CancerGuide: Controversy over the German Fusion Vaccine

In the summer of 2001, a reader clued me in that a controversy had erupted with allegations of fraud and bad science, and that their clinical trial has been suspended pending an investigation. In this article, Steve Dunn presents some background on the controversy, and then Mike Fischer, a member of the kidney-onc list, presents an important update from 2001 Kidney Cancer Symposium. We both believe that this therapy is still promising even if some difficulties need to be overcome.

Background on the Controversy

By Steve Dunn

Much of the information is in German, and I have been unable to get really detailed information about what's going on, but two English language sources I do have are:

A brief news item in the July 5th, 2001 issue of Nature Magazine reports that doctors Kugler and Stuhler are under investigation for scientific fraud and that their clinical trial has been suspended because of endangering patients and careless clinical practice. Nature is one of the world's premier scientific journals, so the source is reliable.
A second article titled, "Doubts Raised Over Cancer Study," appeared in the July 28th, 2001 issue of The British Medical Journal (another reputable publication). This puts a somewhat different spin on the controversy, minimizing the plagiarized picture allegation, while focusing on other claims.

The accusations along with some of my initial reactions are:

A picture of fused cells used in a publication was plagiarized from the Internet
This is definitely disturbing. It doesn't mean that the entire enterprise is fraudulent, however in some other cases, seemingly minor misconduct has proven to be the tip of the iceberg.
Another researcher claims that the technique used to fuse the cells could not actually work
The grounds for this claim are not detailed in the sources I have, but I tend to be skeptical of claims that something simply can't work if it appears that to the contrary it actually has, unless I know of a specific reason it is highly implausible.
The treatment may be dangerous
Again I cannot find the reasons for this claim, however clinically no serious toxic effects were reported by Kugler et. al. Among members of the kidney-onc list who've gotten the vaccine, none have reported any serious side effects. I seriously doubt that the treatment is dangerous.
The responses were not evaluated by independent radiologists
Such evaluations are standard in clinical trials, and not doing them is indicative of poor practice but it doesn't mean that the responses are not real. Instead it means the responses need radiological review, and that has apparently been done (see below).
The BMJ article makes reference to a failed second trial
I not yet found any information on such a trial, but in Mike Fischer's report below, he discusses qualify control problems associated with an expansion of the vaccine program.

Update on the Fusion Vaccine from the 2001 KCA Symposium

By Mike Fischer, November 2001

I have just come back from the second international Kidney Cancer Symposium in Chicago. The Kidney Cancer Association should be congratulated on organizing an excellent event which I am sure will accelerate the progress we need. If you are not already a member of the KCA I urge you to join and support them.

At the meeting Professor Rolf Ringert, head of the department of Urology within which the Kugler and colleagues work was done, gave a very open update. Prof. Ringert told us that there were two kinds of challenges to the integrity of the work - First of all it is established that Dr. Kugler needed to complete a thesis to qualify for professorship and in this thesis used an image showing fused dendritic-tumor cells which a colleague had copied from someone else's work on the Internet.

Acronym Watch!

CR: Complete Response: No cancer can be detected after treatment.
PR: Partial Response: The cancer has shrunk by at least 50%, but some cancer can still be detected.
SD: Stable Disease: The tumors are not growing or shrinking significantly.
RR: Response Rate: The percentage of patient achieving either a PR or a CR.
"40+:" Numbers like this represent the duration of the response in months. A "+" sign means the patient was still in remission at the last follow- up. If the "+" is absent it means that the patient relapsed at the given time.

