Symposium on Surgical Practice at the University of Chicago Clinics
Lung Cancer: An Immunologic Viewpoint and the Prospects for Immunotherapy
Nicholas J. Gross, M.D.,* and Tom. R. DeMeester, M.D. t
The lung cancer problem is enormously challenging by any standards. In terms of size it is the largest cause of death from cancer. Between 70 and 80 thousand people in the United States will develop lung cancer this year, and, by present survival figures, only about 4 thousand of these patients will be alive in 1980.48 The incidence is rising in epidemic fashion. Preventive measures, although more obvious than for any other tumor, have been largely rejected, at least by the nonmedical public. Diagnosis is more often than not made too late for curative treatment,t2 even when the population at risk is screened at short intervals.61 Furthermore, the 'management of lung cancer by surgery and radiation therapy has not advanced significantly in 2 decades although refinements have been 'introduced;38. 43 and chemotherapy has yet to make any impact on this disease. 47 These problems and the difficulties of providing the best current therapy to lung cancer candidates&1 combine to produce one of the most problematic areas in medicine. It is therefore not surprising that considerable attention is being paid to the current boom in tumor immunology in the hope that significant and practical new therapeutic advances will be made which can be applied to lung cancer. There are many hundreds of papers on immunotherapy in animal and human neoplasia; this review deals mainly with human primary lung cancer but certain generalizations are probably justified.
IMMUNOLOGIC STATUS OF PATIENTS WITH LUNG CANCER The facts of tumor immunology, to the extent that these are known, have been reviewed in many journals recently, including the surgical From the Departments of Medicine and Surgery, and the Cancer Research Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois
*Assistant Professor of Medicine t Assistant Professor of Surgery Supported by a grant from the National Cancer Institute, DREW, Grant number CA 14599.
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literature,8 and will not be reviewed here. It is reasonable to assume that these facts apply equally to lung cancer as to other human tumors. The immune status of patients with lung cancer has been the subject of many investigations during the last decade. Relevant studies are those which deal with delayed hypersensitivity and cell-mediated immunity, both of which are aspects of the function of thymus derived lymphocytes, the principal intrinsic antitumor defense mechanism. The delayed hypersensitivity skin responses of patients with lung cancer are very commonly impaired at the time of presentation, whether assayed by the tuberculin skin test or the skin response to several other typical recall antigens or by de novo sensitization to agents such as dinitrochlorbenzene (DNCB).7, 17, 28, 30, 32, 37 In addition, the response of their lymphocytes in culture to nonspecific mitogens such as phytohemagglutinin (PHA) is also impaired,to, 14, 17,22 as is the in vitro response to recall antigens17 and the E-rosette test. 19 The origin of this impairment is not clear, but it is seen in many other tumors. It may be due to inhibiting factors liberated from tumor cells24 , 64 or to circulating antigen-antibody complexes. 51 Alternatively, immunosuppression may be due to carcinogen itself54 and may thus precede the neoplastic change, permitting relatively unopposed growth of nascent tumor cells. In fact, there is evidence that heavy smokers are immunosuppressed46 even in the absence of clinical lung cancer. In spite of this immunosuppression an immune response on the part of the patient directed specifically against his own tumor antigens almost invariably occurs and can be detected in a number of ways. Thus, lymphocytes of patients with lung cancer are often able to kill autochthonous tumor cells in culture,39 and extracts of autochthonous tumor cells often provoke delayed hypersensitivity skin responses in lung cancer patients. 53 ,62 There is also histologic evidence of the generation of an immune response, sinus hyperplasia, in the hilar and mediastinal lymph nodes. 5 Although immune rejection of subclinical, nascent tumors may occur on a continuous basis, the immune sensitization to tumor antigens is unable by itself to eradicate clinically obvious lung cancer. Nevertheless, this immune response may play an important role in the subsequent course of the patient. The likelihood of recovery from lung cancer is directly related to the immunocompetence of the patient at his presentation and following treatment.7' 9,17,34,37 Therapy for lung cancer itself may add to the immunologic impairment already present in many patients. Surgery has a temporary depressant effect on various aspects of immune function. 16 ,63 Furthermore, hilar and mediastinal lymph nodes are removed by surgery and these are the very nodes where a favorable specific immune response against tumor antigens is being generated. In fact, in an analogous situation, breast cancer, there is controversy as to whether the removal of regional lymph nodes improves or jeopardizes survival. Similarly, radiation therapy is markedly and selectively inhibitory for T lymphocytes55 and results in prolonged lymphopenia and immunosuppression42 , 58 although it is not clear yet whether this adversely affects survival in lung cancer.6 The analogy of breast cancer is again instructive: it has been controver-
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sial for many years whether radiation therapy improves or impairs survival following mastecto~y. In lung cancer the immunosuppression following radiation therapy is likely to be most severe because the field of radiation includes the thymus, the thoracic duct, and the entire cardiac output, several times over. Chemotherapy, although not much used at present in the treatment of lung cancer, is also immunosuppressant at least temporarily.9.26 It is clear, therefore, that any treatment which the patient with lung cancer receives is like the double-edged sword; it is likely to produce further immunosuppression while it eradicates tumor cells. The relative importance of immunosuppression cannot be determined at present, but the experience cited above and our concepts of tumor immunology suggest that it is likely to jeopardize survival unless every last tumor cell has been eradicated by, for example, surgery. The fate of the cancer patient probably depends to a large extent on the balance between the two opposing effects of treatment.
RATIONALE OF IMMUNOTHERAPY Immunotherapy, on the other hand, seeks specifically to enhance the immune response against tumor antigens, which is one reason why it is the focus of so much interest and hope. Of the two general forms of immunotherapy currently in human use, specific immunotherapy seeks to enhance immunity to specific tumor antigens by vaccinating the cancer patient with autologous or homologous tumor cells or extracts. NonspeCific immunotherapy, which is more widely practiced, attempts to enhance all aspects of cell-mediated immunologic reactivity of the patient by immunostimulants such as live BCG organisms, or nonliving agents such as Corynebacterium parvum vaccine, extracts of BCG, and other agents. Only BCG immunotherapy has been extensively used in this country. Both specific and nonspecific immunotherapy clearly prolong survival and reduce mortality in a number of animal models.
Immunotherapy Trials in Lung Cancer Numerous trials of various forms of immunotherapy in many tumors have been conducted. Although these trials often indicated an improvement in survival which was attributed to immunotherapy, it is probably too early for definitive generalizations in human cancer. In spite of the fact that it is now the second most common malignant tumor in this country, relatively few trials in patients with primary lung cancer have been reported. 27 Specific immunotherapy has been attempted with aqueous extracts of bronchogenic cancer,! or tumor cells modified and readministered in complete Feund's adjuvant. 57 Another approach has been to cross-immunize two patients with extracts of each other's cancers, and after an "immunizing" period, cross-transfuse leucocytes. 29 Some benefit in terms of tumor regression or prolongation of survival was apparent in each of these reports; the numbers, however, are very small and the studies were uncontrolled.
