"" Ralph Moss—Cancer Consultant: 2017-02-12

Wednesday, February 15, 2017

HISTORY OF IMMUNE CHECKPOINT INHIBITION

Dr. Lloyd J. Old and Helen Coley Nauts (c. 1980)


This month, for the second year in a row, the American Society of Clinical Oncology (ASCO) has chosen cancer immunotherapy as its breakthrough of the year. The emergence of immune checkpoint inhibitor drugs (such as Yervoy®, Opdivo® and Keytruda®) is undoubtedly a very important development in cancer treatment. But I thought readers would be interested in the history of the general idea of "de-blocking" the immune system.

The first researcher to postulate the existence of blocking factors in the blood serum of cancer patients was Ernst Freund, MD (1863-1946), of the University of Vienna. Working with his long-time associate, Gisa Kaminer (1883-1941), they anticipated many of the features of modern immune checkpoint inhibition. To me, they are among the unsung heroes of cancer immunology.

Freund and Kaminer suggested the existence of cancer-dissolving (or “carcinolytic”) factors in normal blood serum. Serum from cancer patients, they said, contained “anti-carcinolytic” elements that protected cancer cells from some destructive element in normal serum. This distinction between normal and cancerous serum formed the basis of their “Freund-Kaminer reaction.” Introduced in 1910, it constituted the first diagnostic test for cancer.

Freund and Kaminer believed that cancer could be diagnosed when a patient’s serum blocked the destruction of cancer cells—in other words, through the presence of these anti-carcinolytic elements. It is hard to interpret these results in terms of modern science, but it is possible that Freund and Kaminer were actually measuring what we now call “PD-L1.” This is a functional part of the linkage between the cancer cell and the immune T cell. 

It is amazing to realize that Freund and Kaminer “attracted attention throughout the scientific world,” according to a 1924 article in Time magazine. The article continued: 
“They have found in…persons with cancer a substance which, when added to the serum of normal persons, changes it to resemble the serum of persons with cancer. The normal serum loses its power to dissolve cancer cells….It is the belief of the Viennese investigators that…the chemical substances mentioned have the power of encouraging or preventing the growth of cancer.”
Freund and Kaminer were of Jewish ancestry, and so, like thousands of others, had to flee for their lives after the Nazi Anschluss (annexation) of Austria in 1938. Like another Viennese professor, Sigmund Freud, MD, Freund and Kaminer found refuge in Great Britain. Kaminer died in 1941 and Freund died five years later. By then the British Medical Bulletin referred to their once-famous test as a “half-forgotten chapter of cancer research.” By the 1950s it was completely forgotten, one of those scientific discoveries that did not survive the turmoil of World War II.

ENTER THE HELLSTROMS

Then, in the late 1960s the husband-and-wife team of Karl Erik and Ingegerd Hellstrom gave new life to the study of blocking factors. The Hellstroms came to the University of Washington from the famed Karolinska Institute. In Seattle, for the next 40 years, they pursued blocking factors in the blood of cancer patients, as well as many other aspects of cancer immunotherapy.

The Hellstroms' starting point was similar to Freund’s, in that they found that adding “tumor fluids” from cancer patients’ blood to immune cells would “specifically block the ability of human lymphocytes to kill…tumor cells.” (Sjorgen 1971).

When these still-undefined factors were removed, immune cells were once again able to attack cancer cells. The Hellstroms wrote:
“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.” (Ibid.)
A search to define these blocking factor began among immunologists. A major problem was that scientists could not reach a consensus over the exact nature of this blocking process. To quote Prasanta K. Ray of the Medical College of Pennsylvania and Hospital in 1981:
"It is not clearly understood how a tumor can grow in an individual despite the fact that the host may have anti-tumor immunity" (Ray 1981).

Prof. Fernando S. Salinas of British Columbia concurred:
"The nature of these blocking factors still remains unclear" (Serrou 1981).
In the past few decades, though, several important discoveries have shown how cancer can block the immune system. The most important of these is the theory of immune checkpoint blockade.

UNCONVENTIONAL PRACTITIONERS

This was also the point at which conventional oncology and CAM converged. Several unconventional practitioners, such as Lawrence Burton, PhD, founder of the Immuno-Augmentative (IAT) treatment center in Freeport, the Bahamas; Valentin I. Govallo, MD, of Moscow, Russia; and M. Rigdon Lentz, MD, an American oncologist who still practices in Prien, Germany, all postulated various methods for “de-blocking” the immune system of cancer patients.

