Immunology,

Virology,

and Cancer

Eugene A. Cornelius, M.D., Ph.D.

I

N THE LAST 10 yr, intensive research in the exciting areas of oncogenic viruses and tumor immunology has revealed a great deal about the causes of cancers in animals, and how they grow. Many such tumors are caused by viruses. In this review, this research and the research on putative human tumor viruses will be summarized. The already substantial evidence that immune processes are involved in surveillance against cancer will be reviewed. The apparently paradoxical situation of tumor escape from this surveillance will be explained. Finally, the present and future possibilities in immunotherapy, immunodiagnosis, and immunoprophylaxis of cancer will be briefly outlined. From the point of view of general clinical application, present knowledge is still embryonic. Zealous investigation at all levels, from embryology and molecular biology to epidemiologic studies and clinical trials is justifiable, for the potential benefits to mankind are incalculable. ORGANIZATION OF THE APPARATUSI

IMMUNE

Two basic types of immunologic response to antigenic foreign material prevail: (1) a humoral response mediated via circulating antibodies synthesized by plasma cells, and (2) a cell-mediated response by lymphocytes that develop under thymic influence. These dual functions trace their origins to a common precursor stem cell population. This lymphoid stem cell population probably originates in the yolk sac and fetal liver and develops later in the bone marrow. Those stem cells migrating to the thymus proliferate

Presented in part at the 26th Annual Midwinter ConSociety, Los ference of the Los Angeles Radiological Angeles, Calif., February l-3, I9 74. Supported by LJSPHS Grants CAO6519, AM12151, and CA 15500. Eugene A. Cornelius, M.D., Ph.D.1 Associate Director, Section of Nuclear Medicine, Yale-New Haven Hospital, and Associate Professor of Nuclear Medicine. Yale University School of Medicine, New Haven, Conn. Reprint requests should be addressed to Dr. Eugene A. Cornelius, Department of Diagnostic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Conn. 06510. 0 I975 by Grune & Stratton, Inc. Seminars

in Roentgenology,

Vol.

X, No. 1 (January),

1975

extensively; most are destroyed but a small proportion differentiate into small lymphocytes that then pass into the circulation where they become part of a pool of immunologically competent post-thymic lymphocytes (T cells). These cells settle in certain thymus-dependent areas of the lymphoid tissue-the deep cortical regions of the lymph nodes and the periarteriolar zone of the white pulp of the spleen. They initiate responses of cellular immunity against fungi, acidfast bacilli, and viruses. In addition, homograft rejection, rejection of solid tumors, and graftversus-host reactions are mediated by them. Stem cells migrating to the bursa of Fabricius of birds (B cells) differentiate into lymphocytes and ultimately, under antigenic stimulation, into plasma cells that are responsible for humoral antibody production. The anatomic equivalent of this bursa has not been defined in man. There is evidence that in the rabbit the appendix and other lymphoid tissues associated with gut epithelium are involved in this function.14 The B-cell system controls immunoglobulin production. Five major classes are known: IgG, IgM, IgA, IgD, and IgE. B cells appear to be designed to handle bacterial infections with encapsulated extracellular pyogenic pathogens such as Pseudomonas, Streptococcus, Pneumococcus, H. influenzae, and Meningococcus. Important advances have been made recently in differentiating cells of the B- and T-cell systems. Current active areas of research involve the study of function of subpopulations of B and T cells, Band T-cell cooperation, and the determination of cell type in the neoplastic disorders of lymphocytes. For example, myeloma and chronic lymphatic leukemia are B-cell neoplasms,’ whereas acute lymphatic leukemia is of T-cell origin.41 Such findings indicate the clonal origin of these tumors and suggest that selective inhibition of cell populations might benefit their therapy. ETIOLOGY

OF CANCER

Concepts

At the present time, the primary cause of human cancer and the essential change at the molecular level within and between cells is unknown. However, two new concepts are under intensive in53

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vestigation. Both involve a merger of the viral and genetic theories of the cause of cancer, with emphasis on a universal causative agent. Huebner and Todaro in 1969 propounded the oncogene hypothesis. a This was based chiefly on their initial observation that single cell clones of embryo cells of both high and low cancer strains of mice may grow for many generations in cell culture as normal cells, then spontaneously begin to make oncogenic virus, with no evidence of external contamination. According to this concept, genomes of C-type RNA viruses, consisting of both oncogenes and virogenes (genes controlling cancer induction and virus formation), were incorporated into the genetic material of vertebrates early in their evolutionary development, and are present in all the ceils of the body. These genes are under the same control as normal genes and subject to repression or expression by host regulator genes. External agents such as carcinogenic chemicals, radiation, and perhaps other agents, such as exogeneous viruses,” act to derepress the viral oncogenes. Naturally occurring tumors result from a mutational derepression of oncogenes. This theory, however, provides no normal role for the oncogene or virogene; there would therefore be no evolutionary pressure for conservation of the gene. In 1970, following the discovery of virus-derived RNA-dependent DNA polymerase (reverse transcriptase), Temin advanced his protovirus hypothesis. 67 A protovirus is a segment of host cell DNA that can replicate RNA, and the latter evolves a new strand of DNA by means of reverse transcriptase. The DNA can be reincorporated into the host cell DNA beside the segment of origin (duplication of genes) or into a new site (insertion of genes) or even into the DNA of another cell. The net result is a mechanism providing for genetic variability while maintaining the stability of the germ line DNA. Oncogenic RNA viruses (oncorna viruses) could insert their genetic information into host cells via reverse transcriptase. Spontaneous cancers could result from integration of new DNA at the wrong place. Exogenous agents could cause cancer by an effect on the nucleic acids or their enzymes. Temin has suggested that avian, and possibly all of the oncorna viruses have evolved from normal cellular components. At some point in evolutionary history, the “endogenous viruses” have mutated so as to free themselves from intracellular genetic