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Nonspecific immunotherapy has been studied in lung cancer with the use of live BCG alone or combined with chemotherapy1l, 30, 35. 59 with a saline extract of BCG,36 and with killed Corynebacterium parvum vaccine. 3t - 33 A single intradermal injection of BCG, which might be expected to produce long-lasting stimulation because the live organisms continue to grow and divide, produced no benefit in one study,30 but in another studyll an approximate two-fold increase in 2-year survival occurred, although the difference between control and BCG treatment groups was not quite significant. In a third study,35 several intradermal BCG injections were given; the duration of survival was approximately doubled as compared to that of a control group. The same authors conducted a trial using a saline extract of BCG36 and reported objective evidence of tumor regression in some cases. When BCG immunotherapy was combined with chemotherapy,59 2-year survival was again approximately twice that of a group which did not receive BCG, but the difference is not significant. France, Israel has used C. parvum extensively as the immunotherapeutic agent in combination with chemotherapy.al-33 In randomized control trials patients with advanced lung cancer who received both C. parvum and chemotherapy survived significantly longer than patients who received chemotherapy alone; 5 months versus 9.1 months for oat cell, 5.6 months versus 9.8 months for epidermoid lung cancer. Finally, an immunotherapeutic trial of nature: it was long suspected that patients who developed empyema following resection for lung cancer fared better than those who did not. When examined critically this suspicion was validated. 44 . 49, 56 It is postulated that the infection itself provides a form of nonspecific immunotherapy which either enhances immunologic reactivity in general or produces an intense local immunologic response in which residual "bystander" tumor cells are eradicated. It seems clear that, in its present forms, immunotherapy is not the penicillin of lung cancer. While there is every indication that immunotherapy, in one form or another, can prolong survival and increase survivorship, a great deal more work is required. Trials from many different groups, particularly trials with randomly assigned controls involving large numbers of well-staged patients with good histologic data, are needed. Such clinical trials are in progress in our center and others and will ultimately provide the best evidence of the value of immunotherapy in lung cancer. While survival data are the only criteria of the value of immunotherapy, immunologic studies can provide useful information. Prognosis in cancer is related to immunocompetence, and the principal objective of nonspecific immunotherapy is to increase immunocompetence. It is possible, therefore, that studies of the immunologic effects of immunotherapy may provide inferential data on the success of immunotherapy regimens in general and possibly in individual patients. This information is available much sooner than survival data. A number of studies have shown that BCG immunotherapy is associated with conversion to positive delayed hypersensitivity skin responses to PPD; a few have shown this for antigens unrelated to PPD.
In
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The effect of C. parvum33 and BCG immunotherapy17, 18 in lung cancer is similar and in the latter reports, in vitro lymphocyte responses to PHA and five non-PPD antigens were also significantly enhanced. The enhancement is generally only seen in patients whose subsequent clinical response is favorable, and this has been the usual experience in reports on other tumors. It seems likely that serial immunologic tests, particularly those which employ assays of many aspects of lymphocyte function in vitro, can provide early information on the efficacy of immunotherapy regimens, and possibly on the prognosis of individual patients.
Requirements for Success of Immunotherapy Experience derived from the above and many other studies indicates that current forms of immunotherapy are most likely to be clinically effective under the following conditions: 1. When the tumor burden is minimal. The success of immunotherapy is probably inversely related to the tumor mass. Patients with any clinically evident tumor remaining after conventional therapy are unlikely to be cured by immunotherapy although survival may be prolonged. The optimal time for immunotherapy is immediately following the completion of conventional therapy when the residual tumor mass is smallest, and not when recurrence occurs. The antitumor potential of the immune system is quite different from that of conventional therapy. Radiation therapy and surgery eradicate large numbers of tumor cells from a defined site but do nothing to eradicate subclinical metastatic deposits. The reticuloendothelial system, in contrast, is very effective in locating and eradicating small numbers of "foreign" cells, but is incapable of killing large numbers of tumor cells and may in fact be inhibited by them. 2. When the host is immunocompetent, by which is meant the host is capable of becoming sensitized to neoantigens. In general, this requirement overlaps with the previous one. 3. Immunotherapy is best administered in a site related to the primary tumor. The reasons for this are largely theoretical but supported by experimentation. 2 ,65 The mechanism of action of nonspecific immunotherapeutic agents is unknown but if they act as an adjuvant in sensitizing the host to residual tumor antigens, it is well known the adjuvant should be located in the immediate proximity of the immunogen. If, on the other hand, they act as immunostimulants, it is important to sensitize the T lymphocyte population resident in the area of the primary tumor as there is now good evidence for the regionalization of these lymphocytes. z5 ,60 Herein lies one of the principal problems for immunotherapy of lung cancer and other visceral tumors, namely how to get the vaccine to the site of residual disease. 4. Immunotherapy which entails the possibility of increasing levels of circulating enhancing or blocking factors is undesirable. Some forms of immunotherapy including passive serum transfer and, possibly, vaccination with tumor cells carry the risk of raising the levels of circulating factors which act in favor of the tumor rather than the tumor host. Only those regimens which selectively augment cell-mediated immunity should be employed. 5. Intratumor injection of immunostimulants is best avoided. This has theoretical attractions but in practice is associated with significant severe complications including sudden death. 40 ,52 Furthermore, intratumor injection is impractical in a large number of visceral tumors including lung cancer.
UNIVERSITY OF CHICAGO LUNG CANCER PROGRAM The above principles represent only the very beginnings of the development of expertise in immunotherapy. The state of the art is anal-
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Table 1. Clinical Staging System for Lung Cancer* POSTSURGICAL CLINICAL
Primary Tumor- T No evidence of primary tumor Tumor proved by the presence of malignant cells in secretions but not visualized roentgenographically or bronchoscopically. A tumor that is 3.0 cm or less in greatest diameter, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy A tumor more than 3.0 cm in greatest diameter or a tumor of any size which, with its associated atelectasis or obstructive pneumonitis, extends to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be at least 2.0 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung and there must be no pleural effusion A tumor of any size with direct extension into an adjacent structure such as the chest wall, the diaphragm, or the mediastinum and its contents; or demonstrable bronchoscopically to be less than 2.0 cm distal to the carina; or any tumor associated with atelectasis or obstructive pneumonitis of an entire lung or a pleural effusion Regional Lymph Nodes-N No demonstrable spread to regional lymph nodes Spread to lymph nodes in the ipsilateral hilar region Spread to lymph nodes in the mediastinum Distant Metastasis-M No distant metastasis Distant metastasis such as in scalene, cervical, or abdominallymph nodes, pleural cytology, liver, brain, contralateral lung, bone, etc.
SURGICAL
EVALUATIVE TREATMENT
VALUE
VALUE
VALUE
TO
TO
TO
TX
TX
TX
T1
T1
T1
T2
T2
T2
T3
T3
T3
NO N1 N2
NO N1 N2
NO N1 N2
MO
MO
MO
M1
M1
M1
"Adapted from Clinical Staging System for Carcinoma of the Lung, published by the American Joint Committee for Cancer Staging and End Results Reporting, September 1973.
ogous to pre-Listerian surgery: we are confident of enormous potential but only just becoming aware of how to go about achieving it. A trial of immunotherapy in progress at this institution is typical of current trials of BCG but has special adaptation to lung cancer. Patients are carefully screened using all conventional techniques including bone, brain, liver-spleen, and gallium scans. Those with disease confined to the thorax and with adequate pulmonary function are then staged according to Table 1. They are then randomized into treatment groups according to stage as shown in Table 2. BCG is given to scarification sites over the thorax at weekly intervals for 3 months, then monthly for a further 3 months, then every 3
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Treatment Protocol for Staged Lung Cancer Patients
Group I: Primary Tumor T, +T2, Regional Lymph Nodes N o+ N,Mo 1. Surgical Resection 2. Surgical Resection + Immunotherapy 3. Surgical Resection + Chemotherapy 4. Surgical Resection + Combined Immunotherapy + Chemotherapy Group II: Primary Tumor T, + T 2, Regional Lymph Nodes N2MO 1. Surgical Resection + Radiation 2. Surgical Resection + Radiation + Immunotherapy 3. Surgical Resection + Radiation + Chemotherapy 4. Surgical Resection + Radiation + Combined Immunotherapy + Chemotherapy Group III: Primary Tumor T 3 , Regional Lymph Nodes N o+ N,Mo 1. Surgical Debulking + Radiation 2. Surgical Debulking + Radiation + Immunotherapy 3. Surgical Debulking + Radiation + Chemotherapy 4. Surgical Debulking + Radiation + Combined Immunotherapy + Chemotherapy Group IV: Primary Tumor T3 , Regional Lymph Nodes N2MO 1. Surgical Debulking + Radiation 2. Surgical Debulking + Radiation + Immunotherapy 3. Surgical Debulking + Radiation + Chemotherapy 4. Surgical Debulking + Radiation + Combined Immunotherapy + Chemotherapy
months for an indefinite period. In those patients who also receive chemotherapy the BCG schedule is given in the 4 weeks before each cycle. Chemotherapy consists of weekly intravenous injections of methotrexate followed by citrovorum rescue. Three cycles of 8 weekly injections are separated by4-week intervals. This protocol involves several departures from conventional therapy, apart from the use of BCG immunotherapy. The use of chemotherapy following resection of Stage I disease is aimed at eradicating residual or subclinical metastatic disease which is the biggest problem in the surgical treatment of lung cancer. The early routine use of radiation therapy in Stage II disease has the same intention. Patients with large tumors adjacent to vital structures are conventionally considered to J?e inoperable because of the lack of tumor-free tissue around the margins of disease. These patients will receive radiation before the tumor is removed to reduce the bulk of tumor tissue. By itself this has not been beneficial in previous trials; however, if followed by additional therapy the prognosis may be considerably improved. In essence, the approach is much more aggressive than conventional practice in the expectation that combinations of all innovations in therapy including immunotherapy will provide greater cure rates and better palliation.
