Cancer immunotherapy During the past 10 years cancer immunotherapy has consisted primarily of nonspecific stimulation of the immune system with the use of adjuvants such as bacille CalmetteGu&in, Corynebacterium parvum and levamisole. Attempts at specific immunization with administration of antigens and adjuvants have been made in patients with leukemia and lung cancer, as reported by Stewart and colleagues.1 Their results of a randomized trial are impressive and suggest that specific immunization with tumour antigens and adjuvants should be explored further. The review by Richman, Gutterman and Hersh in this issue of the Journal (page 322) covers primarily the area of nonspecific immunotherapy. This approach has an effect on the immune system and occasionally produces a favourable response in patients with neoplasia, but it must be regarded as the initial phase of an immunologic approach to cancer treatment. The further application of immunotherapy must involve selective manipulation rather than nonspecific stimulation of the components of the immune system. Is there general depression of immune function in patients with neoplasia, particularly at an early phase? Most of the evidence on this point has been controversial and variable.2 It is possible that certain aspects ot the immune system fail to recognize tumour-specific antigens on spontaneous neoplasms as foreign, and therefore no effective immune response is produced. If the immune
system is considered in terms of its thus allow an adequate immune revarious cellular components, then the sponse to tumour antigens (unpubreason for this lack of an effective lished data, 1978). response may be clarified. In the past Following the elimination of sup5 years evidence has expanded for pressor T-lymphocytes, one should the presence of suppressor cell pop- attempt to stimulate the helper ulations that can block or eliminate mechanisms so that both antibody any minimal reaction that tumour and cytotoxic T-lymphocytes are antigens elicit.3-7 Specific suppression produced. This demands that specific is primarily a function of thymus- adjuvants for different cellular comdependent (T-) lymphocytes. Non- ponents of the immune system be specific immune stimulation must developed. therefore be regarded as a "twoBasic to this concept is the necesedged sword", for it may increase sity to decrease the tumour mass. both a negative and a positive cel- As many of the neoplastic cells as lular response within the immune possible must be eliminated, prefersystem. If immunotherapy is to pro- ably by surgical resection, since this gress, it must encompass recent re- removes the tumour antigen from the sults from experiments that suggest system, or by destruction within the the feasibility of more specific organism. It may be impossible to immune manipulation. The goal effectively realign the immune sysshould be the elimination of sup- tem if the tumour burden is massive. pressor components of the immune It is essential that we progress system, followed by specific stimu- from the present phase of nonspelation of effector or "helper" mech- cific immunotherapy, as reviewed in anisms. Results from experiments the article by Richman and* colsuggest that specific suppressor leagues, to more specific immune T-lymphocytes can be eliminated manipulation of cellular components by low doses of radiation,8. cyclo- of the immune system following phosphamide8'11'12 and antibodies to elimination of suppressor mechan"Ia" antigen.13 While none of these isms with either specific immunizafindings have been applied as yet to tion with antigens and adjuvants or the treatment of neoplasia, the rela- nonspecific adjuvant stimulation of tively limited toxicity of such an ap- the remaining potentially effective proach, as indicated by the results components of the immune system. of experiments with animals, sug- To concentrate further on the initial gests that it may be done in the phase of nonspecific stimulation of near future. I have found that in hu- the immune system, even as an admans various therapeutic maneuvers junct to other more standard forms may cause fortuitous suppression of of therapy, seems unprofitable. What the negative T-lymphocyte compo- is required is intelligent manipulanent of the immune system and tion of the cellular components of CMA JOURNAL/FEBRUARY 3, 1979/VOL. 120 255
the immune system and further definition of tumour-specific antigens. Hypnotic
R.E. FALK, MD, FRCS[C] Associate professor of surgery University of Toronto Toronto, Ont.
