Seminars in Surgical Oncology 7:239-243 (1991)
Role of lmmunotherapy in the Treatment of Bladder and Renal Cell Carcinoma NELSON N. STONE, MD, AND MICHAEL J. DROLLER, MD From the Department of Urology, Mount Sinai Medical Center, New York
Much remains to be learned about the immune response in human neoplasia both in a phenomenological sense and in its therapeutic possibilities. Recruitment of immune response mechanisms in the defense against cancer development and in the cure of advanced disease, though theoretically sound, remains to be proven in demonstration of both its phenomenological and clinical efficacy. The most important steps in this regard will require an analysis of those mechanisms that may truly be active in human cancer. Their enhancement and effective delivery to various tumor sites, then reliable monitoring, and proof of their efficacy will be necessary to accomplish before any conclusive statement can be made as to the usefulness of immunotherapy in the treatment of genitourinary neoplasia and of human cancer in general. KEY WORDS:BCG, human neoplasia
INTRODUCTION Application of the principles of immunology in designing a therapeutic approach to human malignancy is based upon a number of assumptions. First is that human cancers contain and express antigens that can be recognized as foreign by the host. Second is that immune response mechanisms will presumably attack those cells that express these antigens. Third is that immune response mechanisms can be delivered to the site of tumor so as to destroy the cancer cells that they recognize as foreign. Critics of these concepts have suggested that the presence of specific tumor antigens in human tumors remains to be proven. Moreover, failure of immunosurveillance to prevent cancer development from the very beginning implies that attempts to recruit immune response mechanisms to combat disseminated cancer cells might be futile. In addition, selection of one immune response mechanism may be insufficient in eliminating a particular tumor. Moreover, use of that particular mechanism may actually stimulate other mechanisms that may effectively abrogate that mechanism’s efficacy. These are but a few of the theoretical concerns investigators have had in designing immunotherapeutic approaches in cancer therapy. In addition, genetic drift, tumor heterogeneity, and cancer development in sanctuary sites have added 0 1991 Wiley-Liss, Inc.
further complexity in attempting to create effective immunotherapy .
THE NORMAL IMMUNE RESPONSE Much of our knowledge of immune response mechanisms is based upon experimental animal models and in vitro systems. Whether knowledge from these can be applied to the human system remains controversial. Nonetheless, it is valuable to consider these mechanisms as an indication of what might be utilized in the design of a rational immunotherapeutic approach to cancer. Tumor-associated antigens shed from the tumor in question or expressed at their surface are first recognized by macrophages. These cells engulf the antigens and process them for presentation to T and B lymphocytes. As part of this process, a variety of lymphokines and cytokines are produced and secreted by the lymphocytes and macrophages. These result in the proliferation of various subsets of lymphocytes, their maturation into cells with directed function, and their activation to react against the tumor cells that express the initiating antigen. T lymphocytes differentiate into helper T cells (TH), Address reprint requests to Michael J. Droller, M.D., Department of Urology, Mount Sinai Medical Center, Box 1272, 15th Floor, One Gustave L. Levy Place, New York, NY 10029.
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which are necessary for the successful production by B lymphocytes of antibodies directed against the initiating antigen. The T, cells are also important for the proliferation of cytotoxic T lymphocytes (Tc), which are directly toxic to the tumor cells. Suppressor T cells (Ts), which can inhibit both the activity of cytotoxic T lymphocytes and the production of antibody by activated B lymphocytes, are also produced and serve as a regulatory mechanism to limit the extent of immune response expression. Various additional populations of lymphocytes are also amplified. These include natural killer lymphocytes, which are active against tumor cells, LAK cells (lymphokine-activated killer cells), which are stimulated by interleukin 2 to proliferate and kill tumor cells, and antibody-dependent killer lymphocytes, which appear to require the presence of antibody to exert their cytotoxic activity against tumor cells. Macrophages also consist of subsets of cells that may either just recognize and process foreign antigens or actually express cytotoxic activity against any cell that expresses these antigens. A large variety of lymphokines and cytokines have been described. Each has been found to have a variety of activities depending upon the model system studied and the type of target cell/effector cell examined. The most prominent of these are interleukin 1 (IL-1). which stimulates the proliferation of macrophages and T lymphocytes, interleukin 2 (IL-2), which stimulates the proliferation and activity of LAK cells, and interferon (IF), which stimulates activity of natural killer cells and macrophages, and also induces increased expression of surface antigens on cancer cells while being cystostatic (rather than cytotoxic) to a variety of tumor cells. In addition, prostaglandins are produced by macrophages and by tumor cells themselves, and may function to abrogate the expression of immune response activity mounted against that particular tumor cell. The complexity of these interactions has made it extremely difficult to recruit a particular immune response mechanism in isolation of others in attempting to design an approach to the treatment of the variety of malignancies. In addition, the manner by which a particular immune response mechanism has been recruited and the ability to deliver that immune response mechanism to the site of tumor have remained problematic. Nonetheless, a variety of immune response mechanisms have been shown to be effective in various models of cancer. This has continued to encourage exploration and application of these mechanisms in the clinical setting.
