Disease represents a reaction of the organism against some harmful agent or circumstance, from external or internal sources. The balance in the reaction may favor the host, in which case the disease is overcome with or without sequelae. It may favor the causative stimulus to a degree that results in death of the organism. Or the process may achieve a constant or undulating balance between the stimulus and the host.
The reaction of the host is often referred to as “resistance.” An individual catches a cold, or dies from a usually mild disease, and we will hear that his “resistance was low.” This is a relatively meaningless term, because we seldom can measure resistance, or the virulence of the stimulus which confronted the individual.
The nature of host resistance as it relates to cancer is even more vague. Yet we know that it exists, and meaningful quantitative measurement of some expressions of host resistance in cancer is one of the great needs and aims of cancer research.
It seems logical to divide the study of resistance into the phase during the induction of cancer, and resistance after the cancer has developed, because the conditions and the processes may be quite different.
During the induction phase, host resistance will depend on the nature of the stimulus confronting it. Presumably a portion of an organism’s defense, or resistance, to polycyclic hydrocarbons is a well functioning liver that can detoxify and eliminate this noxious agent from the body. As another example, resistance to a self reproducing protein-DNA entity, the Bittner virus, can be induced in an animal by injecting into it serum from rabbits that had been immunized to tissues containing the virus. This classical transfer of passive immunity now protects the animals against live Bittner virus subsequently fed to them. Some strains of mice have a “natural” resistance to this virus, a characteristic at present attributed to genetic factors, which is yet another phrase to cover our ignorance of the process.
We should again emphasize that resistance depends to as great an extent upon the dose or other measure of strength of the stimulus as to the reaction of the host. Thus, the detoxifying enzymes of the organism concerned with a chemical can be overwhelmed by using larger doses of the chemical, as well as by “lowering” the host resistance. At some dose of the stimulus, interacting with a host in a certain state of nutritional, enzymatic and other metabolic competences, the host’s defenses are inadequate and a cancer is produced. It is through the quantitative study of these interacting factors that we shall be able eventually to answer, in part, such questions as, “Why didn’t all the mice develop sarcomas,” or “.Why do only one of eight heavy smokers develop lung cancer?”
The triumphs of the bacterial era of medicine are closely associated with research in immunity, which empowered us to increase the defenses of people against a wide variety of bacterial and viral diseases. Experience going back to antiquity showed that individuals who recovered from such diseases as smallpox were nearly always safe from ever catching the disease again : they were immune. Edward Jenner of England assisted nature’s process by showing in 1796 that a milder form of a related disease, the vaccinia of cattle, would protect against the virulent smallpox. Pasteur’s great contribution was the reproduction of the process by injection of the dead organism of anthrax. Thus, the live, attenuated or killed bodies of several types of bacteria and virus could produce a reaction in the body that empowered the organism to protect itself against later onslaughts of these agents.
We know that the immune response of individuals to bacterial and viral diseases is not expressed as an all-or-none reaction. Partial immunity is manifested by the development of mild or attenuated disease, or, in fact, by subclinical infections. The same effects can also be due to exposure to less virulent strains of organisms.
Early experiences with transplanted tumors, before the days when inbred strains of animals became available, gave rise to hopes that immunity to tumors also could be induced. Many of the noninbred mice and rats would overcome tumor transplants, which would disappear, and the animals would then be immune to further transplants of the same tumor. However, such immunity was quite specific and limited, not protecting the animals against other transplantable tumors, or against the development of spontaneous tumors.
Paul Ehrlich during the early part of this century, and many scientists following him showed that immune reactions are due to the manufacture of specific proteins by cells which tie with and inactivate foreign proteins such as are found not only in bacteria and viruses but in plants, milk and a galaxy of other products. The impress of these foreign antigenic “keys” stimulates the cells to produce “locks” of antibodies.