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CORNELIUS

control, thus permitting replication in other cells (and in other animals). In man, in contrast to other animals, more effective cellular genetic control may have prevented viral escape and the infection of other humans. Recent identification of pathogenic, very low molecular weight “infectious RNA” capable of replicating in two different species of plants blurs even more the distinction between infection and heredity in multicellular organisms.46 What is fantasy today is often fact tomorrow. A third concept that has received less attention but for which there is good evidence is the belief that embryonic genes are switched on again in cancer.” Its basis comes primarily from the discovery in the blood of humans with many types of cancer alpha fetoprotein, carcinoembryonic antigen, and other antigens immunologically identical to normal fetal antigens. Cancer cells have presumably undergone dedifferentiation to a more primitive state, with expression of antigens normally found in embryos. If oncogenic viruses have any place in this mechanism, it may involve viral control of cellular genes of differentiation. Evidence for a viral etiology of human cancer. A large body of data provides solid evidence that in animals viruses cause many kinds of cancer.68 If viruses can cause cancer in animals. then why not in humans? In man, a viral etiology has not yet been proven for any tumor. The best evidence for it has been obtained for the Epstein-Barr (EB) virus as a cause of Burkitt’s lymphoma (BL).3s This consists of inordinately high EB antiviral antibody levels in patients with BL. its ubiquitous presence in BL, its role in causing lymphoblasts to replicate indefinitely in vitro, its ability to cause tumors on injection into marmosets, and the time-space clustering of cases in epidemic BL belts (horizontal transmission). Herpes virus hominis types 1 (oral) and 2 (genital) may play an active role in the causation of a variety of tumors of the nasal-oral-pharyngeal region and of the genitourinary tract, respectively. The evidence is strongest for carcinoma of the cervix.” The situation however may be merely one of coincident infection. Although nucleic acid hybridization studies of breast tumors’ and the demonstration of RNA-and reverse transcriptasecontaining particles in breast milk*’ suggest a viral etiology of breast cancer, most investigators think that viruses, if involved at all, are a contributory

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AND

CANCER

cause of mammary carcinogenesis. Despite reports of clustering of cases of Hodgkin’s disease and leukemia, statistical analysis of such data provides no evidence of an infectious oncogenic agent in these diseases.56Gallo has recently obtained evidence that human acute leukemia cells contain components characteristic of type C RNA viruses.28 Temin68 and Rapp 61 have emphasized that if viruses cause cancer in man, the culprits are not likely to be exotic viruses infecting few people but rather extremely common viruses that infect most people but only rarely cause cancer, eg, EB and herpes viruses. It is also becoming apparent that the simple concept of a “one virus” etiology of a particular tumor (as in laboratory animals) may not hold true for man. A viral etiology of human tumors will be much more complex and may involve two, three, or perhaps more interacting viruses, as may possibly be the case in nasopharyngeal carcinoma. Multiple causes, such as viruses or viral fragments combined with other agents, eg, chemical activators,60 may be responsible. My own studies of virally induced tumors in mice have indicated the greater oncogenic potential of interacting viruses as compared to a single virus2’ as well as a two-phase phenomenon of viral tumor induction. Tumors induced by a graft-versus-host reaction (GVHR) developed either within 50 days or after many months. Presumably in the former situation a critical level of virus was required, above which all barriers to oncogenesis were overcome; in the latter, aging impaired the host’s immune defenses.18 Many scientists estimate that more than half of all cancers that currently develop in the U.S. population are directly related to environmental factors, mostly chemicals.48 The importance of practical control measures, even at the present state of our knowledge of cancer biology, is therefore obvious. INTERRELATIONSHIP VIROLOGY,

OF IMMUNOLOGY, AND CANCER

Immunologic Surveillance Theory The possibility of an immune response to spontaneous tumors was generally discounted until the 1950s when it was shown that tumors induced by chemicals in pure-line mice carried new antigens