(triazolam)
Product Information Action: Halcion (triazolam) is a benzodiazepine nancy. Since triazolam is also a benzodiazepine with short-acting hypnotic properties. derivative, its administration is rarely justified in women of childbearing potential. If the drug is In sleep laboratory studies in man of ito 21 days prescribed to a woman of childbearing potential duration, triazolam reduced sleep latency, inshe should be warned to consult her physician creased duration of sleep and decreased the regarding the discontinuation of the drug if she number of nocturnal awakenings. Some of these intends to become or suspects that she is sleep laboratory studies suggest that rebound pregnant. withdrawal insomnia may occur upon discontinuation of the drug. Precautions: Clinical trials in depressed patients have not demonstrated exacerbation of In tolerance studies, no significant respiratory or depression by Halcion (triazolam). However, cardiovascular depression was observed at theracaution should be exercised if the patient exhibits peutic doses of triazolam. symptoms of depression or reveals evidence of Orally administered triazolam is well absorbed latent depression, particularly when suicidal tenin man. Triazolam was shown to have a short dencies may be present and protective measures half-life of approximately three hours and neither may be required. triazolam nor its metabolites accumulated in Halcion should be given with caution to patients the blood after multiple dose administration. The with impaired renal or hepatic function. main route of excretion of orally administered drug in man is via the urine, with approximately Adverse Reactions: Incidence and severity of 8% appearing in the faeces. sideeffectsof Halcion (triazolam) are dose-related. The most common side effects reported with the Triazolam 0.5 mg, in two separate studies, did not use of Halcion are morning drowsiness, groggiaffect the prothrombin times or plasma warfarin ness, dizziness, lightheadedness, impaired colevels in male volunteers who were administered ordination, headache and nausea. Severe drowsisodium warfarin orally. ness and impaired coordination are indicative of indications and Clinical Uses: Halcion drug intolerance or overdosage. Less frequent (triazolam) is a hypnotic agent useful in the shortadverse reactions reported were restlessness, term management of insomnia. Halcion should taste alterations, depression, blurred vision, irritanot be administered consecutively beyond 21 days. bility, anterograde amnaesia (see WARNINGS), constipation, rash, diarrhoea, epigastric discomContraindications: Halcion (triazolam) is contrafort, nervousness, weakness, confusion, burning indicated in patients with known hypersensitivity eyes, dry mouth, tinnitus, palpitations, tiredness, to the drug, and patients with myasthenia gravis hiccups, hallucinations, visual disturbances, or a history of glaucoma. Safety and effectiveness elevation of SGOT, total and direct bilirubin, and in patients under the age of eighteen have not alkaline phosphatase. Paradoxical reactions rebeen established. lated to stimulation, excitement and hyperactivity Studies in rats have indicated that triazolam have not been reported but may occur. and its metabolites are secreted in milk. Human Symptoms and Treatment of Overdosage: studies have not been performed and therefore, Manifestations of Halcion (triazolam) overdosage nursing should not be undertaken while a patient include extensions of its pharmacological activity, is taking the drug. namely somnolence and hypnosis. Respiration, Warnings: Patients receiving Halcion (triazolam) pulse and blood pressure should be monitored should be cautioned about the possible comand supported by general measures when necesbined effects of alcohol and other central nervous sary. Immediate gastric lavage should be persystem depressants and consideration should be formed. Intravenous fluids should be administered given to potential additive effects. Combination of and an adequate airway maintained. alcohol and therapeutic doses of Halcion have in animals have indicated that caused severe central nervous system depression. Experiments cardiopulmonary collapse can occur with massive Anterograde amnaesia of varying severity intravenous doses of triazolam. This could be rehas been reported following therapeutic doses versed with positive mechanical respiration and of Halcion. Other benzodiazepines have been the intravenous infusion of levarterenol. Animal shown to produce anterograde amnaesia and the experiments have suggested that haemodialysis clinical significance of this effect is under study. and forced diuresis are probably of little value. As Physical and psychological dependence have with the management of intentional overdosage not been demonstrated in patients taking 0.5 mg with any drug, the physician should bear in mind Halcion per day for 90 days or in normal human that multiple agents may have been ingested by volunteers taking 1 mg per day for 42 days. Howthe patient. ever, caution must be exercised in administering Dosage and Administration: It is important Halcion to individuals who have a history of drug to individualise dosage to obtain the desired misuse, or who may tend to increase the dose hypnotic effect while avoiding oversedation and without supervision, and such patients must be other side effects. placed under careful surveillance. Adult Dose: The initial recommended dose is elderly In and/or debilitated patients, or in patients 0.25 mg and it can be titrated to the response of with organic brain disorders, it is recommended the patient within the range of 0.25 mg to 0.5 mg. that treatment with Halcion be initiated at the lowSome hospitalised patients may require doses of est possible dose, increased gradually if necesuptol mg. sary to decrease the possibility of development of Geriatric Dose: Because of the increased senoversedation, dizziness or impaired coordination. sitivity in this age group, the initial dose should be 0.125mg (½ of a 0.25mg tablet). If necessary, Use in Pregnancy: The safety of the use of Halcion in pregnancy has not been established. Therethe dose can be titrated to a maximum of 0.5 mg. fore, Halcion is not recommended for use during Availability: Halcion (triazolam) is available pregnancy or lactation. Several studies have as scored tablets of 0.25 mg (powder blue) and suggested an increased risk of congenital malfor0.5 mg (white) in bottles of 100 and 500; and mations associated with the use of the benzo1 mg (rose) in bottles of 100. diazepines chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregProduct monograph available on request.