IMMUNOTHERAPEUTIC APPROACHES Understanding of immunologic mechanisms has led to both active and passive approaches in immunotherapy in the cancer setting. The active approach has been based upon the stimulation of the host’s own immune response
mechanisms in mounting an attack against a particular cancer. The passive approach has been based upon enhancement of a particular immune response mechanism outside of the host with subsequent transfer of that activity back into the host for it to exert its effect. The major assumption underlying each approach is that the effective immune response activity could be delivered to the tumor site. In each, activated immune response cells would presumably seek out the cancer cells and destroy them. In addition, each approach has been subcategorized as being either specific or nonspecific. Specific approaches would attempt to recruit or enhance an immune response mechanism so that it would recognize a particular tumor antigen and react against that antigen or any cell that expressed that antigen. Nonspecific approaches would be designed to recruit or activate selected immune response mechanisms generically so that they would be active against tumor cells nonspecifically by recognizing the expression of antigens that distinguished those cells as foreign. Results with each of these approaches have generally been disappointing. This is not to say that theoretical considerations or animal models in support of these have not substantiated these approaches. Rather, their clinical application has generally produced minimal or at best nondurable results. A number of reasons have been suggested to explain this. First, adequacy of delivery of a particular immune response activity to the tumor site and efficacy of a particular concentration of stimulant or immune response agent have been questioned. Second, attempts to monitor the efficacy of immune response activity in the host, either as delivered actively or passively, have been unreliable and have therefore prevented any meaningful interpretation of the results of treatment outcome. Third, it has remained unclear as to whether tumor cells at each site expressed antigen in sufficient strength to be recognized by a particular immune response mechanism. Fourth, toxicities of treatment were often great, effectively limiting the extent of treatment and precluding delivery of a presumed full and theoretically effective level of immune response activity in the tumor site. In addition, the role of the host in the success of therapy remained unclear. Cancer often effects the elderly, in whom general physiologic function of various organ systems has deteriorated. Ability to recruit various components of the immune response to their fullest extent in this context might therefore be limited. The presence of the cancer itself might be sufficient to weaken the patient and compromise immune response capabilities. This could occur either because of compromise in the host’s nutritional status, production by the tumor of substances that might either directly or indirectly abrogate immune response capability, and the earlier administration of other forms of treatment (surgery, anesthesia, radiation,
Immunotherapy in Bladder and Renal Cell Carcinoma
chemotherapy) that themselves might compromise the host’s immune response capabilities. Last, even if the transfer or induction of an immune response mechanism were successful, it might conceivably induce other mechanisms that would limit the extent of immune response activity and thereby prevent full expression of such therapy against the cancer. Indeed, the complexity of the immune response system is such that it would undoubtedly have built into it a number of regulatory mechanisms that would serve to modify the extent of expression of any one mechanism. Our inability to monitor with accuracy immune response activity either systemically or at a particular tumor site would limit our ability to understand the role of such mechanisms in limiting the extent of immune response expression. This would seriously hamper any effort to explain success or failure of manipulation of the immune response in mounting an attack against cancer.
