Clinical Trials

OncoPherese has been the subject of multiple animal and human clinical trials over the last 25+ years. It has long been understood that the only histologically mismatched tissue types that the immune system routinely ignores are cancers and the fetus (which contains only half the mother’s DNA). Dr. Rigdon Lentz hypothesized in the 1980’s that both tissue types may evade immune-mediated destruction by shielding themselves with some sort of immune-neutralizing particles. A series of experiments confirmed the existence of — and identified the size of — these particles, though not immediately their nature.

Goat Study

Dr. Lentz’s first prototype of what later became the OncoPherese technology filtered plasma based on the estimated size of suspected inhibitory molecules. In 1984 he used this technology to filter the plasma of 12 pregnant goats nearing term. Each goat then went into labor and delivered normal kids. This demonstrated not only that the removal of these blocking factors did not harm the goats or their progeny, but also, as Dr. Lentz wrote 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.”

Canine Study

The logical next step was to employ the same approach to filter the plasma of animals with advanced, inoperable cancers and see if this would induce immunologic rejection of the tumors. Dr. Lentz used his prototype to filter the plasma of a group of dogs with advanced sarcomas and mammary tumors and confirmed not only that removal of immune blocking factors was not harmful to any of the subjects, but also that the process resulted 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 reviewed the data and found it credible and noteworthy.

Phase I Human Study

In June 1985, Dr. Lentz began the first human clinical trial with a refined version of his technology, which was then called UltraPheresis™. It still filtered suspected inhibitory molecules based on size (versus the current technology, which targets these molecules specifically). This was 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 were treated between June 1985 and April 1986. With three exceptions noted below, there was a general improvement in physical condition in 65 percent, accompanied by improved appetite and weight gain.

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.

Phase II Human Study

In 1986, Dr. Lentz began 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 treated an additional 72 patients with various Stage IV cancers, with no other viable therapeutic options. Dr. Lentz used 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, soft tissue sarcoma, and squamous cell carcinomas of the head and neck. Dr. Lentz did not see any evidence that one tumor type was more sensitive to UltraPheresis™ treatment than any other, leading him to hypothesize 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 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.

Further Trials

From 1996 through 2000, Dr. Lentz used improved UltraPheresis™ filtration equipment — incorporating new Japanese technology — to conduct further clinical studies in Nashville, Tennessee. These were formal “device studies under FDA.” Again the investigators reported significant clinical responses in approximately 50% of patients studied. Reduction in tumor size appeared to correlate with the extent and duration of the lowering of soluble TNF receptor levels. Clinical results of these studies were reported in three publications.

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.

Affinity Column Development

The technology and protocol of UltraPheresis™ had a number of limitations: it was non-specific, i.e. it removed low molecular weight plasma components indiscriminately; and it required fluid replacement with blood bank plasma, with consequent problems of availability, cost, and safety.

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.

German Clinical Trial

mainzreceptorsA formal clinical trial evaluating the new adsorption technology was carried out at Gutenberg University, Mainz, Germany between 2003 and 2004. Of the 13 Mainz study patients, 7 had metastatic breast cancer, and 6 had a variety of other advanced cancers. The endpoint of this device study was to demonstrate that the new affinity column specifically removes soluble tumor necrosis factor inhibitors from blood. This was well documented in all patients (see following table) and was associated with tumor necrosis and shrinkage.

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.”

CE Mark

On April 7, 2008, Med/Cert, a regulatory body of the European Union (EU), awarded Dr. Lentz’s company a Certificate of Conformity (CE mark) for 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 key exceptions).

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.

Stein Study

Robert Stein, M.D., Ph.D., an independent research scientist acting on behalf of prospective investors in OncoPherese, designed a probative or mechanistic study, which Dr. Lentz and others executed within the Lentz Practice. This study was focused not on efficacy but rather on establishing quantitative evidence to support or refute each component of the “Lentz Hypothesis.”

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:

1) Solid tumor cancers express TNF-R1 and / or TNF-R2 messenger RNA. As the diagram on the right indicates (click to enlarge), measured levels of TNF-R expression in 22 different tumor samples from a tumor tissue bank registered several times the expression levels of normal tissue of the same type.

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.

3) OncoPherese treatment consistently reduces sTNF-R1 and sTNF-R2 levels in cancer patients. As the chart on the right indicates, OncoPherese treatment significantly reduced levels of circulating sTNF-Rs on a per treatment – and per patient – basis.

4) sTNF-R1 and sTNF-R2 removed from patient plasma during treatment is collected in corresponding amounts by the OncoPherese affinity column. As the graph on the right shows, the mass of sTNF-Rs collected by the affinity column roughly equals reduction of these inhibitors in plasma.

5) Patients undergo inflammation in tumor regions post treatment with OncoPherese. Given that regional inflammation is associated with spikes in temperature, it was possible to confirm this via thermography as shown at right.

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.

Future Studies

We are planning a new series of clinical studies to document the precise efficacy of OncoPherese in various cancer types and stages. We intend to use the resulting data to obtain private and public reimbursement approval in multiple countries.