Clinically, cancer is manifested by a great diversity in its course. Some cancers of the breast will grow very rapidly and kill the individual within a few months after diagnosis, while others, seemingly identical, will progress slowly; some will metastasize widely while the primary tumor is still small, whereas others will remain relatively localized for many years. Some tumors, especially the neuroblastomas of childhood, melanomas of the eye, and breast cancers, demonstrate temporary and even seemingly permanent regressions. One of the possibilities is that these tumors, and perhaps many others at lesser degrees, stimulate a form of an immune response in the patient. The study of this possibility is an attractive area for research. Yet it should be stated that as of this date, no clear demonstration of such factors in man has become available. Chester Southam and his group at the Sloan-Kettering Institute of New York have transplanted human cancers into normal volunteers, who uniformly reject such transplants. In cancer patients, a few tumor transplants from other patients will show some growth. These findings are important leads to further work, but it is possible that reduced resistance to any tissue transplants occurs in severely sick people rather than being a form of specific anticancer immunity.
Interesting attempts have been made to immunize patients against cancer, by the use of antisera made in animals injected with the patient’s tumor, or by “vaccination” with products of the cancer of the patient. These attempts have been unsuccessful. Perhaps the isolation of purer antigens more specific for cancer may lead to more successful results. Lev Zilber and his school in Moscow have reported evidence for the existence of such antigens by reacting cancer antiserum with pools of normal tissue, presumably leaving antibodies that in turn would precipitate out cancer specific antigens which could then be used for the preparation of more specific antibodies. In all these systems, species foreign systems complicate the picture, and the ultimate results are unpredictable.
The immune response of an organism is one of its manifestations of identity. The genetic mosaic of the body and its cells recognizes and rejects nonidentity. This is the basic mechanism for the nonacceptance of skin or other tissue grafts between individuals with the genetically different characteristics of man or of noninbred animals. Several important lines of investigations have yielded methods by which this immune basis of individuality can be changed. This work has already allowed the opening of a new, long-dreamed-of era in surgery, of replacing organs such as kidneys, livers, and lungs.
Immune responses can be decreased by several procedures: large doses of cortisone, X-rays and certain antimetabolites that block the formation of nucleic acids. The responses can also be modified by chemical changes in the transplanted tissue, such as by preservation of blood vessels and bone. Peter B. Medawar of Great Britain and Macfarlane Burnet of Australia shared the Nobel prize of 1960 in medicine and physiology for their studies on transplantation of skin and other tissues in embryos and newborn animals. If an embryo is injected with tissue from a foreign embryo, the immune reaction is not evoked, and the anima] will later accept tissue from the foreign adult recipient because it is no longer immunologically recognized. Studies of this mechanism have indicated that the immune response develops after birth, and is mediated through the lymphocytes, a specific type of motile cell found in the blood and tissues. In mice, lymphocytes develop in the thymus gland, and by removing this organ at birth, the animal fails to develop immune reactions. Such animals are not normal and die at an early age.
Newborn animals are more susceptible to carcinogenic chemicals than adults, probably because the full complex of detoxifying enzymes of the liver also develops following birth. Thus, smaller doses of polycyclic hydrocarbons or urethane, adjusted for body weight, will evoke more lung tumors earlier in newborn mice than in young adults. Whether these results involve the immune reaction, however, is open to question. The immunological incompetence of the newborn as it relates to cancer is better demonstrated with tumor viruses.
The late Francisco Duran-Reynals of Yale was the first to show that the Rous virus, which produces sarcomas in chickens, could also induce tumors in turkeys if newly hatched birds were used. Previous work with adult birds indicated that the virus was very species-specific; that is, it would survive and show its effects only in chickens. Now, with the use of newborn animals, and the additional methods of blocking immune response with cortisone, as well as the activation of virus by passage through tissue culture, the dogma of species specificity of tumor viruses is almost completely demolished. The polyoma virus exhibits wide cancer activity in several species, and even the Rous chicken virus has now been shown to induce cancers in rats and in monkeys. Although it is still in the realm of conjecture, the possibility of animal tumor viruses being able to infect human beings, while in the uterus or in the immediate period following birth, can no longer be dismissed.
Immunology, with the ever-developing sophistication of immunochemistry and the physicochemical separation of proteins, is certainly a most promising area for research in cancer. There are possibilities of diagnostic reactions for specific viruses and for tumor-specific antigens. The identification of viral entities and tumor proteins of human importance may open the way to the preparation of antigens for antitumor vaccines and sera. It is important to emphasize that all these are but reasonable possibilities for research exploration. Uncritical, premature reports of this type of work, with results that cannot be duplicated by others lead to useless waste of valuable scientific effort and may well discredit a fruitful approach.