IMMUNOTHERAPY IN GENITOURINARY CANCER Bladder Cancer Of the estimated 48,000 new cases of bladder cancer diagnosed each year in the United States, 75-85% will present with superficial disease [ 11. These usually appear as papillary lesions involving the mucosa only (T,) or submucosa (TI) or flat carcinoma in situ (TJ. The majority of these lesions are T, (70%) and usually solitary WI. Effective therapy in treating carcinoma of the bladder encompasses eradication of existing lesions and prevention of recurrence or disease progression (to muscle infiltration or metastases). While transurethral resection of the lesion will undoubtedly prevent these events in most cases of low grade (G,) T, tumors, a significant proportion of patients with higher stage or grade disease will likely develop recurrence or progression [ a ] . Chemotherapeutic agents such as Thiotepa, Mitomycin-C, and Adriamycin have been only moderately successful in either eradicating disease or preventing recurrence. These agents, which rely upon relatively high concentrations of cytotoxic drug to be in contact with the bladder mucosa, have been shown to have a nef benefit of only 6-1 3% over controls in preventing disease recurrence. A great deal of interest has therefore focused on the potential use of immunotherapeutic approaches either in treating superficial disease or in preventing recurrence. Tremendous impetus to this approach was provided by observations that instillation of preparations of bacillus Calmette-GuCrin into the bladder produced an inflammatory response or granulomatous reaction and appeared to be effective both in the treatment of superficial transitional cell cancers of the bladder and in the prophylaxis against their recurrence. Their presumed mechanism of
241
action was the induction of an inflammatory response and presumably a cytotoxicity directed against the bladder tumor cells. Whether treatment or prophylaxis reflected a passive effect of the granulomatous inflammatory reaction that was induced, however, remained unclear. Bacillus Calmette-GuCrin (BCG) was first recognized as an effective immunotherapeutic agent in the treatment of patients with superficial bladder cancer and carcinoma in situ by Morales and associates in 1976 [7]. Since that time it has become established as the most effective intravesical agent in decreasing recurrence and in the prevention of disease progression. Results from several large studies demonstrate a 42% benefit in tumor prophylaxis and a 71% success rate in treatment of existing disease [8]. Unlike cytotoxic chemotherapy, intravesicat BCG provokes a cell-mediated immune response which in most patients is characterized by the formation of granulomatas in the bladder and by the positive conversion of the purified protein derivative (PPD) skin test [9]. However, the exact mechanism of action of BCG remains unknown, and attempts to measure BCG-mediated systemic immune responses have failed to predict clinical response or to help define the optimal course of therapy [lo-121. Although the exact nature of the anti-tumor activity of BCG is unknown, several different mechanisms have been postulated. Elimination of bladder tumors may result from lymphokine-augmented nonspecific cellmediated cytotoxicity or a direct anti-tumor action of lymphokines themselves [13]. IL-2 is one such lymphokine thought to be involved in BCG-mediated activity. IL-2 is produced by antigen stimulation of T lymphocytes [14]. Haaff and associates demonstrated the production of IL-2 in patients treated with BCG [ 131. However, even though these and other authors demonstrated the urinary recovery of IL-2 during BCG treatment, what role IL-2 has in the anti-tumor effect of BCG still needs to be clarified. Pizza and associates [I51 injected IL-2 directly into bladder tumors and noted tumor regression in 50%, supporting a role of IL-2 in this area. Together with the established role of IL-2 as a growth factor for T lymphocytes [14], as an inducer of gamma interferon [ 161, and as an activator of nonspecific 1ymphocyte-mediated tumoricidal activity [ 171, this suggests that there might be multiple effects of BCG-mediated immunoactivity in patients with bladder cancer. Current therapy calls for six weekly instillations of BCG 120 mg in 50 ml of sterile saline, with retention for 2 hours. In a study of 347 patients treated in such fashion, the median duration of response to one course of BCG was 27 months [18]. Twenty-eight patients were treated with a second course of BCG, and 54% had a
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complete or partial response. Catalona and associates also reported that 58% of patients who had recurrence after one course of BCG were rendered free of tumor by a subsequent course [19]. Sarosdy and Lamm [20] followed 120 patients a median of 67 months and retreated ten who failed, increasing their overall success rate from 78% to 89%. Toxicity of BCG is secondary to the intense local inflammatory reaction. Patients often complain of dysuria, frequency, urgency, and hematuria. Unfortunately, the degree of local inflammatory response does not necessarily correlate with likelihood of response (91. Interferons by themselves or in conjunction with other immuno-modulation measures have also been used in bladder cancer. Interferon alpha has been used intravesically with some success as a solitary agent in superficial bladder cancer [21]. More importantly, adjunctive roles for interferons are currently being investigated in this disease. Sarosdy and Kierum [22] enhanced BCG activity with the interferon inducer pyrimidinone in a murine bladder tumor model and Bryan and associates [23] demonstrated chemoprotective activity of interferon alpha/ beta in a formamide-induced bladder cancer model. A recent addition to the immunotherapy armamentarium is tumor necrosis factor (TNF). TNF, produced by monocytes, has been shown to be cytolytic against many transformed cell lines in vitro [24]. By demonstrating TNF production from monocytes in patients with bladder cancer, Ikemoto and associates suggested that enhancement of this process might prove to be therapeutically rewarding [25].