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recognizable by the host.27Y59The significance of these findings for human cancer was first appreciated by Burnet” who wrote: “. . . tumor cells may . . . because of their new antigenic potentialities provoke an effective immunologic reaction with regression of the tumor and no clinical hint of its existence.” Several years later, Thomas69 prophetically stated that immunity of vertebrates had not necessarily evolved primarily as a defense against microbial invasion: “. . . the phenomena of homograft rejection will turn out to represent a primary mechanism for natural defense against neoplasia.” According to the immunosurveillance theory, tumor cells arise constantly in the body, but because of tumor-specific antigens (TSA) they are eliminated by the immune apparatus. The association of immunologic deficiency and cancer. The most convincing evidence for the immunosurveillance theory is provided by the association of immunologic deficiency and cancer. Both in humans and in animals, there is a waning of immune function with age.29 Tumor incidence in man is also highest in the elderly; similar tindings have been demonstrated in animal models. The incidence of tumors, especially of the lymphoreticular type, in patients with primary immunodeficiency states is about 10,000 times that of the general population of the same age range.29 Impressive also is the incidence of tumors in organ transplant recipients; subjected to long-term chemical immunosuppression, they develop tumors, chiefly epithelial and lymphoreticular, at 100 times the incidence of the normal population.” In the laboratory, thymectomized mice have been found to be unduly susceptible to oncogenesis following exposure to chemicals or tumor viruses5rYs2 The most clear-cut animal evidence that immunosuppression leads to cancer is the demonstration that neonatally thymectomized mice that were not subjected to exogeneous oncogenic agents developed spontaneous lymphomas at a rate five times that of normal controls.16 The predominance of lymphomas and epithelial tumors in some of these immunodeficiency states has prompted criticism of the validity of these conclusions.3 Certainly, other nonimmunologic factors may be involved. Also, immune surveillance is not totally effective or perhaps even operative under certain circumstances.

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Immunologic deficiency is associated with malignancy. Conversely, what is the immunologic status of patients with malignancy of lymphoid and nonlymphoid origin? In the former group, the cell-mediated immune deficit of patients with Hodgkin’s disease is well known; on the other hand, patients with myeloma are lacking in humoral immunities. In chronic lymphatic leukemia both B- and T-cell immunity is impaired.*’ Studies of underlying mechanisms are difficult because the immune apparatus itself is involved in the malignant adaptation. One well-designed study of patients with solid tissue tumors (bronchogenic carcinoma) revealed normal humoral responses and a decrease in cellular immunity with progression of the disease.44 Patients with normal cellular immunity had a better prognosis. Impaired cellular immunity in cancer patients apparently is due to a factor in the plasma impairing T-lymphocyte and other response to phytohemagglutinin antigens.29 Spontaneous regression of murine lymphoma is well known. I have observed this phenomenon in both spontaneous and serially transplanted tumors.‘* In humans, it occurs very rarely and more than half the cases involve only four types of tumor: neuroblastoma, malignant melanoma, hypernephroma, and choriocarcinoma. ‘* Although it seems likely that immunologic mechanisms are primarily responsible, a really thorough study of the immunologic parameters in animals and man has yet to be carried out. Autoimmunity

and Cancer

Autoimmune disorders, eg, hemolytic anemia, idiopathic thrombocytopenic purpura, Sjogren’s syndrome, etc., are commonly observed in patients with lymphoreticular neoplasms. Autoimmunity is also often found in association with both genetically determined and acquired immunodeficiency states. There may be a genetic susceptibility to autoimmunity as shown by the high incidence of such diseases in the families of patients with immunodeficiency disorders. There is thus clinical evidence of an association of genetic factors, immunodeficiency, autoimmunity, and neoplasia.29 I found that neonatally thymectomized mice provide a unique laboratory duplicate of these associations.16 These mice were deficient in cellular immunity, produced antinuclear antibodies, demonstrated a wide variety of histologic changes

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considered autoimmune (such as synovitis, myositis, arteritis), and had a high incidence of lymphoreticular hyperplasia and reticulum cell sarcoma. Normal control mice showed none of these changes. The GVHR (graft-versus-host reaction) provides another laboratory model of autoimmunity. When immunologically competent cells (such as spleen cells) from an inbred mouse are injected into a hybrid, produced by mating with another inbred strain, a one-way immune reaction, grafted cells against host, is induced. This is an uncontrolled reaction of an autoimmune nature.62 The GVHR in the control series of mice resulted in a variety of histologic changes practically identical to those in thymectomized mice, including hyperplastic and malignant changes in the lymph nodes and spleen.18 There are many theories concerning the nature of autoimmune disease; a possible viral etiology is being actively investigated in a number of laboratories. The interrelationship of immunology, virology, and cancer has been shown most clearly in mice.*l Two models of abnormal immunologic function, the post-thymectomy state and the GVHR, result in uncontrolled lymphoid tissue proliferation terminating in lymphoma. I have obtained evidence of a viral etiology of the tumors arising in both models.“‘*’ Immunologically specific stimulation and transformation of lymphocytes in the GVHR and even in skin graft rejection has been shown to liberate or activate leukemia virus.37,38 In addition, I have found that lymphoma development is related to viral concentration and viral interaction.17”9,21 IMMUNOLOGIC MECHANISMS TUMOR GROWTH

AFFECTING

Mechanisms affecting tumor growth operate at various levels, are highly complex, and are poorly understood. Although numerous other factors, eg, hormones and tumor angiogenesis factor, may be involved, I will confine my remarks to immunologic phenomena. Much experimental evidence, first obtained in the study of animal tumors and in the last few years on human tumors, indicates that because of TSA (tumor-specific antigens) the immunologic apparatus is aware of a tumor and may then affect its growth. Let us first consider TSA and then dissect the immune response. These are areas of intensive research-new facts and new insights are appearing constantly.

