis fails to perform miracles and shrink these huge tumors it is taken as a sign that this kind of immunotherapy is a failure.
Austrian oncologists Michael Mickshe et al. report on the use of plasmapheresis in treatment of sixteen patients with advanced cancers of various types (12 malignant melanoma, 2 breast cancer, 2 colon cancer); between 1,650 and 3,000 ml of plasma are replaced in one single plasma exchange.
The most common adverse effects (observed in about half the patients) are nausea and chills. There is some temporary change in serum proteins. The ability of lymphocytes to respond to stimuli (i.e., mitogens) is increased in 5 of 9 patients. In 7 of 9 patients pretreatment serum is found to inhibit their own lymphocytes’ ability to react to stimulatory substances (mitogens).
Plasmapheresis is found to “decrease significantly the blocking effect of patients’ sera on normal donor lymphocyte reactivity.” The procedure is tolerated by all the patients, but is “without any clinical efficacy.” This is not surprising since the patients receive just one session of plasma exchange.
Dr. Lentz completes the first prototype of the Ultrapheresis™ technology, which filters plasma based on the estimated size of suspected inhibitory molecules. In 1984 he uses this technology to filter the plasma of 12 pregnant goats nearing term. Each goat then goes into labor and delivers normal kids, demonstrating not only that the removal of these blocking factors does not harm the goats or their progeny, but also, as Dr. Lentz writes in his published report on this study:
“…that soluble mediators of immune suppression may play a role in the maintenance of pregnancy, and that the onset of the first stage of labor may be an immunologic event.”
Also in 1984, Dr. Lentz filters the plasma of dogs with advanced, inoperable sarcomas and mammary tumors to see if this would induce immunologic rejection of the tumors. The study confirms not only that removal of immune blocking factors is not harmful to any of the dogs, but also that the process results in tumor-specific reactions: redness, swelling, tenderness and necrosis at the site of some of their tumors. The US Food and Drug Administration (FDA), various officials of the University of California Medical Center, and the Institutional Review Board (IRB) of UC Irvine all review the data and find it credible and noteworthy.
Dr. Lentz begins his first human clinical trial using a more refined version of his technology, now called UltraPheresis™. This is a Phase I trial, the main purpose of which is to determine the safety of a treatment. A total of 16 patients with late-stage, metastatic disease are treated between June 1985 and April 1986. There is a general improvement in physical condition in 65 percent, accompanied by improved appetite and weight gain. Although this is not an efficacy study, Dr. Lentz notes that “an objective reduction in tumor of 50 percent or more was observed in 6 of the 16 patients.” This was a 37.5 percent response rate, well beyond what would have been expected with the standard of care in this patient group. Dr. Lentz pointed out that 9 of the 16 (56.3 percent) survived more than one year, while 6 of the 16 (37.5 percent) lived more than two years. These clinical trial results were published in the Journal of Biological Response Modifiers in 1989.
Also in 1985, Wulfrank et al. fail to obtain objective regressions of tumors in patients with advanced cancer and suggest that others may have seen positive effects because of some unspecified component in the replacement fluid: “At present, it is unclear whether a possible effect should be ascribed to the removal of immunosuppressive factors or to the addition of some unknown factors present in the replacement fluid.”
Also in 1985, Richard H. Seder et al. at the VA Medical Center in Boston conduct a pilot study. Six patients with advanced squamous cell cancers of the head and neck undergo a trial of six 2-liter plasma exchanges over a 2 to 3-week period. The disease progresses in patients 1, 2, and 4, who die on days 44, 72, and 159 of the trial. But the tumors in patients 3 and 6 “regressed significantly, repeatedly in patient 3 over each of four courses of apheresis.”
Once the treatment is stopped, the tumor recurs in both patients and they die at days 420 and 79. Patient 5, who has inoperable disease, receives full-dose radiotherapy immediately after the course of apheresis, and then shows a complete response in the primary lesion and a major response in the extensive lymph node metastases, dying on day 421 of apparently unrelated causes.
Also in 1985, Jörg H. Beyer, M.D. of Göttingen and his fellow German oncologists treat a total of 32 patients (10 female, 22 male), all of whom have chemotherapy-resistant tumors. After receiving plasmapheresis, they are then re-treated with the previously ineffective chemotherapy. In total, 19 of the 32 patients show a minor response or no change in tumor (stabilization) lasting more than 3-1/2 weeks; in 10 of the 32 patients this response lasts for more than 8 weeks.