FUTURE PROSPECTS FOR IMMUNOTHERAPY IN LUNG CANCER From this point the development of immunotherapy can be considered in two phases; firstly, the optimization of current nonspecific immunotherapy, and secondly, the development of new and probably specific immunotherapy regimens.
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A number of facts need to be learned about current forms of immunotherapy with BCG and C. parvum. For example, present dosages and treatment schedules are more or less arbitrary although some studies bearing on these considerations have been performed in melanoma. 20 We need to know more about the optimal form and strain of BCG; currently available preparations of BCG are usually lyophilized and have been mechanically disrupted so that less than 1 per cent of the organisms is viable. There is evidence that suggests that preparations with higher viability are more potent immunostimulants.23 Should we be using fully viable BCG, perhaps taken directly out of culture? The route of immunotherapy is another unknown and possibly critically important factor. Although it is desirable to administer it in the site of the primary tumor for the reasons given above, one would like to know whether it is practical and beneficial to administer BCG into the thoracic cavity producing a deliberate empyema as has been attempted. 41 BCG vaccine could be inserted into the thoracic cavity at the time of resection of the tumor, perhaps combined with injection of BCG into the mediastinum in the vicinity of the lymphatic drainage. Alternatively, it could be injected into the pleural space at intervals following surgery. Other possible approaches are embolization of BCG through the venous system or direct injection into the mediastinum and/or bronchial stump at bronchoscopy. The hazards of these approaches would need very careful study. Recently aerosol inhalation of BCG has been used for other purposes. 3 This may prove to be the simplest and most practical technique of BCG immunotherapy of lung cancer; again, the hazards of this need to be evaluated. One needs also to know about the combination of immunotherapy with surgery and other conventional therapy. Two areas of outstanding import can be cited. The results of surgical resection of oat cell cancer are presently so poor, about 6 per cent 2-year survival for Stage I disease, that surgery is widely regarded as contraindicated in this type of lung cancer. Can immunotherapy combined with surgery improve survival enough to reverse this view? Early results suggest that it may be able toY Again, patients whose lung cancer involves the chest wall or vital organs such as esophagus or major bronchi are also regarded as inoperable even when mediastinal nodes are clear and there are no distant deposits, because of the certainty that the primary tumor cannot be removed with enough normal tissue to ensure tumor-free margins. It may be that removal of as much as possible of the tumor ("debulking") followed by radiation will result in a residual tumor mass which is small enough to be eradicated by immunotherapy. Even if this does not effect a cure it may afford better palliation than radiation alone. The combination of immunotherapy with radiation therapy and/or chemotherapy also presents many possibilities. As already mentioned, both of these forms of therapy are immunosuppressive. Furthermore, there is some evidence that irradiated lung cancer patients do not experience the same degree of immunoenhancement following immunotherapy as nonirradiated patients,18 a fact which might jeopardize survival. Indeed, accel-
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erated tumor growth following radiation or chemotherapy is occasionally seen. Can immunotherapy either before or during conventional therapy minimize the immunosuppressive effect? If so, does this improve prognosis? Is there a hazard of systemic infection associated with giving live organisms to a patient undergoing immunosuppressive therapy? If so, would C. parvum vaccine or extracts of BCG serve the purpose of maintaining immunologic competence as well? It is important that these questions be answered before BCG or another form of immunotherapy gains such a position in medical practice or public awareness that controlled trials can no longer be performed. Looking further ahead one can conceive of far more ambitious forms of immunotherapy, regimens which will possibly have the ability to eradicate large tumor masses. The justification of this optimism is that the same immune system, the T lymphocyte system, has the ability to reject huge tissue masses such as homo grafts even when it is suppressed by therapy. If this enormous potential for immune rejection could be brought to bear on neoplastic tissue, the prognosis for malignant disease would be transformed. It seems inevitable that if immunotherapy is to achieve this potential it will be by specific immunotherapy, the use of autochthonous tumor cells, or antigens or lymphocytes sensitized to these. Appropriate vaccines could consist of tumor cells removed from the patient at surgery; bronchoscopy probably would not yield enough tissue. These cells could be inactivated either by x-irradiation or mitomycin; killed cells appear not to be as immunogenic as live inactivated cells. The immunogenicity of such cells can be enhanced by treating them with neuraminidase in vitr04 or possibly by coupling them to other agents such as protein or concanavalin.57 A vaccine composed of inactivated, neuraminidase treated cells, together with BCG as adjuvant, has been used in colon cancer with some success.50 An alternative approach is to infuse lymphocytes immunized against the patient's tumor. The hilar and mediastinal lymph nodes removed at surgery and currently discarded form an excellent source for such lymphocytes as they have already been sensitized, presumably, to autochthonous tumor antigens, although they may be immature because they have not yet been released into the circulation. They could, however, be grown in culture and possibly amplified by mitogens. 13 Problems such as the induction of latent virus would have to be considered and overcome. Attempts could also be made to sensitize or "educate" lymphocytes in vitro by special techniques. 15 It is also possible that the host's lymphocytes could be educated in vivo by the use of transfer factotl 5 developed either from cured patients, in which case the tumor antigens are likely not to be identical to those of the recipient, or, more ambitiously, from animals immunized with the patient's tumor. Possibly "immune RNA" can confer the same degree of lymphocyte immunity.21 The above approaches have as their goal the development of a population of T lymphocytes sensitized against tumor antigens. Although this is desirable, a detailed immunologic analysis of the immune status of patients with lung cancer may well demonstrate that certain patients
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already have a well developed and specifically directed cellular response against autochthonous tumor antigens, but that blocking or enhancing factors are responsible for its failure to reject the tumor. In this case, innovative techniques will be required to selectively remove circulating tumor antigens, possibly by an immunoabsorbent technique, or to suppress the host's antibody-forming capacity by an immunosuppressant which does not affect cell-mediated immunity. Possibly new agents such as levamisole or tilorone will alternatively be useful in this respect. Although many future approaches can be conceived which have a reasonable prospect for success, certain principles should be kept in mind. The ideal immunotherapy of the future will probably be specific for the patient's tumor and will certainly be one in which cell-mediated immunity is induced; the possibility of inducing circulating antibody with its attendant risks of blocking or enhancing effect must be minimal. Equally important from a practical standpoint, the regimen must be relatively simple; a procedure which requires an inordinate amount of lab work, technician time, and skill is unlikely to gain widespread use and thus have much impact on the cancer problem, however effective it may in fact be. Granted that complicated procedures can often be developed into simpler more practical ones for routine application, the clinical validation of an immunotherapy regimen necessarily involves many patients and several years of follow-up. A program which is inordinately complex has less chance of receiving convincing trials, or of being adopted for widespread use. One might be forgiven for looking even further ahead to an era of immunoprophylaxis. If cancer statistics continue on their present course, lung cancer or colon cancer will afflict one new victim of every 1000 of our entire population each year before the end of the next decade. As obvious preventive measures for lung cancer have been largely ignored by the public, it is relevant to consider all other possible preventive measures. Here again immunologic techniques may playa role. It is clear from animal experiments that many tumors can be prevented by both specific and nonspecific immunologic means. Specific immunoprophylaxis is unlikely to be successful in the human situation because of the nature of chemical oncogenesis; each tumor has unique antigenicity, although some overlap occurs. Probably nonspecific immunoenhancement could reduce the incidence of cancer in the population which will be entering the high risk phase in the 1980's and beyond.