IMMUNOLOGY,

VIROLOGY,

AND

CANCER

The discovery of TSA was based on the finding that mice could be immunized against a tumor that had been induced by a chemical in another mouse of the same inbred strain. This tumor was transplanted subcutaneously in the leg and after a period of growth was excised. Such a host mouse rejected subsequent injections of the tumor. Inbred mice resemble identical twins in that grafts of normal tissue are not rejected. Obviously, the tumor contained a component that was antigenitally different from normal tissue.27359Different tumors induced by the same chemical were found to possess individually distinct antigens. By contrast, TSA of tumors of known viral origin are common to all tumors induced by the same virus, irrespective of their morphology, but differ from the TSA of tumors induced by different viruses. 64 Animal studies utilized transplantation techniques, but in vitro serologic techniques, necessary for the study of human tumors, have been developed only recently. Every human tumor that has been adequately studied has been found to carry TSA. 53 Human tumors of the same type cross-react antigenically, while tumors of different types do not. For example, breast carcinomas have a common antigen not shared by bladder carcinomas, and vice versa.34 The discrepancy between the antigenic nature of experimental animal tumors and human tumors has resulted in certain reservations as to whether human tumor antigens really play any role as targets for a host defense against neoplasms. Our knowledge of the nature of human tumor antigens, however, is quite insufficient. Many questions remain to be answered, particularly in regard to antigenic specificity. Cellular and humoral mediators of the immune response have different effects on tumor growth. Cellular immunity, which is mediated by cytotoxic T-lymphocytes, is the major immune mechanism operating against tumors. This has been shown in cell culture3r and also in vivo. There is more rapid growth and greater lethality of a tumor transplanted into thymectomized mice as compared to its effect on normal controls,20 confirming early experiments in which transfer of sensitized spleen cells conveyed tumor specific immunity.54 At the present time, humoral immune mechanisms are not thought to provide a major antitumor effect. On the other hand, humoral immunity has pronounced tumor enhancing effects. A “blocking factor” has been detected in the

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serum of animals with growing tumors that specifically inhibits cell-mediated cytotoxicity in vitro32 and enhances tumor growth in vivo.66 Serum from an animal whose tumor has regressed or has been removed does not block.32 Blocking factor has been detected in humans with melanoma and neuroblastoma.34 Blocking factor was originally thought to be antibody but recent evidence favors a complex of antitumor antibody with tumor antigen6’ in a proper ratio,6 or tumor antigen alone.’ In contrast to blocking factor, the Hellstroms and co-workerssF33 have demonstrated an “unblocking factor” in serum that can abrogate the blocking effect of another serum, thus inhibiting tumor growth. Unblocking factor is most likely free antibody, although the evidence is not yet conclusive. In addition, complement-fixing cytotoxic humoral antibodies are induced by tumors. Such antibodies were not detectable in rats with growing polyoma tumors, but were demonstrable after tumor excision, regression, or treatment with unblocking serum.’ Macrophages have been shown to kill lymphoma and sarcoma cells by direct contact, in an immunologically specific way. Macrophage function has been found to be defective in animals with growing tumors but this activation defect could be remedied by incubation with supernatants from cultures of immune T cells and tumor cells.3 In order to act, macrophages must be able to recognize foreign matter. This depends on a recognition factor, which, combined with tumor cells, may be the first step required for recognition and subsequent attack by macrophages.24 Recognition factor activity is low in patients with advanced cancer. A failure of recognition mechanisms may permit tumor cells to escape destruction by macrophages, contributing to tumor growth. The presence of a growing tumor in a patient obviously indicates failure of host defenses in the immunologic battle against a tumor. One may therefore consider the mechanisms of escape from immunologic surveillance. This is a complex phenomenon and probably has no single explanation. It is not unique to tumor cells. An exact parallel is seen in microbial and parasitic diseases.3 Countless numbers of humans whose immune systems were reacting normally have been killed by infections. The immune defenses are clearly not perfect. Let us examine possible causes of immunologic

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failure. Instances of immunodeficiency, primary or secondary (as from drugs, radiation, or viral infection), are usually readily recognized. However, such cases account for only a tiny fraction of the total malignant tumors in a given population. The decline in immunologic vigor with age, especially cellular immunity, is probably an important factor. Neoplasms generally develop from small foci of cells that may not provide sufficient antigenic stimulation at an early stage of tumor growth to elicit a vigorous immunologic reaction. They therefore “sneak through” the immune defenses of their host. Experiments on animals utilizing injections of various doses of tumor cells provide evidence for this phenomenon.54 Mediumsized inocula of tumor cells were rejected because of TSA, whereas smaller or larger inocula were accepted. In this context, a nonimmunologic factor, inherent tumor growth rate, seems quite significant. A rapidly growing tumor is much more likely to overcome host defenses than a relatively indolent neoplasm. “Immunoselection” of the least antigenic of a population of tumor cells may occur. 26 I have found that tumors arising in thymectomized mice have a much lower acceptance rate on transplantation into normal hosts than do tumors arising in normal mice.” In thymectomized mice, tumors that are highly antigenic have not been eliminated by the immune apparatus. This mechanism may account for the relatively low antigenicity of spontaneous tumors compared to those induced experimentally with chemicals or viruses. Probably of great importance in tumor escape is the ability of the tumor to shed antigen.3’4149 The antigen can block by combining with receptors on cytotoxic T lymphocytes. Alternatively, blocking antigen-antibody complexes are formed. Large complexes of antibody with antigen can bind to tumor cells through the antibody component, preventing access of lymphocytes to tumor cells6 The effect would be to saturate and overwhelm the antitumor immune response. A primary tumor under natural conditions is not likely to start growing because of blocking factors. Blocking antigen-antibody complexes are formed upon stimulation of antibody production by antigen released from the tumor. There is sound evidence that the blocking effect facilitates tumor growth in vivo in animals. In humans, blocking activity correlates well with the clinical status of the