A more promising study is published on colorectal cancer. A total of 23 patients with advanced metastatic colorectal cancer, all with measurable metastases, are treated with chemotherapy until they become resistant to it. Chemotherapy is administered once more, combined with a large-volume exchange of plasma. Of the 23 patients, 15 respond for 4 to 45 weeks, with an average duration of 13 weeks. The effect is thought to be due to the reduction of “serum-blocking factors.” The effect is measured by a mixed lymphocyte culture (MLC) assay. In all, 16 of 20 patients show a positive correlation between their clinical course and MLC activity.
Dr. Lentz begins a Phase II clinical trial at the John F. Kennedy Memorial Hospital near Palm Springs, California under the auspices of the FDA. In this trial, Dr. Lentz treats an additional 72 patients with various Stage IV cancers. Dr. Lentz uses the UltraPheresis™ device to induce significant responses in cancers as diverse as breast, prostate, renal (kidney), ovarian, non-small cell lung, and colon as well as melanoma and soft tissue sarcoma. Dr. Lentz hypothesizes that cancerous tumors of all types share a common vulnerability to immune-mediated destruction once immune blocking factors are removed. During this period, a series of experiments by Dr. Lentz and others identifies the nature of these inhibitors as shed receptors of TNF – Tumor Necrosis Factor – a powerful cytotoxic (cell-killing) cytokine (signal molecule).
Dr. Lentz’s discovery of TNF inhibition via shedding of TNF receptors lead to the development of the anti-inflammatory drug Enbrel® (etanercept).
In Japan, Kameda et al. of Osaka University suggest that a post-centrifugal filter can selectively remove large immunosuppressive molecules during plasma exchange. They report that such removal sometimes leads to subjective and objective improvement in patients with advanced cancers. In all, they treat 25 advanced cancer patients, who are no longer responding to conventional therapy. An improvement in subjective symptoms is seen in 60 percent and a reduction of tumor size in 28 percent of these patients. The authors conclude that “immunosuppressive factors of a large molecular size” could be selectively removed by the post-centrifugal filter. However, there is apparently no attempt made to extend these findings, much less to specify the exact nature of the blocking factors.
Publication: Lentz, M. R.: Continuous whole blood ultrafiltration in patients with metastatic cancer. Journal Biologic Response Modifiers, 8:511-527, 1989.
Sucha Nand, M.D., an oncologist in the Loyola University Health System, Chicago, writes review articles in 1990 and again in 1997 about his and others’ attempts to use TA in cancer as early as the 1970s.
Nand discusses a kind of TA that involves the use of staphyloccal protein A (SPA) as a treatment for cancer. In this procedure, the patient’s plasma is passed over SPA that has been attached to a silica matrix. The SPA procedure results in the adsorption of IgG as well as “circulating immune complexes,” which at the time are thought to be one of several possible blocking factors in cancer.
Nand also discusses a procedure now called PUVA (psoralen plus ultraviolet A) in which blood plasma is subjected to extracorporeal circulation in order to expose circulating cutaneous T-cell lymphoma cells to ultraviolet A light after administration of the drug psorolen. (This procedure is still in current use.)
Publication: Lentz, M. R.: Phylogeny of oncology, Molecular Biotherapy, 2:137-144, Sep 1990.
Publication: 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.
Publication: 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.
Publication: 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.
Publication: Brocklous M, Schoenfield HJ, Laetscher H; Identification of two types of tumor necrosis factor receptors on human cells lines by monoclonal antibodies. Proc Natl Acad Sci 1990; 87: 31271131.
Publication: 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.
Publication: 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.
Publication: 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.
Publication: 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.
Publication: 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. Eur J Cancer 1993; 29A:2232-2235.
Publication: 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
A team at the University of Texas M.D. Anderson Cancer Center, Houston, and Oxford University demonstrates an overabundance of TNF receptors on the surface of cells in fresh tumor biopsies taken from 28 patients. They do not observe equivalent expression of TNF receptors in normal breast tissue, either from the non-malignant portion of the breasts of women with cancer or from women without cancer. A key point is that receptors for TNF-alpha are found in all of the tumors or surrounding tissue that the scientists examine.
In addition, they observe that TNF-alpha (the cytokine itself, not its receptor) is expressed focally in 50 percent of the tumors studied, where it is largely localized to macrophages or macrophage-like cells that have invaded the stromal tissue (i.e., the non-malignant portion of the tumor). This could certainly be interpreted to mean that macrophages were producing TNF while tumor cells were surrounding themselves with an excess of soluble receptors as a protective device. They publish their observations in the British Journal of Cancer.
Publication: Langkopf, F., Atzpodien, J.: Soluble tumour necrosis factor receptors as prognostic factors in cancer patients. Lancet 1994; 344:57-8.