A new era began when James P. Allison, PhD, now head of immunotherapy at the University of Texas MD Anderson Cancer Center, Houston, showed that directing monoclonal antibodies ("guided missiles") against a so-called checkpoint protein, CTLA-4, helped mice fend off tumors. In a now classic paper, he and his colleagues wrote:
“It has recently become apparent that CTLA-4…is a negative regulator of T cell activation….Antibodies to CTLA-4 resulted in the rejection of tumors, including pre-established tumors….These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.” (Leach 1996).
In other words, if you could eliminate the factors that are blocking the immune system, you might eliminate the cancer as well. This was the beginning of the development of "immune checkpoint inhibitors" (or blockade), the most important development in cancer immunotherapy in many years. 

The first drug that directly targeted CTLA-4 was approved 15 years later, ipilimumab (Yervoy®). The U.S. Food and Drug Administration subsequently approved other checkpoint drugs, including nivolumab (Opdivo®) and pembrolizumab (Keytruda®), both of which target a related protein, PD-1. In 2015, Allison won the Lasker-DeBakey Clinical Medical Research Award. This is frequently a precursor to the Nobel Prize in Medicine or Physiology, for which he allegedly has been short-listed.


LINE OF DESCENT

Almost 50 years ago, Helen Coley Nauts, the dynamic founder of the Cancer Research Institute (CRI), New York, published a series of 17 detailed monographs on the beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy on a variety of cancers. The series included almost 1,000 cases of advanced cancer that had been successfully treated by her father, the great William B. Coley, MD, using a combination of killed microbes called Coley’s toxins, Coley’s fluid or mixed bacterial vaccine (MBV). I keep the set that she gave me almost 40 years ago close at hand and consult it frequently. But, at the time, Mrs. Nauts’ valiant attempts to defend and revive her father’s epochal work was almost entirely ignored or ridiculed. I remember seeing her monographs on a shelf of Cornell University Medical College, literally gathering dust, unread and unappreciated. At the time, almost the only scientist who took her work seriously was Lloyd J. Old, MD, the young vice president of Sloan-Kettering Institute, who became the first scientific director of the CRI. 

Fast-forward 40 years, and the present-day director of the the Cancer Research Institute’s Scientific Advisory Council is none other than James Allison, who, as I said, developed the first immune checkpoint inhibitor. So, through these individuals--Nauts, Old and Allison--there is direct line of descent from William B. Coley’s toxins to the present generation of immune-checkpoint inhibitors. But we must also pay homage to the unsung heroes of this tale--Freund, Kaminer, the Hellstroms, Burton and Lentz. Without them, I doubt if this field would ever have come to its present-day position of eminence.

References

Anonymous. Medicine: Chemistry of Cancer. Time, Jan. 28, 1924.

British Council Medical Department. Lactation: Function and Product, British Medical Bulletin. London: Churchill Livingstone1947, p. 259.

Freund E and Kaminer G. Ueber die Beziehungen zwischen Tumorzellen und Blutserum. Biochem Ztschr. 1910;26:312-324.

Govallo VI. Immunology of Pregnancy and Cancer. Moscow: Nova Publishers, 2003.

Leach, DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-2 blockade. Science 1996;271:1734-1736.

Lentz, MR. The Role of Therapeutic Apheresis in the Treatment of Cancer: A Review. Therapeutic Apheresis: Official Journal of the International Society for Apheresis and the Japanese Society for Apheresis 3, no. 1 (February 1999): 40–49.

Paulson, Tom. 40 years ago, this Swedish couple pioneered cancer immunology. Seattle PI, Feb. 23, 2006; I can find no references to Freund and Kaminer in their writings.

Ray, P. K., and S. Raychaudhuri. Low-Dose Cyclophosphamide Inhibition of Transplantable Fibrosarcoma Growth by Augmentation of the Host Immune Response. Journal of the National Cancer Institute 67, no. 6 (December 1981): 1341–45.

Bernard Serrou, Claude Rosenfeld. Immune Complexes and Plasma Exchanges in Cancer Patients. Elsevier/North-Holland Biomedical Press, Jan 1, 1981, p. 253.

Sjögren, H. O., I. Hellström, S. C. Bansal, and K. E. Hellström. Suggestive Evidence That The ‘blocking Antibodies’ of Tumor-Bearing Individuals May Be Antigen--Antibody Complexes. Proceedings of the National Academy of Sciences of the United States of America 68, no. 6 (June 1971): 1372–75.