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tumor. It is present in association with growing tumor, disappears with tumor excision, and reappears with relapse, often before relapse is evident clinically.M The ability of tumors to metastasize may also be related to their proclivity to shed antigen. Not only does circulating tumor antigen interfere with the effector limb of the immune process, but it has also been found to be a poor immunogen.4 Theoretically, as humoral antibody production increasesin response to finite antigenic stimulation, the antigen-antibody ratio moves from antigen excess through equivalence to antibody excess. Is this last serum unblocking serum? Is it also cytotoxic with complement? If so, a single antibody might be involved in multiple phenomenablocking, unblocking, and tumor cell cytolysis. Alexander has emphasized that the complexity of the immune response and the unequal expression of its components at different anatomic sites can lead to tumor escape because of the problem of immunologic accessibility to the tumor.2-4 The different types of humoral antibodies (IgA, IgE, IgG, IgM) are distributed very unequally in blood, lymph, and the various secretory fluids. The components of the cellular immune system and their anatomic localization are still poorly known but undoubtedly will also be complex. It was found that in rats a subcutaneously-growing sarcoma provides considerable protection against intraperitoneal or intravenous tumor challenge but much less against intramuscular or subcutaneous challenge. Antigen released from the primary tumor interferes with the release of cytotoxic immunoblasts from the draining lymph node. Since the immunoblasts are involved in the protection of intramuscular and subcutaneous sites, these sites are ineffectively protected. Intraperitoneal protection, on the other hand, is due to cytotoxic macrophages. The growth of lung metastases following intravenous tumor injection was largely prevented. In additional experiments4 it was shown that the prevention of lung metastases in rats with sarcoma growing in the leg was due to an immunologically specific humoral factor that exerted its antitumor action in the blood or lung. It was not conventional antibody. It may be a factor produced by T cells that combines with macrophages, rendering them cytotoxic for tumor cells in an immunologically specific way. On the other hand, he found that cytotoxic humoral

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VIROLOGY,

AN0

CANCER

antibody appeared to be important in preventing metastases in humans with malignant melanoma.’ Such experiments are of the greatest importance in learning how cancers spread to the lungs. The heretofore mysterious disappearance of pulmonary metastases of hypernephroma and choriocarcinoma following removal of the primary tumor may have a logical immunologic explanation. These procedures reduce the total burden of antigen. As a result, cellular immunity to the metastatic foci would be augmented by elimination of blocking factor (tumor antigen and tumor antigen-antibody complexes) from the blood, and by release of immunoblasts from the lymph nodes draining the primary tumor site. IMMUNOTHERAPY

In man, localized primary tumors can in most casesbe effectively eradicated by surgery or radiotherapy and the problem is to deal with metastatic spread. Removal of the primary tumor may release immunoblasts from the draining nodes and increase the level of circulating antibody. These immune cells will then be available for attack on existing metastases whereas cytotoxic antibody reduces the likelihood of the occurrence of new metastases. The requirements for immunotherapy have been summarized by McKhann.49 Obviously, TSA must be present on the tumor cells. If the source of tumor is another patient, the TSA must be the same as in the patient receiving immunotherapy. No tumor cells capable of division are to be injected. Surgery, radiation, or chemotherapy must have been used to achieve minimal residual tumor mass, since the capacity of the immune system is finite. If active immunization is contemplated, the patient must be immunologically competent and should be maximally immunized. Active Immunotherapy The rationale is to induce a maximal host response to his tumor by increasing tumor antigenicity (eg, with neuraminadase63) or by augmenting his immune response.53 Whole tumor cell vaccines (irradiated or treated with mitomycin C) or subcellular components containing TSA with immune adjuvants, such as BCG, have been used. The ideal vaccine would be pure cell surface TSA. Encouraging results have been obtained using BCG