766 REGISTERED TRADEMARK. HALCION CEgiRT.,
kfl. ii THE UPJOHN COMPANY OF CANADA . 865 YORK MILLS ROAD DON MILLS, ONTARIO
IPAABI .
References 1. STEWART THM, HOLLINSHEAD AC, HAIuus JE, et al: Survival study of immunochemotherapy in lung cancer, in Immunotherapy of Cancer: Present Status of Trials in Man, TERRY WD, WINDHORST D (eds), Raven, New York, 1978, p 203 2. HAIuus JE, SINKoVIcs JG: The Immunology of Malignant Disease, 2nd ed, Mosby, St Louis, 1970 3. FuJiMoTo 5, GREEN MI, SEHON AH: Regulation of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts. J Immunol 116: 791, 1976 4. Idem: Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts. Thid, p 800 5. RrnNsscii CL, ANDREW Sb, SCHOLSSMAN SF: Suppressor cell regulation of immune- response to tumors - abrogation by adult thymectomy. Proc Natl Acad Sci USA 74: 2989, 1977 6. TAKET F, LEvY JG, KILBURN DG: Characterization of suppressor cells in mice bearing syngeneic mastocytoma. J Immunol 118: 412, 1977 7. Yu A, WArrs H, JAFFE N, et al: Concomitant presence of tumor-specific cytotoxic and inhibitor lymphocytes in patients with osteogenic sarcoma. N Engi J Med 297: 121, 1977 8. CmoRAzzI N, Fox DA, KArz DH: Hapten-specific IgE antibody responses in mice. 6. Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide. J Immunol 117: 1629, 1976 9. FAuc RE, NossAL NA, SAMUEL ESS, et al: Increased resistance to established tumor metastases after elimination of thymus - T-cell mediated suppression. Surg Forum 28: 161, 1977 10. FALK RE, NossM. NA, FALK JA: Effective antitumor immunity following elimination of suppressor T-cell function. Surgery 84: 483, 1978 11. Poi,ix L, Tunic JL: Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature 249: 654, 1974 12. ASKENASE PW, HAYDEN BJ, GERSHON RK: Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which did not affect antibody responses. J Exp Med 141: 697, 1975 13. GREEN MI, MARTIN ED, PIEnxEs M, et al: Reduction of syngeneic tumor growth by an anti-I-J alloantiserusn. Proc Natl Acad Sci USA 74: 5118,
1977
system is considered in terms of its thus allow an adequate immune revarious cellular components, then the sponse to tumour antigens (unpubreason for this lack of an effective lished data, 1978). response may be clarified. In the past Following the elimination of sup5 years evidence has expanded for pressor T-lymphocytes, one should the presence of suppressor cell pop- attempt to stimulate the helper ulations that can block or eliminate mechanisms so that both antibody any minimal reaction that tumour and cytotoxic T-lymphocytes are antigens elicit.3-7 Specific suppression produced. This demands that specific is primarily a function of thymus- adjuvants for different cellular comdependent (T-) lymphocytes. Non- ponents of the immune system be specific immune stimulation must developed. therefore be regarded as a "twoBasic to this concept is the necesedged sword", for it may increase sity to decrease the tumour mass. both a negative and a positive cel- As many of the neoplastic cells as lular response within the immune possible must be eliminated, prefersystem. If immunotherapy is to pro- ably by surgical resection, since this gress, it must encompass recent re- removes the tumour antigen from the sults from experiments that suggest system, or by destruction within the the feasibility of more specific organism. It may be impossible to immune manipulation. The goal effectively realign the immune sysshould be the elimination of sup- tem if the tumour burden is massive. pressor components of the immune It is essential that we progress system, followed by specific stimu- from the present phase of nonspelation of effector or "helper" mech- cific immunotherapy, as reviewed in anisms. Results from experiments the article by Richman and* colsuggest that specific suppressor leagues, to more specific immune T-lymphocytes can be eliminated manipulation of cellular components by low doses of radiation,8. cyclo- of the immune system following phosphamide8'11'12 and antibodies to elimination of suppressor mechan"Ia" antigen.13 While none of these isms with either specific immunizafindings have been applied as yet to tion with antigens and adjuvants or the treatment of neoplasia, the rela- nonspecific adjuvant stimulation of tively limited toxicity of such an ap- the remaining potentially effective proach, as indicated by the results components of the immune system. of experiments with animals, sug- To concentrate further on the initial gests that it may be done in the phase of nonspecific stimulation of near future. I have found that in hu- the immune system, even as an admans various therapeutic maneuvers junct to other more standard forms may cause fortuitous suppression of of therapy, seems unprofitable. What the negative T-lymphocyte compo- is required is intelligent manipulanent of the immune system and tion of the cellular components of CMA JOURNAL/FEBRUARY 3, 1979/VOL. 120 255
the immune system and further definition of tumour-specific antigens. Hypnotic
R.E. FALK, MD, FRCS[C] Associate professor of surgery University of Toronto Toronto, Ont.