Renal Cell Carcinoma The unpredictable natural history of renal cell cancer and descriptions of apparent spontaneous remission of metastases has prompted many to suggest that the immune response might be active in this malignancy [26]. This has led to numerous attempts to design active and passive immunotherapeutic approaches to control metastatic renal cell cancer [27]. These have included in vivo stimulation of autologous lymphocytes by RNA and transfer of activated lymphocytes back into the host [28], inoculation with specific and nonspecific vaccine prepared from autologous cancer cells or antigen preparations [29,30], injection with nonspecific stimulants such as BCG, Corynebacteriumpamum, and phytohemagglutinin [31,32], and the use of various lymphokines (IF, IL,, TNF) (33-351 either alone or together with a number of cell preparations (LAK cells, tumor-infiltrating lymphocytes) [36-381. All of these approaches have been reported to produce several partial responses, and an occasional but rare complete response, and all of limited durability. Most recent interest has focused on the use of IL, and
LAK cells or TILs from the tumor to treat patients with regionally advanced and metastatic renal cell carcinoma [36,38]. Toxicity with this approach has been great. Moreover, although experimental results have been highly promising, clinical results have been suggestive but generally disappointing. Those considerations that had previously made many critical of the immune response as an effective modality to treat human cancer were still of concern and were not answered by the results of investigation with interleukin either alone or with activated lymphocytes. If anything, those who previously were skeptical became even more so, not only because of the types of results that have been reported but also because of the manner in which observations were described (with selectivity, with short-term followup, and with lack of valid controls or appropriate experimental design). Recent reports have described a new immunotherapeutic approach for the treatment of renal cell cancer [39,40]. This has involved the use of autologousstimulated lymphocytes together with cimetidine, an inhibitor of suppressor T lymphocytes. Experimental design has incorporated a control group of patients with metastatic renal cell cancer treated with cimetidine alone. Preliminary results have indicated not only remissions with this regimen but also prolonged survivals in comparison with control patients. Whether these observations will be durable, however, remains to be seen.
REFERENCES 1. Silverberg E, Boring CC, Squires TS: Cancer Statistics, 1990. CA 40:9, 1990. 2. Toni FM, Lum BL, Aston D, et al.: Superficial bladder cancer: The primacy of grade in the development of invasive disease. J Clin Oncol 5125, 1987. 3. England HR, Paris AMI, Blandy JP: The correlation of TI bladder tumor history with prognosis and follow-up requirements. Br J Urol 53593. 1981. 4. Heney NM. Nocks BN, Day JJ, et al.: T, and TI bladder cancer: Locations. recurrence and progression. Br J Urol 54:152, 1982. 5 . Prout GR, Cox E, Cummings KB, et al.: Surveillance, initial assessment and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res 37:2907, 1977. 6. Loening S. Naroyana A, Yoder L, et al.: Factors influencing the recurrence rate of bladder cancer. J Urol 12324, 1980. 7. Morales A, Eidinger D, Bruce AW: Intracavitary (?) bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 116:180, 1976. 8. Herr HW,Laudone VP: Intravesical therapy for superficial bladder cancer. Updates. Vol. 2, No. 4. p. 1-10. 1988. 9. Kelly DR, Haaff EO, Beich M, et al.: Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guerin. J Urol 135:268-271, 1986. 10 Lamm DL, Thor DE, Winters WD, et al.: BCG immunotherapy of bladder cancer: Inhibition of tumor recurrence and associated immune responses. Cancer 48:82-88, 1981. 1 1 Fleischmann JD, Toossi 2, Ellner JJ, et al.: Urinary interleukins in patients receiving intravesical bacillus Calrnette-Guerin therapy for superficial bladder cancer. Cancer 64: 1447-1454, 1989. 12. Torrence RJ, Kovassi LR. Catalona WJ, et al.: Prognostic factors
Immunotherapy in Bladder and Renal Cell Carcinoma
13. 14. 15.
16. 17. 18. 19.
20. 21. 22. 23. 24. 25. 26.
in patients treated with intravesical bacillus Calmette-Guerin for superficial bladder cancer. J Urol 139:941-944, 1988. Haaff EO, Catalona WJ, Ratliff JL: Detection of interleuhn-2 in the urine of patients with superficial bladder tumors after treatment with intravesical BCG. J Urol 136:970-974, 1986. Watson J, Mochizuki D, Gillis S: T-cell growth factors: Interleulun-2. Immunol Today 1:113, 1980. Pizza G, Sevorini G, Mennetti D, et al.: Tumor regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. Preliminary report. Int J Cancer 34:359, 1984. Kashahara T, Hooks JJ, Dougherty SF, et al.: Interleukin-2mediated immune interferon (IFN,) production by human T cells and T cell subsets. J Immunol 130:1784, 1983. Rosenberg SA, Grimm EA, McGrogan M, et al.: Biological activity of recombinant human interleukin-2 produced in E. coli. Science 223:1412, 1984. Bretton PR, Herr HW, Kimmel M, et al.: The response of patients with supemcia1 bladder cancer to a second course of intravesical bacillus Calmette-Guerin. J Urol 143:710-713, 1990. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for supeficial bladder cancer. J Urol 137:220, 1987. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 142:719-722, 1989. Torti FM, Shortliffe LD, Williams RD, et al.: Alpha interferon in superficial bladder cancer: A Northern California oncology group study. J Clin Oncol 6:476. 1988. Sarosdy MF, Kierum CA: Combination immunotherapy of murine transitional cell cancer using BCG and interferon-inducing pyrimidinone. J Urol 142:137&-1379, 1989. Bryan GT. Sidky YA, Erturk E, et al.: Protection by interferon (IFN) and inducer against chemical carcinogensis in the mouse bladder. Proc Am Assoc Cancer Res 30:172, 1989. Mannel DN, Moore RN, Mergenhagen SE: Macrophages as a source of tumoricidal activity (tumor necrotizing factor). Infect Immunol 30:52>530, 1980. Ikemoto S, Kishimoto T, Nishio S, et al.: Correlation of tumor necrosis factor and prostaglandin E, production of monocytes in bladder cancer patients. Cancer 64:207&2080, 1989. Ritchie AWS, Chisholm GD: The natural history of renal carcinoma. Semin Oncol 10:390. 1983.