59

adjuvant therapy in acute lymphoblastic leukemia47 and in acute myelogenous leukemia.58 Passive Immunotherapy In animals, antitumor immunity has been transferred using antisera (cytotoxic or unblocking antibody)8 or lymphocytes (cellular immunity)53 obtained from animals immunized against the tumor. Experiments in humans have been less successful because of sensitization to normal tissue antigens. An area of great promise is the use of transfer factor4’ and immune RNA. 23 These informational molecules can induce a specific immune response in the recipient but are themselves not immunogenic. Nonspecific Immunotherapy The local injection of superficial melanoma nodules with BCGs7 and of skin cancers with dinitrochlorobenzene (DNCB)42 has been highly successful. Tumor regression occurs because the tumor cells are engulfed by the local hypersensitivity reaction. In a small proportion of cases,uninjected melanoma nodules have also regresseddue to augmented active immunity. Serious handicaps and complications beset immunotherapy. Transfer of cells or serum from another individual results in an immune reaction against normal tissue antigens, attenuating any benefit or causing complications such as anaphylaxis, serum sickness, graft-versus-host-reactions, and enhancement of tumor growth. BCG may also cause tumor growth enhancement, as well as severe hypersensitivity reactions and local abscesses.s7Immunotherapy may conceivably induce the emergence of immunoresistant clones of tumor cells.43 A theoretically attractive approach involves selective active stimulation of the patient’s cellular immunity with pure tumor antigen. Immunoradiotherapy and immunochemotherapy should also be investigated. These would involve the coupling of radionuclides or chemotherapeutic agents to antiTSA antibodies, which bind to TSA, thereby localizing their effects to the tumor cells. IMMUNODIAGNOSIS

OF CANCER

Radioimmunoassays of serum for alpha-fetoprotein” and carcinoembryonic antigen (CEA)‘l are now being widely investigated as possible screening tests for cancer. Alpha-fetoprotein is a

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major serum protein during early embryonic life. In normal adults, its serum level is extremely low. Elevated values have been found not only in hepatoma but also in a variety of other tumors, notably testicular, pancreatic, gastric, colonic, and bronchogenic carcinoma. Values are related to total tumor mass. These tests are of no value as screening tests for early small tumors but are helpful in detecting residual or recurrent tumor. The old dream of detecting tumors by means of radioactive antibodies has received renewed attention. Recently, CEA-producing tumors in animals and man were demonstrated by photoscan, using radioactive anti-CEA preparations.30339 The practicality of such a test for screening purposes will depend on the presence of CEA in a variety of tumors. On the other hand, radiolabeled antibody (irrespective of the specificity of tumor antigen) would be very helpful in staging the extent of a known tumor. Unfortunately this test involves the injection of foreign (goat) protein with the possible risk of an immune reaction, especially if multiple injections are given. PROPHYLAXIS

OF CANCER

Prophylactic Immunotherapy Prophylactic immunization against cancer represents the ultimate immunologic technique in cancer control. Such immunization could be specific against TSA or oncogenic viral antigens, or nonspecific, eg, using BCG. For specific immunization to be of value, TSA common to different types of tumors in different individuals would be a requirement. CEA might be a candidate. Such a vaccine would be even better if it stimulated cellular immunity but did not induce blocking activity.34 Since nonspecific immunization could theoretically be effective against all types of human tumors, and since animal studies have shown its worth, this technique has real promise. Preliminary confirmation has already been reported. Children receiving BCG were found to have a significantly lower incidence of acute leukemia.” Antiviral

Vaccines

These vaccines are potentially useful only in the case of tumors caused by horizontally transmitted viruses. A state of natural tolerance exists for vertically transmitted viruses. Marek’s disease of chickens, which is a lymphoma caused by a horizontally transmitted herpes type of DNA virus,

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can be effectively prevented by immunization with a related nonpathogenic herpes virus of turkeys. If herpes virus hominis types 1 and 2 should prove to be a cause of human tumors, immunization against the virus might be beneficial. Such a vaccine must make use of glycoproteins of the viral envelope, since the viral DNA is potentially oncogenic. Epstein-Barr virus, strongly suspected of being the causal virus of Burkitt’s lymphoma grows poorly in vitro. As a model of a horizontally transmitted human RNA tumor virus, vaccine to cat leukemia virus is under development .36 Antiviral Chemotherapy The use of such agents in man is predicated on the recognition of a viral etiology of human tumors. Since endogenously produced interferon inhibits viral replication, interferon inducers such as the analogs of RNA (eg, poly I:C) are under study in viral tumor systems of animals. Reverse transcriptase inhibitors should, at least theoretically, inhibit oncogenesis by RNA viruses by preventing viral genome incorporation into host cell DNA. I have found evidence for this effect in GVHRinduced tumors in mice using streptovaricin.” The principles of immunology outlined herein apply to pulmonary neoplasms no less than to tumors elsewhere in the body, as wasdemonstrated in one of the few investigations of immunologic changes in bronchogenic carcinoma.44 However, because of the aggressive growth pattern of this tumor, it seemsdoubtful that immunotherapy will be of value, although immunoradiotherapy and immunochemotherapy might be explored. Metastatic pulmonary disease, on the other hand, must be considered in the context of metastatic disease in general. The elucidation of immunologic mechanisms in the metastatic spread of cancer and their therapeutic application offer promise in the prevention or treatment of metastases. REFERENCES 1. Aisenberg AC, Block KJ, Long JC: Cell-surface immunoglobulins in chronic lymphocytic leukemia and allieddisorders. Am J Med 55:184-191, 1973 2. Alexander P, Hall JG: The role of immunoblasts in host resistance and immunotherapy of primary sarcomata. Adv Cancer Res 13: l-37, 1970 3. Alexander P: Tumor immunology in perspective. Front Radiation Ther and One 7:213-222,1972 4. Alexander P: Host defense mechanisms. First Meeting: Spontaneous Regression of Cancer. Baltimore, American Cancer Society, 1974 (in press)