SUMMARY The size of the lung cancer problem and the dismal results of conventional therapy justify close attention to the possibilities of immunotherapy. Lung cancer patients, like other tumor patients, are often relatively immunosuppressed although an immune response directed against autochthonous tumor cells can usually be demonstrated. All conventional forms of therapy, surgery, chemotherapy, and particularly radiation therapy, are further immunosuppressive, which, there is rea-
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son to believe, jeopardizes a successful outcome. Immunotherapy seeks to counteract this either by nonspecific immunoenhancement or by enhancing reactivity to tumor specific antigens. The results of immunotherapy trials in lung cancer patients suggest that survival can be prolonged and survivorship increased by immunotherapy, although the benefit is inconclusive at present. Optimal conditions for immunotherapy, as presently understood, are outlined. Practical questions about the optimal use of current immunotherapy regimens need to be answered, but a more aggressive approach to lung cancer therapy when combined with immunotherapy seems justified. In particular, the criteria for operability will need to be redefined, particularly as regards oat cell cancer and large tumors which cannot be completely resected but in which "debulking" may contribute to the success of subsequent radiation and immunotherapy. Possible future immunotherapy regimens applicable to lung cancer are proposed, with the reservation that their success is likely to be directly related to their practicability.
REFERENCES 1. Alth, G., Denck, H., Fischer, M., et al.: Aspects of the immunologic treatment of lung cancer. Cancer Chemother. Rep., 4:271, 1973. 2. Baldwin, R. W., and Pimm, M. V.: BCG immunotherapy of rat tumors of defined immunogenicity. Nat!. Cancer Inst. Monogr., 39:11,1973. 3. Barclay, W. R., Busey, W. M., Dalgard, D. W. et al.: Protection of monkeys against airborne tuberculosis by aerosol vaccination with BCG. Am. Rev. Resp. Dis., 107:351, 1973. 4. Bekesi, J., St. Arneault, G., Walter, L., and Holland, J. F.: Immunogenicity of leukemia L1210 cells after neuraminidase treatment. J. Nat. Cancer Inst., 49:107,1972. 5. Black, M. M.: and Speer, F. D.: Sinus histocytosis of lymph nodes in cancer. Surg. Gynec. Obstet., 106:163,1958. 6. Braeman, J., and Deeley, T. J.: Radiotherapy and the immune response in cancer of the lung. Br. J. Radiol., 46:446, 1973. 7. Brugarolas, A., and Takita, H.: Immunologic status in lung cancer. Chest, 64:427,1973. 8. Burk, M. W., and McKhann, C. F.: The immunology of tumors. Surg. Ann., 5:1,1973. 9. Cardozo, E. L., and Harting, M. C.: Immunologic behavior before and during cytostatic treatment in bronchus carcinoma. Oncology, 25 :520, 1971. 10. Ducos, J., Migueres, J., Colombies, P., Kessous, A., and Poujoulet, N.: Lymphocyte response to PHA in patients with lung cancer. Lancet, 1 :1111,1970. 11. Edwards, F. R., and Whitwell, F.: Use of BCG as an immunostimulant in the surgical treatment of carcinoma of the lung. Thorax, 29:654,1974. 12. End Results in Cancer. Report No.3. End Results Section, Biometry Branch, National Institutes of Health, Publication 30, Bethesda, Md., 1968, p. 81. 13. Frenster, J., and Rogoway, W. M.: Clinical use of activated autologous lymphocytes for human cancer immunotherapy. In Cumley, R. N., and McKay, T. E. (eds.): Oncology 1970 (Abstract). Chicago, Year Book Medical Publishers, Inc., 1970, p. 327. 14. Garrioch, D. B., Good, R. A., and Gatti, R. A.: Lymphocyte response to PHA in patients with nonlymphoid tumors. Lancet, 1 :618, 1970. 15. Golub, S. H., and Morton, D. L.: Sensitization of lymphocytes in vitro against human melanoma associated antigens. Nature, 251 :161,1974. 16. Gross, N. J., and DeMeester, T.: Unpublished observations. 17. Gross, N. J, and Quartey, A. E.: Immune responses following BCG therapy. In Crispen, R. (ed.): Neoplasm Immunity: Theory and Application. 1975, p. 127. 18. Gross, N. J., and Quartey, A. C. E.: Immunologic monitoring in BCG therapy for malignant disease, Cancer, in press, 1975. 19. Gross, R. L., Latty, A., Williams, E. A., and Newberne, P. M.: Abnormal spontaneous rosette formation and rosette inhibition in lung carcinoma. N. Eng. J. Med., 292:439, 1975. 20. Gutterman, J. V., Mavligit, G., McBride, C., et al.: Immunoprophylaxis of malignant melanoma with systemic BCG: study of strain, dose and schedule. Natl. Cancer Inst. Monogr. 39:205, 1973.
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21. Han, T.: "Immune" RNA-mediated transfer of delayed skin reactivity in patients with Hodgkin's disease. Clin. Exp. Immunol., 14:213, 1973. 22. Han, T., and Takita, H.: Immunologic impairment in bronchogenic carcinoma: a study of lymphocyte response to phytohemagglutinin. Cancer, 30:616, 1972. 23. Hawrylka, E., and Mackaness, G. B.: Immunopotentiation with BCG. IV. Factors affecting the magnitude of an antitumor response. J. NatL Cancer Inst., 51 :1683,1973. 24. Hellstrom, I., Sjogren, H. 0., Warner, G., et al.: Blocking of cell mediated immunity by sera from patients with growing neoplasms. J. Natl. 'Cancer Inst., 7:226, 1971. 25. Henney, C. S., and Waldman, R. H.: Cell-mediated immunity shown by lymphocytes from the respiratory tract. Science, 169:696, 1970. 26. Hersh, E. M.: Cancer Medicine. Philadelphia, Lea and Febiger, 1973, p. 951. 27. Hersh, E. M., Mavligit, G. M., and Gutterman, J U.: Immunotherapy as related to lung cancer: a review. Sem. Oncology, 1 :273, 1974. 28. Hughes, L. E., and Mackay, W. D.: Suppression of the tuberculin response in malignant disease. Br. Med. J., 2:1346,1965. 29. Humphrey, L. J., Jewell, W. R., Murray, D. R., et al.: Immunotherapy for the patient with cancer. Ann. Surg., 173:47,1971. . 30. Israel, L.: Contribution a l'etude des phenomfme d'immunite cellulaire chez les cancereux bronchopulmonaires avant traitement palliatif ou chirurgical. Poumon Coeur, 24:339, 1968. ' 31. Israel, L.: Preliminary results of nonspecific immunotherapy for lung cancer. Cancer Chemother. Rep., 4:285,1973. 32. Israel, L.: Nonspecific immunostimulation in bronchogenic cancer. Scand. J Resp. Dis., SuppL 89:95, 1974. 33. Israel, L., and Edelstein, R. L.: Nonspecific immunostimulation with Corynebacterium parvum in human cancer. In: Immunologic Aspects of Neoplasia. M. D. Anderson Hospital and Tumor Institute at Houston. Baltimore, Williams and Wilkins, 1974. 34. Israel L., Mugica, J., and Chahinian, P. H.: Progress ,of early bronchogenic carcinoma. Survival curves of 451 patients after resection of lung cancer in relation to the results of preoperative tuberculin skin test. Biomedicine,19:68, 1973. 35. Kadziev, S., and Kavaklieva-Dimitrova, J.: Application du BCG dans Ie cancer chez l'homme. Folia Med. (Plovdiv), 11 :8, 1969. 36. Kadziev, S., and Kavaklieva-Dimitrova, J.: The treatment of patients with bronchial cancer with a water-saline extract of BCG. Vopr. Onkol., 17(8):51,1971. 