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27. McCune CS: Immunologic therapies of kidney carcinoma. Semin Oncol 10:431, 1983. 28. DeKernion JB, Ramming W:The therapy of renal adenocarcinoma with immune RNA. Invest Urol 17:378, 1980. 29. Tallberg T, Tykka H, Mahlberg K, et al.: Active specific immunotherapy with supportive measures in the treatment of palliatively nephrectomized renal adenocarcinoma patients. Eur Urol 11:233, 1985. 30. Neidhardt JA, Gagen M, Young D, et al.: A randomized study of polymerized tumor antigen admixed with adjuvant (PTA) for therapy of renal cancer. Proc Am Soc Clin Oncol 2:49, 1983. 31. Morales A, Wilson JL, Pater JL, et al.: Cytoreductive surgery and systemic bacillus Calmette-Guerin therapy in metastatic renal cancer: A phase I1 trial. J Urol 127:230, 1982. 32. Neidhardt JA, Murphy SG, Herrick LA, et al.: Active specific immunotherapy of stage IV renal carcinoma with aggregated tumor antigen adjuvant. Cancer 46:1128, 1980. 33. Quesada JR, Gutterman JV, Rios A: Investigational therapy of renal cell carcinoma with recombinant alpha interferon. Roc Am Assoc Cancer Res 24:195, 1983. 34. Rinehart JJ, Young D, Laforge J , et al.: Phase I/II trial of recombinant gamma interferon in patients with renal cell carcinoma: Immunologic and biologic effects. J Biol Response Mod 6:302, 1987. 35. Rosenberg SA, Lotze MT, Muul LM, et al.: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high dose interleukin-2 alone. N Engl J Med 316:889, 1987. 36. Rosenberg SA: New immunotherapies for the treatments of cancer. Ann Surg 208:120, 1988. 37. Mule JJ, Shu S, Schwarz SL. et al.: Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225:1487, 1984. 38. Rosenberg SA: Immunotherapy of cancer using interleukin-2. Immunol Today 9 5 8 , 1988. 39. Osband MS, Carpinato GA, Levine S1, et al.: Successful adoptive immunotherapy of metastatic renal cell carcinoma with in vitro immunized autologous lymphocytes and cimetidine. World J Urol 4:217, 1987. 40. Osband MS, Lavin PT, Babayan RK, et al.: Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet 335:994, 1990.
Role of lmmunotherapy in the Treatment of Bladder and Renal Cell Carcinoma NELSON N. STONE, MD, AND MICHAEL J. DROLLER, MD From the Department of Urology, Mount Sinai Medical Center, New York
Much remains to be learned about the immune response in human neoplasia both in a phenomenological sense and in its therapeutic possibilities. Recruitment of immune response mechanisms in the defense against cancer development and in the cure of advanced disease, though theoretically sound, remains to be proven in demonstration of both its phenomenological and clinical efficacy. The most important steps in this regard will require an analysis of those mechanisms that may truly be active in human cancer. Their enhancement and effective delivery to various tumor sites, then reliable monitoring, and proof of their efficacy will be necessary to accomplish before any conclusive statement can be made as to the usefulness of immunotherapy in the treatment of genitourinary neoplasia and of human cancer in general. KEY WORDS:BCG, human neoplasia
INTRODUCTION Application of the principles of immunology in designing a therapeutic approach to human malignancy is based upon a number of assumptions. First is that human cancers contain and express antigens that can be recognized as foreign by the host. Second is that immune response mechanisms will presumably attack those cells that express these antigens. Third is that immune response mechanisms can be delivered to the site of tumor so as to destroy the cancer cells that they recognize as foreign. Critics of these concepts have suggested that the presence of specific tumor antigens in human tumors remains to be proven. Moreover, failure of immunosurveillance to prevent cancer development from the very beginning implies that attempts to recruit immune response mechanisms to combat disseminated cancer cells might be futile. In addition, selection of one immune response mechanism may be insufficient in eliminating a particular tumor. Moreover, use of that particular mechanism may actually stimulate other mechanisms that may effectively abrogate that mechanism’s efficacy. These are but a few of the theoretical concerns investigators have had in designing immunotherapeutic approaches in cancer therapy. In addition, genetic drift, tumor heterogeneity, and cancer development in sanctuary sites have added 0 1991 Wiley-Liss, Inc.
further complexity in attempting to create effective immunotherapy .