(triazolam)
Product Information Action: Halcion (triazolam) is a benzodiazepine nancy. Since triazolam is also a benzodiazepine with short-acting hypnotic properties. derivative, its administration is rarely justified in women of childbearing potential. If the drug is In sleep laboratory studies in man of ito 21 days prescribed to a woman of childbearing potential duration, triazolam reduced sleep latency, inshe should be warned to consult her physician creased duration of sleep and decreased the regarding the discontinuation of the drug if she number of nocturnal awakenings. Some of these intends to become or suspects that she is sleep laboratory studies suggest that rebound pregnant. withdrawal insomnia may occur upon discontinuation of the drug. Precautions: Clinical trials in depressed patients have not demonstrated exacerbation of In tolerance studies, no significant respiratory or depression by Halcion (triazolam). However, cardiovascular depression was observed at theracaution should be exercised if the patient exhibits peutic doses of triazolam. symptoms of depression or reveals evidence of Orally administered triazolam is well absorbed latent depression, particularly when suicidal tenin man. Triazolam was shown to have a short dencies may be present and protective measures half-life of approximately three hours and neither may be required. triazolam nor its metabolites accumulated in Halcion should be given with caution to patients the blood after multiple dose administration. The with impaired renal or hepatic function. main route of excretion of orally administered drug in man is via the urine, with approximately Adverse Reactions: Incidence and severity of 8% appearing in the faeces. sideeffectsof Halcion (triazolam) are dose-related. The most common side effects reported with the Triazolam 0.5 mg, in two separate studies, did not use of Halcion are morning drowsiness, groggiaffect the prothrombin times or plasma warfarin ness, dizziness, lightheadedness, impaired colevels in male volunteers who were administered ordination, headache and nausea. Severe drowsisodium warfarin orally. ness and impaired coordination are indicative of indications and Clinical Uses: Halcion drug intolerance or overdosage. Less frequent (triazolam) is a hypnotic agent useful in the shortadverse reactions reported were restlessness, term management of insomnia. Halcion should taste alterations, depression, blurred vision, irritanot be administered consecutively beyond 21 days. bility, anterograde amnaesia (see WARNINGS), constipation, rash, diarrhoea, epigastric discomContraindications: Halcion (triazolam) is contrafort, nervousness, weakness, confusion, burning indicated in patients with known hypersensitivity eyes, dry mouth, tinnitus, palpitations, tiredness, to the drug, and patients with myasthenia gravis hiccups, hallucinations, visual disturbances, or a history of glaucoma. Safety and effectiveness elevation of SGOT, total and direct bilirubin, and in patients under the age of eighteen have not alkaline phosphatase. Paradoxical reactions rebeen established. lated to stimulation, excitement and hyperactivity Studies in rats have indicated that triazolam have not been reported but may occur. and its metabolites are secreted in milk. Human Symptoms and Treatment of Overdosage: studies have not been performed and therefore, Manifestations of Halcion (triazolam) overdosage nursing should not be undertaken while a patient include extensions of its pharmacological activity, is taking the drug. namely somnolence and hypnosis. Respiration, Warnings: Patients receiving Halcion (triazolam) pulse and blood pressure should be monitored should be cautioned about the possible comand supported by general measures when necesbined effects of alcohol and other central nervous sary. Immediate gastric lavage should be persystem depressants and consideration should be formed. Intravenous fluids should be administered given to potential additive effects. Combination of and an adequate airway maintained. alcohol and therapeutic doses of Halcion have in animals have indicated that caused severe central nervous system depression. Experiments cardiopulmonary collapse can occur with massive Anterograde amnaesia of varying severity intravenous doses of triazolam. This could be rehas been reported following therapeutic