|Dr. Lloyd J. Old and Helen Coley Nauts (c. 1980)|
HISTORY OF IMMUNE CHECKPOINT INHIBITION
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.
“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.”
“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.
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.
“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.
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.
See our other blog posts:
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.
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.
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.