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5. Axe1 R, Schlom J, Spiegelman S: Presence in human breast cancer of RNA homologous to mouse mammary tumor virus RNA. Nature (Lond) 235:32-36,1972 6. Baldwin RW, Embleton MJ, Robbins RA: Humoral factors influencing cell-mediated immune responses to tumor-associated antigens. Proc Roy Sot Med 66:466468,1973 7. Baldwin RW, Embleton MJ, Price MR: Inhibition of lymphocyte cytotoxicity for human colon carcinoma by treatment with solubilized tumor membrane fractions. Int J Cancer 12:84-92, 1973 8. Bansal SC, Sjogren HO: Unblocking serum activity in vitro in the polyoma system may correlate with antitumor effects of antiserum in vivo. Nature (New Biol) 233: 76-77, 1971 9. Bansal SC, Sjogren HO: Counteraction of the blocking of cell-mediated tumor immunity by inoculation of unblocking sera and splenectomy. Int J Cancer 9:490509,1972 10. Biomedical News, October 1973, p 7 11. Burnet FM: Cancer: A biological approach. Br Med J 1:779-786,841-847, 1957 12. Cole W: Opening address. First Meeting: Spontaneous Regression of Cancer. Baltimore, American Cancer Society, 1974 (in press) 13. Cooper MD, Perey DY, Peterson RDA, et al: The two component concept of the lymphoid system, in Bergsma P (ed): Immunologic Deficiency Diseases in Man. Birth Defects Original Article Series, ~014. New York, National Foundation-March of Dimes, 1968, p 7 14. Cooper MD, Perey DY, Gabrielsen A, et al: Production of an antibody deficiency syndrome in rabbits by neonatal removal of organized intestinal lymphoid tissues. Int Arch Allergy Appl Immunol33:65-88, 1968 15. Cornelius EA: Rapid viral induction of murine lymphomas in the graft-versus-host-reaction. J Exp Med 136:1533-1544, 1972 16. Cornelius EA: Induction of tumors and autoimmune changes in thymectomized mice. Am J Roentgen01 114:784-791,1972 17. Cornelius EA: Rapid immunological induction of murine lymphomas: Evidence for a viral etiology. Science 177:524-525,1972 18. Cornelius EA: Development of tumors as a result of the graft-versus-host reaction. Exp Hematol 1:135-149, 1973 19. Cornelius EA: Unpublished observations 20. Cornelius EA: Immune mechanisms in experimental leukemia. Proceedings of XI International Cancer Congress, Florence, 1974 (in press) 21. Cornelius EA: Comparison of immunologically induced and radiation induced tumors in mice. 22nd Annual Meeting, Association of University Radiologists, New York, NY, May 9, 1974 22. Davignon L, Lemonde P, St-Pierre J, et al: B.C.G. vaccination and leukemia mortality. Lancet 1:80-81, 1971 23. Deckers PJ, Pilch YH: Transfer of immunity to tumor isografts by the systemic administration of xenogeneic “immune” RNA. Nature (Lond) 231:181-183, 1971

61 24. DiLuzio NR, McNamee R, Miller EF, et al: Macrophage recognition-factor depletion after administration of particulate agents and leukemic cells. J Reticuloendothel Sot 12:314-323, 1972 25. Feldman SP, Schlom J, Spiegelman S: Further evidence for oncorna viruses in human milk: The production of cores. Proc Nat1 Acad Sci USA 70:1976-1980, 1973 26. Fenyo EM, Klein E, Klein G, et al: Selection of an immunoresistant Moloney lymphoma subline with decreased concentration of tumor-specific surface antigens. J Nat1 Cancer Inst 40:69-89, 1968 27. Foley EJ: Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 13:835-837, 1953 28. Gallo RC: Virus-specific markers in human leukemia. Cancer 34 (Suppl), 1974 (in press) 29. Gatti RA, Good RA: Occurrence of malignancy in immunodeficiency disease. Cancer 28:89-98, 1971 30. Goldenberg DM, Preston DF, Primus HF, et al: Photoscan localization of GW-39 tumors in hamsters using radiolabeled anticarcinoembryonic antigen in immunoglobulin G. Cancer Res 34:1-9, 1974 31. Hellstrom KE, Hellstrom 1: Cellular immunity against tumor antigens. Adv Cancer Res 12:167-223. 1969 32. Hellstrom I, Hellstrom KE: Colony inhibition studies on blocking and nonblocking serum effect on cellular immunity to Moloney sarcoma. Int J Cancer 5:195-201,197O 33. Hellstrom I, Hellstrom KE, Sjogren HO, et al: Serum factors in tumor free patients cancelling the blocking of cell mediated tumor immunity. Int J Cancer 8:185191,197l 34. Hellstrom KE, Hellstrom I: Immunity to neuroblastomas and melanomas. Ann Rev Med 23: 19-38, 1972 35. Henle W: Epstein-Barr virus. Cancer 34 (Suppl), 1974 (in press) 36. Hilleman MR: Potential of vaccines in the control of human cancer. Cancer 34 (Suppl), 1974 (in press) 37. Hirsch MS, Phillips SM, Solnik C, et al: Activation of leukemia viruses by graft-versus-host and mixed lymphocyte reactions in vitro. Proc Nat1 Acad Sci USA 69: 1069-1072, 1972 38. Hirsch MS, Ellis DA, Black PH, et al: Leukemia virus activation during homograft rejection. Science 180: 500-502,1973 39. Hoffer PB, Lathrop K, Bekerman C, et al: Use of 13’I-CEA antibody as a tumor scanning agent. J Nucl Med 151323-327, 1974 40. Huebner RJ, Todaro GJ: Oncogenes of RNA tumor viruses as determinants of cancer. Proc Nat1 Acad Sci USA 64:1087-1090,1969 41. Kersey, JH, Sabad A, GajlPeczalska K, et al: Acute lymphoblastic leukemia cells with T (thymusderived) lymphocyte markers. Science 182:1355-1356,1973 42. Klein E: Nonspecific antigen reactions. First Meeting: Spontaneous Regression of Cancer. American Cancer Society, Baltimore, 1974 (in press) 43. Klein G: Host defense mechanisms. First Meeting: Spontaneous Regression of Cancer. American Cancer Society, Baltimore, 1974 (in press)