THE NORMAL IMMUNE RESPONSE Much of our knowledge of immune response mechanisms is based upon experimental animal models and in vitro systems. Whether knowledge from these can be applied to the human system remains controversial. Nonetheless, it is valuable to consider these mechanisms as an indication of what might be utilized in the design of a rational immunotherapeutic approach to cancer. Tumor-associated antigens shed from the tumor in question or expressed at their surface are first recognized by macrophages. These cells engulf the antigens and process them for presentation to T and B lymphocytes. As part of this process, a variety of lymphokines and cytokines are produced and secreted by the lymphocytes and macrophages. These result in the proliferation of various subsets of lymphocytes, their maturation into cells with directed function, and their activation to react against the tumor cells that express the initiating antigen. T lymphocytes differentiate into helper T cells (TH), Address reprint requests to Michael J. Droller, M.D., Department of Urology, Mount Sinai Medical Center, Box 1272, 15th Floor, One Gustave L. Levy Place, New York, NY 10029.
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which are necessary for the successful production by B lymphocytes of antibodies directed against the initiating antigen. The T, cells are also important for the proliferation of cytotoxic T lymphocytes (Tc), which are directly toxic to the tumor cells. Suppressor T cells (Ts), which can inhibit both the activity of cytotoxic T lymphocytes and the production of antibody by activated B lymphocytes, are also produced and serve as a regulatory mechanism to limit the extent of immune response expression. Various additional populations of lymphocytes are also amplified. These include natural killer lymphocytes, which are active against tumor cells, LAK cells (lymphokine-activated killer cells), which are stimulated by interleukin 2 to proliferate and kill tumor cells, and antibody-dependent killer lymphocytes, which appear to require the presence of antibody to exert their cytotoxic activity against tumor cells. Macrophages also consist of subsets of cells that may either just recognize and process foreign antigens or actually express cytotoxic activity against any cell that expresses these antigens. A large variety of lymphokines and cytokines have been described. Each has been found to have a variety of activities depending upon the model system studied and the type of target cell/effector cell examined. The most prominent of these are interleukin 1 (IL-1). which stimulates the proliferation of macrophages and T lymphocytes, interleukin 2 (IL-2), which stimulates the proliferation and activity of LAK cells, and interferon (IF), which stimulates activity of natural killer cells and macrophages, and also induces increased expression of surface antigens on cancer cells while being cystostatic (rather than cytotoxic) to a variety of tumor cells. In addition, prostaglandins are produced by macrophages and by tumor cells themselves, and may function to abrogate the expression of immune response activity mounted against that particular tumor cell. The complexity of these interactions has made it extremely difficult to recruit a particular immune response mechanism in isolation of others in attempting to design an approach to the treatment of the variety of malignancies. In addition, the manner by which a particular immune response mechanism has been recruited and the ability to deliver that immune response mechanism to the site of tumor have remained problematic. Nonetheless, a variety of immune response mechanisms have been shown to be effective in various models of cancer. This has continued to encourage exploration and application of these mechanisms in the clinical setting.