doses versed with positive mechanical respiration and of Halcion. Other benzodiazepines have been the intravenous infusion of levarterenol. Animal shown to produce anterograde amnaesia and the experiments have suggested that haemodialysis clinical significance of this effect is under study. and forced diuresis are probably of little value. As Physical and psychological dependence have with the management of intentional overdosage not been demonstrated in patients taking 0.5 mg with any drug, the physician should bear in mind Halcion per day for 90 days or in normal human that multiple agents may have been ingested by volunteers taking 1 mg per day for 42 days. Howthe patient. ever, caution must be exercised in administering Dosage and Administration: It is important Halcion to individuals who have a history of drug to individualise dosage to obtain the desired misuse, or who may tend to increase the dose hypnotic effect while avoiding oversedation and without supervision, and such patients must be other side effects. placed under careful surveillance. Adult Dose: The initial recommended dose is elderly In and/or debilitated patients, or in patients 0.25 mg and it can be titrated to the response of with organic brain disorders, it is recommended the patient within the range of 0.25 mg to 0.5 mg. that treatment with Halcion be initiated at the lowSome hospitalised patients may require doses of est possible dose, increased gradually if necesuptol mg. sary to decrease the possibility of development of Geriatric Dose: Because of the increased senoversedation, dizziness or impaired coordination. sitivity in this age group, the initial dose should be 0.125mg (½ of a 0.25mg tablet). If necessary, Use in Pregnancy: The safety of the use of Halcion in pregnancy has not been established. Therethe dose can be titrated to a maximum of 0.5 mg. fore, Halcion is not recommended for use during Availability: Halcion (triazolam) is available pregnancy or lactation. Several studies have as scored tablets of 0.25 mg (powder blue) and suggested an increased risk of congenital malfor0.5 mg (white) in bottles of 100 and 500; and mations associated with the use of the benzo1 mg (rose) in bottles of 100. diazepines chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregProduct monograph available on request.
766 REGISTERED TRADEMARK. HALCION CEgiRT.,
kfl. ii THE UPJOHN COMPANY OF CANADA . 865 YORK MILLS ROAD DON MILLS, ONTARIO
IPAABI .
References 1. STEWART THM, HOLLINSHEAD AC, HAIuus JE, et al: Survival study of immunochemotherapy in lung cancer, in Immunotherapy of Cancer: Present Status of Trials in Man, TERRY WD, WINDHORST D (eds), Raven, New York, 1978, p 203 2. HAIuus JE, SINKoVIcs JG: The Immunology of Malignant Disease, 2nd ed, Mosby, St Louis, 1970 3. FuJiMoTo 5, GREEN MI, SEHON AH: Regulation of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts. J Immunol 116: 791, 1976 4. Idem: Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts. Thid, p 800 5. RrnNsscii CL, ANDREW Sb, SCHOLSSMAN SF: Suppressor cell regulation of immune- response to tumors - abrogation by adult thymectomy. Proc Natl Acad Sci USA 74: 2989, 1977 6. TAKET F, LEvY JG, KILBURN DG: Characterization of suppressor cells in mice bearing syngeneic mastocytoma. J Immunol 118: 412, 1977 7. Yu A, WArrs H, JAFFE N, et al: Concomitant presence of tumor-specific cytotoxic and inhibitor lymphocytes in patients with osteogenic sarcoma. N Engi J Med 297: 121, 1977 8. CmoRAzzI N, Fox DA, KArz DH: Hapten-specific IgE antibody responses in mice. 6. Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide. J Immunol 117: 1629, 1976 9. FAuc RE, NossAL NA, SAMUEL ESS, et al: Increased resistance to established tumor metastases after elimination of thymus - T-cell mediated suppression. Surg Forum 28: 161, 1977 10. FALK RE, NossM. NA, FALK JA: Effective antitumor immunity following elimination of suppressor T-cell function. Surgery 84: 483, 1978 11. Poi,ix L, Tunic JL: Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature 249: 654, 1974 12. ASKENASE PW, HAYDEN BJ, GERSHON RK: Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which did not affect antibody responses. J Exp Med 141: 697, 1975 13. GREEN MI, MARTIN ED, PIEnxEs M, et al: Reduction of syngeneic tumor growth by an anti-I-J alloantiserusn. Proc Natl Acad Sci USA 74: 5118,
1977