62 44. Krant MJ, Manskopf G, Brandrup CS, et al: Immunologic alterations in bronchogenic cancer: Sequential study. Cancer 21:623-631, 1968 4.5. LoBuglio AF: Transfer factor in the treatment of human malignancy. Cancer 34 (Suppl), 1974 (in press) 46. Marx JL: “Viroids”: A new kind of pathogen. Science 178:734, 1972 47. Mathe G, Amiel JL, Schwarzenberg L, et al: Active immunotherapy for acute lymphoblastic leukemia. Lancet 1:697-698,1969 48. Maugh TH: Chemical carcinogenesis. Science 183: 940-944,1974 49. McKhann CF: Possibilities of immunotherapy. Cancer 34 (Suppl), 1974 (in press) 50. Melnick JL: Herpes type 2 virusCancer 34 (Suppl), 1974 (in press) 5 1. Miller JF,Grant GA, Roe FJ: Effect of thymectomy on induction of skin tumors by 3,4-benzopyrene. Nature (Lond) 199:920-922,1963 52. Miller JF, Ting RC, Law LW: Influence of thymectomy on tumor induction by polyoma virus in C57BL mice. Proc Sot Exp Biol Med 116:323-328, 1964 53. Morton DL: Immunotherapy of cancer. Cancer 30: 1647-1655,1972 54. Old LJ, Boyse EA: Immunology of experimental tumors. Ann RevMed 15:167-186, 1964 55. Penn I: Chemical immunosuppression and human cancer. Cancer 34 (Suppl), 1974 (in press) 56. Pike MC: Clustering of cases of Hodgkin’s disease and leukemia. Cancer 34 (Suppl), 1974 (in press) 57. Pinsky CM: Immunotherapy of melanomas with intralesional BCG. Cancer 34 (Suppl), 1974 (in press) 58. Powles RL: Immunotherapy of acute myelogenous leukemia. Cancer 34 (Suppl), 1974 (in press)

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59. Prehn RT, Main JM: Immunity to methylcholanthrene-induced sarcoma. J Nat1 Cancer Inst 18:769-778, 1957 60. Price PJ,Suk WA, Freeman AE: Type C RNA tumor viruses as determinants of chemical carcinogenesis: Effects of treatment. Science 177:1003-1004, 1972 61. Rapp F: Herpes type 2 virus. Cancer 34 (Suppl), 1974 (in press) 62. Schwartz RS: Activation of latent viruses. Cancer 34 (Suppl), 1974 (in press) 63. Simmons RL: Cell surface modification in the treatment of cancer. Cancer 34 (Suppl), 1974 (in press) 64. Sjogren HO: Transplantation methods as a tool for detection of tumor specific antigens. Prog Exp Tumor Res 6:289-322,1965 65. Sjogren HO, Hellstrom I, Bansal SC, et al: Suggestive evidence that the “blocking antibodies” of tumorbearing individuals may be antigen-antibody complexes. Proc Nat1 Acad Sci USA 68:1372-1375, 1971 66. Sjogren HO, Bansal SC: Antigens in virally induced tumors, in Amos B (ed): Progress in Immunology, vol 13. New York, Academic Press, 1971, pp 921-938 67. Temin HM: Malignant transformation of cells by viruses. Perspect Biol Med 14:11-26, 1970 68. Temin HM: Introduction to virus caused cancer. Cancer 34 (Suppl), 1974 (in press) 69. Thomas L: Discussion in Cellular and Humoral Aspects of Hypersensitivity States. New York, Harper & Row, 1961, p 529 70. Waldman TA: Alpha fetoprotein.Cancer 34 (Suppl), 1974 (in press) 71. Zamcheck N: Carcinoembryonic antigen. Cancer 34 (Suppl), 1974 (in press)

Immunology, virology, and cancer.

Immunology, Virology, and Cancer Eugene A. Cornelius, M.D., Ph.D. I N THE LAST 10 yr, intensive research in the exciting areas of oncogenic virus...
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