IMMUNOTHERAPEUTIC APPROACHES Understanding of immunologic mechanisms has led to both active and passive approaches in immunotherapy in the cancer setting. The active approach has been based upon the stimulation of the host’s own immune response
mechanisms in mounting an attack against a particular cancer. The passive approach has been based upon enhancement of a particular immune response mechanism outside of the host with subsequent transfer of that activity back into the host for it to exert its effect. The major assumption underlying each approach is that the effective immune response activity could be delivered to the tumor site. In each, activated immune response cells would presumably seek out the cancer cells and destroy them. In addition, each approach has been subcategorized as being either specific or nonspecific. Specific approaches would attempt to recruit or enhance an immune response mechanism so that it would recognize a particular tumor antigen and react against that antigen or any cell that expressed that antigen. Nonspecific approaches would be designed to recruit or activate selected immune response mechanisms generically so that they would be active against tumor cells nonspecifically by recognizing the expression of antigens that distinguished those cells as foreign. Results with each of these approaches have generally been disappointing. This is not to say that theoretical considerations or animal models in support of these have not substantiated these approaches. Rather, their clinical application has generally produced minimal or at best nondurable results. A number of reasons have been suggested to explain this. First, adequacy of delivery of a particular immune response activity to the tumor site and efficacy of a particular concentration of stimulant or immune response agent have been questioned. Second, attempts to monitor the efficacy of immune response activity in the host, either as delivered actively or passively, have been unreliable and have therefore prevented any meaningful interpretation of the results of treatment outcome. Third, it has remained unclear as to whether tumor cells at each site expressed antigen in sufficient strength to be recognized by a particular immune response mechanism. Fourth, toxicities of treatment were often great, effectively limiting the extent of treatment and precluding delivery of a presumed full and theoretically effective level of immune response activity in the tumor site. In addition, the role of the host in the success of therapy remained unclear. Cancer often effects the elderly, in whom general physiologic function of various organ systems has deteriorated. Ability to recruit various components of the immune response to their fullest extent in this context might therefore be limited. The presence of the cancer itself might be sufficient to weaken the patient and compromise immune response capabilities. This could occur either because of compromise in the host’s nutritional status, production by the tumor of substances that might either directly or indirectly abrogate immune response capability, and the earlier administration of other forms of treatment (surgery, anesthesia, radiation,
Immunotherapy in Bladder and Renal Cell Carcinoma
chemotherapy) that themselves might compromise the host’s immune response capabilities. Last, even if the transfer or induction of an immune response mechanism were successful, it might conceivably induce other mechanisms that would limit the extent of immune response activity and thereby prevent full expression of such therapy against the cancer. Indeed, the complexity of the immune response system is such that it would undoubtedly have built into it a number of regulatory mechanisms that would serve to modify the extent of expression of any one mechanism. Our inability to monitor with accuracy immune response activity either systemically or at a particular tumor site would limit our ability to understand the role of such mechanisms in limiting the extent of immune response expression. This would seriously hamper any effort to explain success or failure of manipulation of the immune response in mounting an attack against cancer.
IMMUNOTHERAPY IN GENITOURINARY CANCER Bladder Cancer Of the estimated 48,000 new cases of bladder cancer diagnosed each year in the United States, 75-85% will present with superficial disease [ 11. These usually appear as papillary lesions involving the mucosa only (T,) or submucosa (TI) or flat carcinoma in situ (TJ. The majority of these lesions are T, (70%) and usually solitary WI. Effective therapy in treating carcinoma of the bladder encompasses eradication of existing lesions and prevention of recurrence or disease progression (to muscle infiltration or metastases). While transurethral resection of the lesion will undoubtedly prevent these events in most cases of low grade (G,) T, tumors, a significant proportion of patients with higher stage or grade disease will likely develop recurrence or progression [ a ] . Chemotherapeutic agents such as Thiotepa, Mitomycin-C, and Adriamycin have been only moderately successful in either eradicating disease or preventing recurrence. These agents, which rely upon relatively high concentrations of cytotoxic drug to be in contact with the bladder mucosa, have been shown to have a nef benefit of only 6-1 3% over controls in preventing disease recurrence. A great deal of interest has therefore focused on the potential use of immunotherapeutic approaches either in treating superficial disease or in preventing recurrence. Tremendous impetus to this approach was provided by observations that instillation of preparations of bacillus Calmette-GuCrin into the bladder produced an inflammatory response or granulomatous reaction and appeared to be effective both in the treatment of superficial transitional cell cancers of the bladder and in the prophylaxis against their recurrence. Their presumed mechanism of
241