37. Krant, M. J.: Immunologic alterations in bronchogenic, cancer; sequential study. Cancer, 21 :623, 1968. 38. Lee, R. E.: Radiotherapy of bronchogenic carcinoma. Sem. Oncology, 1 :245,1974. 39. Mavligit, G. M., Gutterman, J. U., McBride, C. M., et al.: Cell mediated immunity to human solid tumors in vitro. Detection by lymphocyte blastogenic responses to cell associated and .solubilized tumor antigens. NatL Cancer Inst. Monogr., 37: 167, 1973. 40. McKhann, C. F., Hendrickson, C. G., Spitler, L. E., etal.: Immunotherapy of melanoma with BCG. Two fatalities following intralesional injection. Cancer, 35:514,1975. 41. McKneally, M.: Intrapleural BCG after surgery for lung cancer. In Crispen, R. (ed.): Neoplasm Immunity: Theory and Application. 1975; p. 153. 42. Millard, R. E.: Effect of previous irradiation in the transformation of blood lymphocytes. J. Clin. Path., 18:783, 1965. 43. Mountain, C. F.: Surgical therapy in lung cancer: biologic physiologic and technical determinants. Sem. Oncology, 1 :253, 1974. 44. Ruckdeschel, J. C., Codish, S. D., Stranahan, et al.: Post-operative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N. Eng. J. Med., 287:1013, 1972. , 45. Neidhart, J. A., and LoBuglio, A. F.: Transfer-factor therapy of malignancy. Sem. Oncology, 1 :379, 1974. 46. Rumke, P., and Vos-Brat, L. C.: Immunoglobuline concentraties, PHA reacties van lymphocyten in vitro en entale antistoftitres van ge'zonde rokers. Jaarboek Kankeronderzoek, 49: 1969. 47. Selawry, O. S.: The role of chemotherapy in the treatment of lung cancer. Sem. Oncology, 1 :259, 1974. 48. Selawry, O. S., and Hansen, H. H.: Cancer Medicine, Philadelphia, Lea and Febiger, 1973, p. 1473. 49. Sensenig, D. M., Rossi, N. P., and Ehrenhaft, J. L.: Results of surgical treatment of bronchogenic carcinoma. Surg. Gynec. Obstet., 116:279, 1963. 50. Simmons, R. L., and Rios, A.: Immunotherapy of cancer: immunospecific rejection of tumors in recipients of neuraminidase treated tumor cells plus BCG. Science, 174:591, 1971. 51. Sjogren, H. 0., Helstrom, I., Bansal, S. C., et al.: Suggestive evidence that the "blocking antibodies" of tumor bearing individuals may be antigen-antibody complexes. Proc. Nat. Acad. Sci., 68:1372,1971.
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52. Sparks, F. C., Silverstein, M. J., Hunt, J. S., et al.: Complications of BCG immunotherapy in patients with cancer. N. Eng. J. Med., 289:827, 1973. 53. Stewart, T. H. M.: The presence of delayed hypersensitivity reactions in patients toward cellular extracts of their malignant tumors. Cancer, 23: 1380, 1970. 54. Stjernsward, J.: Immunodepressive effect of 3-methyl-cholanthrene. Antibody formation at the cellular level and reaction against weak antigenic homografts. J. NatL Cancer Inst., 35:885,1965. 55. Stjernsward, J., Jondal, M., Vanky, F., et al.: Lymphopenia and change in distribution of human B and T lymphocytes in peripheral blood induced by irradiation for mammary carcinoma. Lancet, 1 :1352, 1972. 56. Takita, H.: Effect of post operative empyema in survival of patients with bronchogenic carcinoma. J. Thorac. Cardiovasc. Surg., 59:642,1970. 57. Takita, H., and Brugarolas, A.: Adjuvant immunotherapy for bronchogenic carcinoma: preliminary results. Cancer Chemother. Rep., 4:293,1973. 58. Thomas, J. W., Lewis, H. S., and Yuen, A.: Effect of therapeutic irradiation on lymphocyte transformation in lung cancer. Cancer, 27:1046, 1971. 59. Villasor, R. P.: Clinical use of BCG vaccine in stimulating host resistance to cancer. J. Philip. Med. Assoc., 41 :619, 1965. 60. Waldman, R. H., Spencer, J. C., and Johnson, J. E.: Respiratory and systemic cellular and humoral immune response to influenza virus vaccine administered parenterally or by nose drops. Cell ImmunoL, 3 :294, 1972. 61. Weiss, W., Seidman, H., and Boucot, K. R.: The Philadelphia Pulmonary Neoplasm Research Project. Thwarting factors in periodic screening for lung cancer. Am. Rev. Resp. Dis., 111 :289, 1975. 62. Wells, S. A., Burdick, J. F., Christiansen, C., et al.: Demonstration of tumor associated delayed cutaneous hypersensitivity reactions in patients with lung cancer and in patients with carcinoma of the cervix. Natl. Cancer Inst. Monogr. 37:197, 1973. 63. Wingard, D. W., Lang, R., and Humphrey, L. J.: Effect of anesthesia on immunity. J. Surg. Res., 7:430, 1967. 64. Yachnin, S.: Fetuin, an inhibitor of lymphocyte transformation. The interaction of fetuin with mitogens and a possible role for fetuin in fetal development. J. Exp. Med., 141 :242, 1975. 65. Zbar, B., Bernstein, I. D., and Rapp, H. J.: Suppression of tumor growth at the site of injection with liVIng bacillus Calmette-Guerin. J. Natl. Cancer Inst., 46:831, 1971. Department of Medicine The University of Chicago Pritzker School of Medicine 950 East 59th Street Chicago, Illinois 60637
Lung Cancer: An Immunologic Viewpoint and the Prospects for Immunotherapy
Nicholas J. Gross, M.D.,* and Tom. R. DeMeester, M.D. t
The lung cancer problem is enormously challenging by any standards. In terms of size it is the largest cause of death from cancer. Between 70 and 80 thousand people in the United States will develop lung cancer this year, and, by present survival figures, only about 4 thousand of these patients will be alive in 1980.48 The incidence is rising in epidemic fashion. Preventive measures, although more obvious than for any other tumor, have been largely rejected, at least by the nonmedical public. Diagnosis is more often than not made too late for curative treatment,t2 even when the population at risk is screened at short intervals.61 Furthermore, the 'management of lung cancer by surgery and radiation therapy has not advanced significantly in 2 decades although refinements have been 'introduced;38. 43 and chemotherapy has yet to make any impact on this disease. 47 These problems and the difficulties of providing the best current therapy to lung cancer candidates&1 combine to produce one of the most problematic areas in medicine. It is therefore not surprising that considerable attention is being paid to the current boom in tumor immunology in the hope that significant and practical new therapeutic advances will be made which can be applied to lung cancer. There are many hundreds of papers on immunotherapy in animal and human neoplasia; this review deals mainly with human primary lung cancer but certain generalizations are probably justified.
IMMUNOLOGIC STATUS OF PATIENTS WITH LUNG CANCER The facts of tumor immunology, to the extent that these are known, have been reviewed in many journals recently, including the surgical From the Departments of Medicine and Surgery, and the Cancer Research Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois
*Assistant Professor of Medicine t Assistant Professor of Surgery Supported by a grant from the National Cancer Institute, DREW, Grant number CA 14599.