Secondly, a number of questions were raised about the actual data and process. Two key allegations were that cell fusion had not taken place and that the validity of the remissions was in doubt because the scan evaluation had been done by the researchers rather than by the radiology department. The investigation has determined that cell fusion was working and that radiology had done the evaluations. The original paper in Nature March 2000 showed 7 responses in 17 patients (4 CR 23%, 3 PR 17%, total RR 41%. A follow up investigation as of June 2001 showed that all 4 CRs were enduring at 29+ to 40+ months and that one PR is enduring at 40+ months, and one SD at 33+ months. So the important news is that the validity of the early treatments is essentially confirmed, and the indications of benefit have been extended by one more year of persistence of all 4 of the original CRs. These are probably the most thoroughly reviewed CRs on the planet! Remember though that for fundamental statistical reasons, on average, the response rate of large scale application of a technique is lower than the rate found in small initial trials. Nevertheless, an essentially non-toxic treatment which produces a relatively durable CR rate of even half of this 23% for selected patients would still be a breakthrough.

Now for the bad news. The department OK'd the treatment of many more patients on compassionate grounds. 309 more were treated in about one year and process quality was not maintained with this rapid ramp-up. It appears that vaccine production was contracted out and that in the beginning the contractors had trouble with the fusion process (now corrected). It also appears that the fusion quality was not determined for each batch of vaccine. An outside organization, Quintiles (a research services contractor), is conducting a review of the results for these 309 patients. Prof. Ringert was hoping that the results would be available for the symposium, but, partly due to the delays in getting copies of scans from the overseas patients, there will be some delay.

Prof. Ringert did not say when/if the process of accepting more patients would restart.

Conclusions

Although some conclusions will have to wait for the publication of the full report (and even then the process quality shortcomings will limit the ability to judge the effectiveness of this treatment), the results in the original 17 patients appear to be solid, and this treatment has great potential, despite the controversy.

See Prof. Ringert's Presentation for Yourself!

A web cast of the 2001 International Symposium, including Prof. Ringert's presentation is now available courtesy of the Kidney Cancer Association.

To see this presentation, go to the Symposium Webcast Page, scroll down to Session Eight, and click on, "Dendritic Tumor Cell Hybrid: Update."

Update, December 2002 (by Steve Dunn)

News articles published by two of the world's most prominent scientific journals give some additional glimmers of information on the controversy and on the status of the therapy. It's important to remember these are news articles, not formal reports of new data or research.

Science's news article about the investigation, "German Inquiry Finds Flaws, Not Fraud" (Science, Nov 22 2002: 1531-1533), says that the Gottingen investigation has been completed and that they didn't find fraud - only sloppiness which supports our conclusions above. They also again confirmed that some of the responses were real. Interestingly they say that four papers about the fusion technique will be submitted soon - we don't know if these will be clinical or pre-clinical, but in this situation even pre-clinical work showing that a fusion vaccine could be reproduced reliably would be important.

Nature's news article, "Cancer Researcher Found Guilty of Negligence" (Nature, Nov 21, 2002: 258) says that 400 patients had been treated after the original 17 reported on in the Nature Medicine paper. While the results in 300 are still unknown, very significantly, Nature says it obtained an unpublished analysis of 100 patients treated by Dr. Muller and that there were no tumor regressions. Although the responses in the 17 original patients have been verified, this revelation shows that they, in fact, did not have reproducible process for making a vaccine. The big question in any future trial has to be whether they have a process that recovers the efficacy that was apparent in the original paper. Also this article says that a new trial sponsored by Biotech company Fresenius will be starting "shortly".

Update, November 2003 (by Steve Dunn)

The paper in Nature Medicine has now been formally retracted. The retraction is in Nature Medicine's September 2003 issue. Among the things which motivated it were the discovery that the study didn't have formal ethics board approval. The retraction is a formal acknowledgment of the problems with the study but doesn't change the underlying facts particularly that the responses were real. At the same time the science has been criticized so frequently that one has to question whether they actually had tumor cell-dendritic cell fusions and whether the vaccine can be made reproducibly. Whether the efficacy seen in the original 17 patients can ever be recovered is a serious question. At the same time none of this invalidates the concept behind this vaccine, and there is still hope something good will come of it in the end.

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This CancerGuide Page By Mike Fischer and Steve Dunn. © Mike Fischer and Steve Dunn
Page Created: November 2001, Last Updated: November 11, 2003