action was the induction of an inflammatory response and presumably a cytotoxicity directed against the bladder tumor cells. Whether treatment or prophylaxis reflected a passive effect of the granulomatous inflammatory reaction that was induced, however, remained unclear. Bacillus Calmette-GuCrin (BCG) was first recognized as an effective immunotherapeutic agent in the treatment of patients with superficial bladder cancer and carcinoma in situ by Morales and associates in 1976 [7]. Since that time it has become established as the most effective intravesical agent in decreasing recurrence and in the prevention of disease progression. Results from several large studies demonstrate a 42% benefit in tumor prophylaxis and a 71% success rate in treatment of existing disease [8]. Unlike cytotoxic chemotherapy, intravesicat BCG provokes a cell-mediated immune response which in most patients is characterized by the formation of granulomatas in the bladder and by the positive conversion of the purified protein derivative (PPD) skin test [9]. However, the exact mechanism of action of BCG remains unknown, and attempts to measure BCG-mediated systemic immune responses have failed to predict clinical response or to help define the optimal course of therapy [lo-121. Although the exact nature of the anti-tumor activity of BCG is unknown, several different mechanisms have been postulated. Elimination of bladder tumors may result from lymphokine-augmented nonspecific cellmediated cytotoxicity or a direct anti-tumor action of lymphokines themselves [13]. IL-2 is one such lymphokine thought to be involved in BCG-mediated activity. IL-2 is produced by antigen stimulation of T lymphocytes [14]. Haaff and associates demonstrated the production of IL-2 in patients treated with BCG [ 131. However, even though these and other authors demonstrated the urinary recovery of IL-2 during BCG treatment, what role IL-2 has in the anti-tumor effect of BCG still needs to be clarified. Pizza and associates [I51 injected IL-2 directly into bladder tumors and noted tumor regression in 50%, supporting a role of IL-2 in this area. Together with the established role of IL-2 as a growth factor for T lymphocytes [14], as an inducer of gamma interferon [ 161, and as an activator of nonspecific 1ymphocyte-mediated tumoricidal activity [ 171, this suggests that there might be multiple effects of BCG-mediated immunoactivity in patients with bladder cancer. Current therapy calls for six weekly instillations of BCG 120 mg in 50 ml of sterile saline, with retention for 2 hours. In a study of 347 patients treated in such fashion, the median duration of response to one course of BCG was 27 months [18]. Twenty-eight patients were treated with a second course of BCG, and 54% had a
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complete or partial response. Catalona and associates also reported that 58% of patients who had recurrence after one course of BCG were rendered free of tumor by a subsequent course [19]. Sarosdy and Lamm [20] followed 120 patients a median of 67 months and retreated ten who failed, increasing their overall success rate from 78% to 89%. Toxicity of BCG is secondary to the intense local inflammatory reaction. Patients often complain of dysuria, frequency, urgency, and hematuria. Unfortunately, the degree of local inflammatory response does not necessarily correlate with likelihood of response (91. Interferons by themselves or in conjunction with other immuno-modulation measures have also been used in bladder cancer. Interferon alpha has been used intravesically with some success as a solitary agent in superficial bladder cancer [21]. More importantly, adjunctive roles for interferons are currently being investigated in this disease. Sarosdy and Kierum [22] enhanced BCG activity with the interferon inducer pyrimidinone in a murine bladder tumor model and Bryan and associates [23] demonstrated chemoprotective activity of interferon alpha/ beta in a formamide-induced bladder cancer model. A recent addition to the immunotherapy armamentarium is tumor necrosis factor (TNF). TNF, produced by monocytes, has been shown to be cytolytic against many transformed cell lines in vitro [24]. By demonstrating TNF production from monocytes in patients with bladder cancer, Ikemoto and associates suggested that enhancement of this process might prove to be therapeutically rewarding [25].
Renal Cell Carcinoma The unpredictable natural history of renal cell cancer and descriptions of apparent spontaneous remission of metastases has prompted many to suggest that the immune response might be active in this malignancy [26]. This has led to numerous attempts to design active and passive immunotherapeutic approaches to control metastatic renal cell cancer [27]. These have included in vivo stimulation of autologous lymphocytes by RNA and transfer of activated lymphocytes back into the host [28], inoculation with specific and nonspecific vaccine prepared from autologous cancer cells or antigen preparations [29,30], injection with nonspecific stimulants such as BCG, Corynebacteriumpamum, and phytohemagglutinin [31,32], and the use of various lymphokines (IF, IL,, TNF) (33-351 either alone or together with a number of cell preparations (LAK cells, tumor-infiltrating lymphocytes) [36-381. All of these approaches have been reported to produce several partial responses, and an occasional but rare complete response, and all of limited durability. Most recent interest has focused on the use of IL, and
LAK cells or TILs from the tumor to treat patients with regionally advanced and metastatic renal cell carcinoma [36,38]. Toxicity with this approach has been great. Moreover, although experimental results have been highly promising, clinical results have been suggestive but generally disappointing. Those considerations that had previously made many critical of the immune response as an effective modality to treat human cancer were still of concern and were not answered by the results of investigation with interleukin either alone or with activated lymphocytes. If anything, those who previously were skeptical became even more so, not only because of the types of results that have been reported but also because of the manner in which observations were described (with selectivity, with short-term followup, and with lack of valid controls or appropriate experimental design). Recent reports have described a new immunotherapeutic approach for the treatment of renal cell cancer [39,40]. This has involved the use of autologousstimulated lymphocytes together with cimetidine, an inhibitor of suppressor T lymphocytes. Experimental design has incorporated a control group of patients with metastatic renal cell cancer treated with cimetidine alone. Preliminary results have indicated not only remissions with this regimen but also prolonged survivals in comparison with control patients. Whether these observations will be durable, however, remains to be seen.
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