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literature,8 and will not be reviewed here. It is reasonable to assume that these facts apply equally to lung cancer as to other human tumors. The immune status of patients with lung cancer has been the subject of many investigations during the last decade. Relevant studies are those which deal with delayed hypersensitivity and cell-mediated immunity, both of which are aspects of the function of thymus derived lymphocytes, the principal intrinsic antitumor defense mechanism. The delayed hypersensitivity skin responses of patients with lung cancer are very commonly impaired at the time of presentation, whether assayed by the tuberculin skin test or the skin response to several other typical recall antigens or by de novo sensitization to agents such as dinitrochlorbenzene (DNCB).7, 17, 28, 30, 32, 37 In addition, the response of their lymphocytes in culture to nonspecific mitogens such as phytohemagglutinin (PHA) is also impaired,to, 14, 17,22 as is the in vitro response to recall antigens17 and the E-rosette test. 19 The origin of this impairment is not clear, but it is seen in many other tumors. It may be due to inhibiting factors liberated from tumor cells24 , 64 or to circulating antigen-antibody complexes. 51 Alternatively, immunosuppression may be due to carcinogen itself54 and may thus precede the neoplastic change, permitting relatively unopposed growth of nascent tumor cells. In fact, there is evidence that heavy smokers are immunosuppressed46 even in the absence of clinical lung cancer. In spite of this immunosuppression an immune response on the part of the patient directed specifically against his own tumor antigens almost invariably occurs and can be detected in a number of ways. Thus, lymphocytes of patients with lung cancer are often able to kill autochthonous tumor cells in culture,39 and extracts of autochthonous tumor cells often provoke delayed hypersensitivity skin responses in lung cancer patients. 53 ,62 There is also histologic evidence of the generation of an immune response, sinus hyperplasia, in the hilar and mediastinal lymph nodes. 5 Although immune rejection of subclinical, nascent tumors may occur on a continuous basis, the immune sensitization to tumor antigens is unable by itself to eradicate clinically obvious lung cancer. Nevertheless, this immune response may play an important role in the subsequent course of the patient. The likelihood of recovery from lung cancer is directly related to the immunocompetence of the patient at his presentation and following treatment.7' 9,17,34,37 Therapy for lung cancer itself may add to the immunologic impairment already present in many patients. Surgery has a temporary depressant effect on various aspects of immune function. 16 ,63 Furthermore, hilar and mediastinal lymph nodes are removed by surgery and these are the very nodes where a favorable specific immune response against tumor antigens is being generated. In fact, in an analogous situation, breast cancer, there is controversy as to whether the removal of regional lymph nodes improves or jeopardizes survival. Similarly, radiation therapy is markedly and selectively inhibitory for T lymphocytes55 and results in prolonged lymphopenia and immunosuppression42 , 58 although it is not clear yet whether this adversely affects survival in lung cancer.6 The analogy of breast cancer is again instructive: it has been controver-
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sial for many years whether radiation therapy improves or impairs survival following mastecto~y. In lung cancer the immunosuppression following radiation therapy is likely to be most severe because the field of radiation includes the thymus, the thoracic duct, and the entire cardiac output, several times over. Chemotherapy, although not much used at present in the treatment of lung cancer, is also immunosuppressant at least temporarily.9.26 It is clear, therefore, that any treatment which the patient with lung cancer receives is like the double-edged sword; it is likely to produce further immunosuppression while it eradicates tumor cells. The relative importance of immunosuppression cannot be determined at present, but the experience cited above and our concepts of tumor immunology suggest that it is likely to jeopardize survival unless every last tumor cell has been eradicated by, for example, surgery. The fate of the cancer patient probably depends to a large extent on the balance between the two opposing effects of treatment.
RATIONALE OF IMMUNOTHERAPY Immunotherapy, on the other hand, seeks specifically to enhance the immune response against tumor antigens, which is one reason why it is the focus of so much interest and hope. Of the two general forms of immunotherapy currently in human use, specific immunotherapy seeks to enhance immunity to specific tumor antigens by vaccinating the cancer patient with autologous or homologous tumor cells or extracts. NonspeCific immunotherapy, which is more widely practiced, attempts to enhance all aspects of cell-mediated immunologic reactivity of the patient by immunostimulants such as live BCG organisms, or nonliving agents such as Corynebacterium parvum vaccine, extracts of BCG, and other agents. Only BCG immunotherapy has been extensively used in this country. Both specific and nonspecific immunotherapy clearly prolong survival and reduce mortality in a number of animal models.
Immunotherapy Trials in Lung Cancer Numerous trials of various forms of immunotherapy in many tumors have been conducted. Although these trials often indicated an improvement in survival which was attributed to immunotherapy, it is probably too early for definitive generalizations in human cancer. In spite of the fact that it is now the second most common malignant tumor in this country, relatively few trials in patients with primary lung cancer have been reported. 27 Specific immunotherapy has been attempted with aqueous extracts of bronchogenic cancer,! or tumor cells modified and readministered in complete Feund's adjuvant. 57 Another approach has been to cross-immunize two patients with extracts of each other's cancers, and after an "immunizing" period, cross-transfuse leucocytes. 29 Some benefit in terms of tumor regression or prolongation of survival was apparent in each of these reports; the numbers, however, are very small and the studies were uncontrolled.
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Nonspecific immunotherapy has been studied in lung cancer with the use of live BCG alone or combined with chemotherapy1l, 30, 35. 59 with a saline extract of BCG,36 and with killed Corynebacterium parvum vaccine. 3t - 33 A single intradermal injection of BCG, which might be expected to produce long-lasting stimulation because the live organisms continue to grow and divide, produced no benefit in one study,30 but in another studyll an approximate two-fold increase in 2-year survival occurred, although the difference between control and BCG treatment groups was not quite significant. In a third study,35 several intradermal BCG injections were given; the duration of survival was approximately doubled as compared to that of a control group. The same authors conducted a trial using a saline extract of BCG36 and reported objective evidence of tumor regression in some cases. When BCG immunotherapy was combined with chemotherapy,59 2-year survival was again approximately twice that of a group which did not receive BCG, but the difference is not significant. France, Israel has used C. parvum extensively as the immunotherapeutic agent in combination with chemotherapy.al-33 In randomized control trials patients with advanced lung cancer who received both C. parvum and chemotherapy survived significantly longer than patients who received chemotherapy alone; 5 months versus 9.1 months for oat cell, 5.6 months versus 9.8 months for epidermoid lung cancer. Finally, an immunotherapeutic trial of nature: it was long suspected that patients who developed empyema following resection for lung cancer fared better than those who did not. When examined critically this suspicion was validated. 44 . 49, 56 It is postulated that the infection itself provides a form of nonspecific immunotherapy which either enhances immunologic reactivity in general or produces an intense local immunologic response in which residual "bystander" tumor cells are eradicated. It seems clear that, in its present forms, immunotherapy is not the penicillin of lung cancer. While there is every indication that immunotherapy, in one form or another, can prolong survival and increase survivorship, a great deal more work is required. Trials from many different groups, particularly trials with randomly assigned controls involving large numbers of well-staged patients with good histologic data, are needed. Such clinical trials are in progress in our center and others and will ultimately provide the best evidence of the value of immunotherapy in lung cancer. While survival data are the only criteria of the value of immunotherapy, immunologic studies can provide useful information. Prognosis in cancer is related to immunocompetence, and the principal objective of nonspecific immunotherapy is to increase immunocompetence. It is possible, therefore, that studies of the immunologic effects of immunotherapy may provide inferential data on the success of immunotherapy regimens in general and possibly in individual patients. This information is available much sooner than survival data. A number of studies have shown that BCG immunotherapy is associated with conversion to positive delayed hypersensitivity skin responses to PPD; a few have shown this for antigens unrelated to PPD.
In
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The effect of C. parvum33 and BCG immunotherapy17, 18 in lung cancer is similar and in the latter reports, in vitro lymphocyte responses to PHA and five non-PPD antigens were also significantly enhanced. The enhancement is generally only seen in patients whose subsequent clinical response is favorable, and this has been the usual experience in reports on other tumors. It seems likely that serial immunologic tests, particularly those which employ assays of many aspects of lymphocyte function in vitro, can provide early information on the efficacy of immunotherapy regimens, and possibly on the prognosis of individual patients.
