Friday, September 14, 2018


Ralf Kleef, MD, Vienna, Austria

In mid-September 2018, the medical journal Integrative Cancer Therapies (SAGE), published a peer-reviewed article on a highly significant finding in breast cancer from a European integrative cancer clinic. Here is a link to the full article:


The title is self-explanatory: "Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2."

The paper is the result of an international collaboration that involved more than two years of intense effort by scientists in five countries. The first author is the treating physician, Ralf Kleef, MD, of the Kleef Clinic, Vienna, Austria. The other authors are Prof. A. Marcell Szasz of Semmelweis University, Budapest and Lund University, Sweden; Dr. Arthur Bohdjalian of the Rudolfinahaus Hospital, Vienna's leading private hospital; Prof. Hans Bojar of the NextGen Cancer Group, Dusseldorf, Germany; and Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences. I (RWM) am the second author of the article.

In this paper, we report on the case of a 50-year-old woman with breast cancer who experienced disease recurrence at the axillary (armpit) lymph nodes and, later on, lung metastases in both lungs with severe shortness of breath.

The woman in question received low-doses of two Food and Drug Administration (FDA)-approved immune checkpoint blockade drugs (nivolumab {Opdivo®} and ipilimumab {Yervoy®}) weekly over 3 weeks. She also received regional hyperthermia (heat therapy) 3 times a week. This was followed by systemic fever-range hyperthermia induced by another FDA-approved drug, interleukin-2 (IL-2) for 5 days. The patient then went into a complete remission of her lung metastases with only transient grade I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of this treatment. Eventually, there was a recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases and she passed away in the summer of 2017. 

The authors concluded that this exceptional response should instigate further research efforts with this protocol, which consisted only of FDA-approved drugs and treatments. We believe that at these reduced doses, when combined with complementary treatments such as hyperthermia, the results are at least as good as with conventional higher doses, and the rate of serious side effects is concomitantly lower.

A patient with such far advanced lung metastasis would typically have had an extremely 
limited expected survival. Therefore, we wanted to report this case as an exceptional response to lower-dose immune checkpoint blockade therapy, resulting in a more than two year survival from the beginning of immune treatment.

The idea of using a lower-than-typical doses of immune checkpoint drugs was derived from a January 2014 article in the peer-reviewed journal Pharmacological Research. The authors of that pioneering article were Prof. Shimon Slavin, of Tel Aviv, Israel and Dr. Tibor Bakacs of Budapest. (Again, I was second author.) Here is the link:


The development of immune checkpoint blockade drugs, first approved in 2011, has been among the most important breakthrough in cancer treatment. I believe that James P. Allison, PhD, of the M.D. Anderson Cancer Center, Houston, is fully deserving of a Nobel Prize in Physiology or Medicine for this epochal discovery. But Ralf Kleef, Tibor Bakacs and their medical collaborators also deserve great credit, since they have paved the way for a safer and more effective method of using these same agents.

NOTE: Integrative Cancer Therapies has an Impact Factor of 2.657. In 2017, Pharmacological Research had an Impact Factor of 4.897. 
Sources: http://journals.sagepub.com/home/ict and http://www.letpub.com/