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 reviewed the data and found it credible and noteworthy.
Although this was not an efficacy study, Dr. Lentz noted 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.
The three exceptions mentioned above were the first three patients treated; all died after developing tumor lysis syndrome (TLS), normally a rare but very dangerous condition brought on by excessively rapid disintegration of large tumors, usually following chemotherapy. TLS can lead to kidney and other organ failure from excessive levels of calcium, phosphate, and potassium being released by dying tumors. What’s profound about the deaths of these patients is that autopsies of the three showed that “all measurable disease” had been eradicated by a massive immune-mediated necrosis of their tumors, which resembled organ transplant rejection.
Dr. Lentz learned through this experience that UltraPheresis™ – and of course subsequent versions of the technology – could destroy tumors faster than the body could eliminate the necrotic debris, and thus the reaction must be carefully regulated and clinical responses carefully observed. There have been no subsequent TLS incidents since this first human trial.
During this period, a series of experiments by Dr. Lentz and others identified the nature of these inhibitors as shed receptors of TNF – Tumor Necrosis Factor – a powerful cytotoxic (cell-killing) cytokine (signal molecule). Tumors shed TNF receptors to neutralize incoming TNF, which explained how patients who were immunologically healthy overall could still get cancer.
Following this successful Phase II study, FDA scientists, as well as Dr. Lentz’s scientific advisors, recommended that he build a “commercializable” system, which could be mass-produced, approved, and then made available to the general public. However, there were critical gaps in the enabling technology and therefore in 1990, Dr. Lentz decided to return to the practice of medicine and defer further development of the UltraPheresis™ system.
Administrative errors on Dr. Lentz’s third human clinical trial led to sanctions from the FDA. Although unfortunate in terms of public perception, these errors had no medical or scientific significance.
In 2000-2001, a more specific form of treatment was developed, combining therapeutic apheresis with an affinity column containing polyclonal antibodies for the adsorption of specific soluble inhibitors: soluble TNF receptors type 1 and 2, plus soluble IL-2 receptors. Use of an affinity column increased the efficiency of the device at removing target inhibitors and keeping them down for longer durations, and the higher specificity of the process eliminated the need for plasma replacement.
This was significant in that only these inhibitors were removed from the blood and no replacement plasma was required to perform the treatment. These results were published by Lentz and Kumar in 2008.
An additional 10 patients were 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 had 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 was 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 reviewed all clinical results (safety, adverse events, and clinical response) and concluded that OncoPherese “might be a promising treatment approach with benefits for the patients both with regard to anti-tumor effect and quality of life.”
A CE mark indicates compliance with the health and safety requirements of the EU and is thus similar to FDA device approval. A new trial is currently being planned with U.S. partners specifically to attain FDA approval to enter the U.S. and Japanese markets.
Dr. Stein’s study involved discreet experiments and analyses using tumor tissue from oncology sample repositories as well as plasma collected from 6 patients receiving OncoPherese treatment between 1/9/12 – 2/20/12. The main tenets of the Lentz Hypothesis tested in the Stein Study are as follows:
2) sTNF-R1 and sTNF-R2 levels are elevated in the plasma of metastatic cancer patients. This has been confirmed by multiple independent published reports, and it was also observed in this study.
6) Inflammation in tumor region(s) correlates with tumor necrosis and eventual shrinkage. Radiographic follow-up from patient physicians was voluntary and incomplete, though trending correctly at the conclusion of the study.
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