Requirements for Success of Immunotherapy Experience derived from the above and many other studies indicates that current forms of immunotherapy are most likely to be clinically effective under the following conditions: 1. When the tumor burden is minimal. The success of immunotherapy is probably inversely related to the tumor mass. Patients with any clinically evident tumor remaining after conventional therapy are unlikely to be cured by immunotherapy although survival may be prolonged. The optimal time for immunotherapy is immediately following the completion of conventional therapy when the residual tumor mass is smallest, and not when recurrence occurs. The antitumor potential of the immune system is quite different from that of conventional therapy. Radiation therapy and surgery eradicate large numbers of tumor cells from a defined site but do nothing to eradicate subclinical metastatic deposits. The reticuloendothelial system, in contrast, is very effective in locating and eradicating small numbers of "foreign" cells, but is incapable of killing large numbers of tumor cells and may in fact be inhibited by them. 2. When the host is immunocompetent, by which is meant the host is capable of becoming sensitized to neoantigens. In general, this requirement overlaps with the previous one. 3. Immunotherapy is best administered in a site related to the primary tumor. The reasons for this are largely theoretical but supported by experimentation. 2 ,65 The mechanism of action of nonspecific immunotherapeutic agents is unknown but if they act as an adjuvant in sensitizing the host to residual tumor antigens, it is well known the adjuvant should be located in the immediate proximity of the immunogen. If, on the other hand, they act as immunostimulants, it is important to sensitize the T lymphocyte population resident in the area of the primary tumor as there is now good evidence for the regionalization of these lymphocytes. z5 ,60 Herein lies one of the principal problems for immunotherapy of lung cancer and other visceral tumors, namely how to get the vaccine to the site of residual disease. 4. Immunotherapy which entails the possibility of increasing levels of circulating enhancing or blocking factors is undesirable. Some forms of immunotherapy including passive serum transfer and, possibly, vaccination with tumor cells carry the risk of raising the levels of circulating factors which act in favor of the tumor rather than the tumor host. Only those regimens which selectively augment cell-mediated immunity should be employed. 5. Intratumor injection of immunostimulants is best avoided. This has theoretical attractions but in practice is associated with significant severe complications including sudden death. 40 ,52 Furthermore, intratumor injection is impractical in a large number of visceral tumors including lung cancer.
UNIVERSITY OF CHICAGO LUNG CANCER PROGRAM The above principles represent only the very beginnings of the development of expertise in immunotherapy. The state of the art is anal-
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Table 1. Clinical Staging System for Lung Cancer* POSTSURGICAL CLINICAL
Primary Tumor- T No evidence of primary tumor Tumor proved by the presence of malignant cells in secretions but not visualized roentgenographically or bronchoscopically. A tumor that is 3.0 cm or less in greatest diameter, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy A tumor more than 3.0 cm in greatest diameter or a tumor of any size which, with its associated atelectasis or obstructive pneumonitis, extends to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be at least 2.0 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung and there must be no pleural effusion A tumor of any size with direct extension into an adjacent structure such as the chest wall, the diaphragm, or the mediastinum and its contents; or demonstrable bronchoscopically to be less than 2.0 cm distal to the carina; or any tumor associated with atelectasis or obstructive pneumonitis of an entire lung or a pleural effusion Regional Lymph Nodes-N No demonstrable spread to regional lymph nodes Spread to lymph nodes in the ipsilateral hilar region Spread to lymph nodes in the mediastinum Distant Metastasis-M No distant metastasis Distant metastasis such as in scalene, cervical, or abdominallymph nodes, pleural cytology, liver, brain, contralateral lung, bone, etc.
SURGICAL
EVALUATIVE TREATMENT
VALUE
VALUE
VALUE
TO
TO
TO
TX
TX
TX
T1
T1
T1
T2
T2
T2
T3
T3
T3
NO N1 N2
NO N1 N2
NO N1 N2
MO
MO
MO
M1
M1
M1
"Adapted from Clinical Staging System for Carcinoma of the Lung, published by the American Joint Committee for Cancer Staging and End Results Reporting, September 1973.
ogous to pre-Listerian surgery: we are confident of enormous potential but only just becoming aware of how to go about achieving it. A trial of immunotherapy in progress at this institution is typical of current trials of BCG but has special adaptation to lung cancer. Patients are carefully screened using all conventional techniques including bone, brain, liver-spleen, and gallium scans. Those with disease confined to the thorax and with adequate pulmonary function are then staged according to Table 1. They are then randomized into treatment groups according to stage as shown in Table 2. BCG is given to scarification sites over the thorax at weekly intervals for 3 months, then monthly for a further 3 months, then every 3
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Treatment Protocol for Staged Lung Cancer Patients
Group I: Primary Tumor T, +T2, Regional Lymph Nodes N o+ N,Mo 1. Surgical Resection 2. Surgical Resection + Immunotherapy 3. Surgical Resection + Chemotherapy 4. Surgical Resection + Combined Immunotherapy + Chemotherapy Group II: Primary Tumor T, + T 2, Regional Lymph Nodes N2MO 1. Surgical Resection + Radiation 2. Surgical Resection + Radiation + Immunotherapy 3. Surgical Resection + Radiation + Chemotherapy 4. Surgical Resection + Radiation + Combined Immunotherapy + Chemotherapy Group III: Primary Tumor T 3 , Regional Lymph Nodes N o+ N,Mo 1. Surgical Debulking + Radiation 2. Surgical Debulking + Radiation + Immunotherapy 3. Surgical Debulking + Radiation + Chemotherapy 4. Surgical Debulking + Radiation + Combined Immunotherapy + Chemotherapy Group IV: Primary Tumor T3 , Regional Lymph Nodes N2MO 1. Surgical Debulking + Radiation 2. Surgical Debulking + Radiation + Immunotherapy 3. Surgical Debulking + Radiation + Chemotherapy 4. Surgical Debulking + Radiation + Combined Immunotherapy + Chemotherapy
months for an indefinite period. In those patients who also receive chemotherapy the BCG schedule is given in the 4 weeks before each cycle. Chemotherapy consists of weekly intravenous injections of methotrexate followed by citrovorum rescue. Three cycles of 8 weekly injections are separated by4-week intervals. This protocol involves several departures from conventional therapy, apart from the use of BCG immunotherapy. The use of chemotherapy following resection of Stage I disease is aimed at eradicating residual or subclinical metastatic disease which is the biggest problem in the surgical treatment of lung cancer. The early routine use of radiation therapy in Stage II disease has the same intention. Patients with large tumors adjacent to vital structures are conventionally considered to J?e inoperable because of the lack of tumor-free tissue around the margins of disease. These patients will receive radiation before the tumor is removed to reduce the bulk of tumor tissue. By itself this has not been beneficial in previous trials; however, if followed by additional therapy the prognosis may be considerably improved. In essence, the approach is much more aggressive than conventional practice in the expectation that combinations of all innovations in therapy including immunotherapy will provide greater cure rates and better palliation.
FUTURE PROSPECTS FOR IMMUNOTHERAPY IN LUNG CANCER From this point the development of immunotherapy can be considered in two phases; firstly, the optimization of current nonspecific immunotherapy, and secondly, the development of new and probably specific immunotherapy regimens.