Publication: Pusztai L., Clover L.M., Cooper K., Starkey P.M., Lewis C.E., McGee J.O.: Expression of tumour necrosis factor alpha and its receptors in carcinoma of the breast. Br. J. Cancer 1994;70:289-292
Publication: 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
Publication: Lentz, M.R.: The Role of Therapeutic Apheresis in the Treatment of Cancer: A Review. Therapeutic Apheresis 1999 3 ( I ):40-49
Publication:Selinsky, CL, Howell, MD: Soluble tumor necrosis factor receptor type I enhances tumor development and persistence in vivo. Cell Immunology 2000; 200:81-7.
Dr. Lentz uses improved UltraPheresis™ filtration equipment to conduct further clinical studies in Nashville, Tennessee. These are “device studies under FDA.” Again the investigators report significant clinical responses in approximately 50% of patients studied. Reduction in tumor size appears to correlate with the extent and duration of the lowering of soluble TNF receptor levels. Clinical results of these studies are reported in three publications.
The FDA sanctions Dr. Lentz for administrative errors on the last of the above human trials. These errors have no medical or scientific significance.
Also in 2001, Dr. Lentz completes an improved version of his technology combining therapeutic apheresis with an affinity column containing polyclonal antibodies for the adsorption of specific inhibitors: mainly soluble receptors for TNF (type 1 and 2), plus IL-2. Use of an affinity column not only increases the efficiency of the device at removing target inhibitors and keeping them down for longer durations, but the higher specificity of the process eliminates the need for plasma replacement. The prior technology, UltraPheresis™, removed low molecular weight plasma components indiscriminately, requiring fluid replacement with blood bank plasma and consequent problems of availability, cost, and safety.
A formal clinical trial evaluating the new adsorption technology is carried out in affiliation with Gutenberg University, Mainz, Germany. Of the 13 Mainz study patients, 7 have metastatic breast cancer, and 6 have a variety of other advanced cancers. The endpoint of this device study is to demonstrate that the new affinity column specifically removes soluble tumor necrosis factor inhibitors from blood. This is well documented in all patients and is associated with tumor necrosis and shrinkage. This is significant in that only these inhibitors are removed from the blood and no replacement plasma is required to perform the treatment. These results are published by Lentz and Kumar in 2008.
An additional 10 patients are treated on a compassionate use basis in Prien, Germany between December 2005 and October 2006 using a further improved version of the column. Two of these patients were been treated before in the Mainz trial, so a total of 21 patients populate a registry prepared in November 2007. An independent review of data on the 21 patients treated in Mainz and Prien is conducted by an external assessor, Dr. Håkan Mellstedt, Professor of Oncologic Biotherapy at the Karolinska Institute in Stockholm (a top European research hospital comparable to the Mayo Clinic in the U.S.). He reviews all clinical results (safety, adverse events, and clinical response) and concludes that OncoPherese “might be a promising treatment approach with benefits for the patients both with regard to anti-tumor effect and quality of life.”
On April 7, 2008, Med/Cert, a regulatory body of the European Union (EU), awards Dr. Lentz’s company a Certificate of Conformity (CE mark) for a precursor of the OncoPherese technology, based largely on German study data. The CE mark confers regulatory approval throughout the entire EU as well as other countries that acknowledge the CE mark (the U.S. and Japan being notable exceptions).
Publication: 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
Publication: Bambauer, R., Latza R., Lentz, M.R.: Therapeutic Plasma Exchange and Selective Plasma Separation Methods, Dustri Verlag, 2009. (a standard reference text book on Therapeutic Apheresis)
Publication: 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
An independent research scientist named Robert Stein, M.D., Ph.D., designs a study on behalf of a non-profit foundation; Dr. Lentz and others execute this study within the Prien clinic. This study is a probative or mechanistic one, meaning it focuses not on efficacy but rather on establishing quantitative evidence to support or refute each component of the “Lentz Hypothesis.” Dr. Stein’s study involves analyses of tumor tissue from oncology sample repositories as well as plasma collected from 6 patients under treatment in Dr. Lentz’ clinic between 1/9/12 – 2/20/12. Dr. Stein’s final report, delivered May 8th, 2012, concludes that “The evidence supporting Lentz’s approach to treatment has been mechanistically strengthened by these studies. The pieces line up and are consistent, although there are still holes.”
Publication: Bellanti, J.; Immunology 4, I Care Press, 2012. (Dr. Lentz is contributing editor/author to this textbook)
Following extensive research, Parker Hannifin Corporation, a $13 billion engineering company headquartered in Cleveland, Ohio, employing 58,000 people in 49 countries, approves OncoPherese as a fully reimbursable cancer treatment for their employees and dependents – a total of 250,000 insured.
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