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A number of facts need to be learned about current forms of immunotherapy with BCG and C. parvum. For example, present dosages and treatment schedules are more or less arbitrary although some studies bearing on these considerations have been performed in melanoma. 20 We need to know more about the optimal form and strain of BCG; currently available preparations of BCG are usually lyophilized and have been mechanically disrupted so that less than 1 per cent of the organisms is viable. There is evidence that suggests that preparations with higher viability are more potent immunostimulants.23 Should we be using fully viable BCG, perhaps taken directly out of culture? The route of immunotherapy is another unknown and possibly critically important factor. Although it is desirable to administer it in the site of the primary tumor for the reasons given above, one would like to know whether it is practical and beneficial to administer BCG into the thoracic cavity producing a deliberate empyema as has been attempted. 41 BCG vaccine could be inserted into the thoracic cavity at the time of resection of the tumor, perhaps combined with injection of BCG into the mediastinum in the vicinity of the lymphatic drainage. Alternatively, it could be injected into the pleural space at intervals following surgery. Other possible approaches are embolization of BCG through the venous system or direct injection into the mediastinum and/or bronchial stump at bronchoscopy. The hazards of these approaches would need very careful study. Recently aerosol inhalation of BCG has been used for other purposes. 3 This may prove to be the simplest and most practical technique of BCG immunotherapy of lung cancer; again, the hazards of this need to be evaluated. One needs also to know about the combination of immunotherapy with surgery and other conventional therapy. Two areas of outstanding import can be cited. The results of surgical resection of oat cell cancer are presently so poor, about 6 per cent 2-year survival for Stage I disease, that surgery is widely regarded as contraindicated in this type of lung cancer. Can immunotherapy combined with surgery improve survival enough to reverse this view? Early results suggest that it may be able toY Again, patients whose lung cancer involves the chest wall or vital organs such as esophagus or major bronchi are also regarded as inoperable even when mediastinal nodes are clear and there are no distant deposits, because of the certainty that the primary tumor cannot be removed with enough normal tissue to ensure tumor-free margins. It may be that removal of as much as possible of the tumor ("debulking") followed by radiation will result in a residual tumor mass which is small enough to be eradicated by immunotherapy. Even if this does not effect a cure it may afford better palliation than radiation alone. The combination of immunotherapy with radiation therapy and/or chemotherapy also presents many possibilities. As already mentioned, both of these forms of therapy are immunosuppressive. Furthermore, there is some evidence that irradiated lung cancer patients do not experience the same degree of immunoenhancement following immunotherapy as nonirradiated patients,18 a fact which might jeopardize survival. Indeed, accel-
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erated tumor growth following radiation or chemotherapy is occasionally seen. Can immunotherapy either before or during conventional therapy minimize the immunosuppressive effect? If so, does this improve prognosis? Is there a hazard of systemic infection associated with giving live organisms to a patient undergoing immunosuppressive therapy? If so, would C. parvum vaccine or extracts of BCG serve the purpose of maintaining immunologic competence as well? It is important that these questions be answered before BCG or another form of immunotherapy gains such a position in medical practice or public awareness that controlled trials can no longer be performed. Looking further ahead one can conceive of far more ambitious forms of immunotherapy, regimens which will possibly have the ability to eradicate large tumor masses. The justification of this optimism is that the same immune system, the T lymphocyte system, has the ability to reject huge tissue masses such as homo grafts even when it is suppressed by therapy. If this enormous potential for immune rejection could be brought to bear on neoplastic tissue, the prognosis for malignant disease would be transformed. It seems inevitable that if immunotherapy is to achieve this potential it will be by specific immunotherapy, the use of autochthonous tumor cells, or antigens or lymphocytes sensitized to these. Appropriate vaccines could consist of tumor cells removed from the patient at surgery; bronchoscopy probably would not yield enough tissue. These cells could be inactivated either by x-irradiation or mitomycin; killed cells appear not to be as immunogenic as live inactivated cells. The immunogenicity of such cells can be enhanced by treating them with neuraminidase in vitr04 or possibly by coupling them to other agents such as protein or concanavalin.57 A vaccine composed of inactivated, neuraminidase treated cells, together with BCG as adjuvant, has been used in colon cancer with some success.50 An alternative approach is to infuse lymphocytes immunized against the patient's tumor. The hilar and mediastinal lymph nodes removed at surgery and currently discarded form an excellent source for such lymphocytes as they have already been sensitized, presumably, to autochthonous tumor antigens, although they may be immature because they have not yet been released into the circulation. They could, however, be grown in culture and possibly amplified by mitogens. 13 Problems such as the induction of latent virus would have to be considered and overcome. Attempts could also be made to sensitize or "educate" lymphocytes in vitro by special techniques. 15 It is also possible that the host's lymphocytes could be educated in vivo by the use of transfer factotl 5 developed either from cured patients, in which case the tumor antigens are likely not to be identical to those of the recipient, or, more ambitiously, from animals immunized with the patient's tumor. Possibly "immune RNA" can confer the same degree of lymphocyte immunity.21 The above approaches have as their goal the development of a population of T lymphocytes sensitized against tumor antigens. Although this is desirable, a detailed immunologic analysis of the immune status of patients with lung cancer may well demonstrate that certain patients
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already have a well developed and specifically directed cellular response against autochthonous tumor antigens, but that blocking or enhancing factors are responsible for its failure to reject the tumor. In this case, innovative techniques will be required to selectively remove circulating tumor antigens, possibly by an immunoabsorbent technique, or to suppress the host's antibody-forming capacity by an immunosuppressant which does not affect cell-mediated immunity. Possibly new agents such as levamisole or tilorone will alternatively be useful in this respect. Although many future approaches can be conceived which have a reasonable prospect for success, certain principles should be kept in mind. The ideal immunotherapy of the future will probably be specific for the patient's tumor and will certainly be one in which cell-mediated immunity is induced; the possibility of inducing circulating antibody with its attendant risks of blocking or enhancing effect must be minimal. Equally important from a practical standpoint, the regimen must be relatively simple; a procedure which requires an inordinate amount of lab work, technician time, and skill is unlikely to gain widespread use and thus have much impact on the cancer problem, however effective it may in fact be. Granted that complicated procedures can often be developed into simpler more practical ones for routine application, the clinical validation of an immunotherapy regimen necessarily involves many patients and several years of follow-up. A program which is inordinately complex has less chance of receiving convincing trials, or of being adopted for widespread use. One might be forgiven for looking even further ahead to an era of immunoprophylaxis. If cancer statistics continue on their present course, lung cancer or colon cancer will afflict one new victim of every 1000 of our entire population each year before the end of the next decade. As obvious preventive measures for lung cancer have been largely ignored by the public, it is relevant to consider all other possible preventive measures. Here again immunologic techniques may playa role. It is clear from animal experiments that many tumors can be prevented by both specific and nonspecific immunologic means. Specific immunoprophylaxis is unlikely to be successful in the human situation because of the nature of chemical oncogenesis; each tumor has unique antigenicity, although some overlap occurs. Probably nonspecific immunoenhancement could reduce the incidence of cancer in the population which will be entering the high risk phase in the 1980's and beyond.
SUMMARY The size of the lung cancer problem and the dismal results of conventional therapy justify close attention to the possibilities of immunotherapy. Lung cancer patients, like other tumor patients, are often relatively immunosuppressed although an immune response directed against autochthonous tumor cells can usually be demonstrated. All conventional forms of therapy, surgery, chemotherapy, and particularly radiation therapy, are further immunosuppressive, which, there is rea-
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son to believe, jeopardizes a successful outcome. Immunotherapy seeks to counteract this either by nonspecific immunoenhancement or by enhancing reactivity to tumor specific antigens. The results of immunotherapy trials in lung cancer patients suggest that survival can be prolonged and survivorship increased by immunotherapy, although the benefit is inconclusive at present. Optimal conditions for immunotherapy, as presently understood, are outlined. Practical questions about the optimal use of current immunotherapy regimens need to be answered, but a more aggressive approach to lung cancer therapy when combined with immunotherapy seems justified. In particular, the criteria for operability will need to be redefined, particularly as regards oat cell cancer and large tumors which cannot be completely resected but in which "debulking" may contribute to the success of subsequent radiation and immunotherapy. Possible future immunotherapy regimens applicable to lung cancer are proposed, with the reservation that their success is likely to be directly related to their practicability.
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