- Email: [email protected]
Immunomodulating agents
J. Descotes
39
Immunomodulating agents
It is now clear that immunomodulating agents are no longer in their infancy. More attention is being paid to establishing sounder criteria for the study of their mechanisms of action (IR), preclinical evaluation (2R), clinical efficacy (3R) and finally their side effects (4R), even though these drugs still have many promises to keep (5R--7R). I M M U N O M O D U L A T I N G AGENTS OF N A T U R A L O R I G I N (SEDA-9, 319;
SEDA-IO, 331) Corynebacterium parvum ( S ED A-9 , 318) When 21 patients with epithelial ovarian cancer received 9 intraperitoneal injections of Corynebacterium parvum every 2 weeks: abdominal pain occurred in 78% of cases, fever ( > 38~ in 56%, nausea in 40%, vomiting in 22% and hypotension in 8% (8c).
Monoclonal antibodies Dillman et al (11 c) reported a total of 82 patients with 10 different malignancies who received one or several courses of murine monoclonal antibodies. The most common side effects were fever, rigors and chills which occurred in 21-23% of patients. Urticaria and pruritus were noted in 15-18% of patients. There have been three severe complications: one episode of anaphylaxis and two of bronchospasm. All three episodes responded to adequate therapy. Interestingly, there was no apparent relation between dose, infusion rate and side effects. RU-41740
Nausea and gastralgia have been reported in 40 of 2997 patients with chronic respiratory infection treated with RU-41740 daily for 3 weeks, every 2 weeks. Skin eruptions were present in 10 patients (12c).
Interleukin-2 (SEDA-IO, 331) Rosenberg et al (9c) treated 25 patients for metastatic cancer with a combination of autologous killer cells and recombinant interleukin-
2. Malaise, fever, nausea or vomiting, dyspnea, eosinophilia and anemia were observed in nearly all patients. Diarrhea, weight gain, pruritus, thrombocytopenia and increased serum creatinine and bilirubin were present in 50-75% of patients.
Propionibacterium granulosum KP-45 Intratumoral injection of Propionibacterium granulosum KP-45 was found to be associated with pain, redness and swelling at the site of injection while 25% of these 25 patients with advanced breast cancer developed fever and chills which disappeared spontaneously the next day (10%
Side Effects of Drugs Annual I 1 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987
Thymic hormones (SED-IO, 713; SEDA-8, 342; SEDA-9, 319; SEDA-IO, 331) An increasing number of thymic factors are now being employed therapeutically in patients with a wide variety of diseases including immunodeficiency disorders and cancer (see 13R). Thymo~ntin (SEDA-IO, 331) This thymic factor has been extensively used. Clumeck et al (14c) treated 10 African patients for AIDS with 50 mg thymopentin intravenously, 3 times a week for 2 consecutive months, and observed no side effects. Twenty-seven patients with herpes simplex infections received subcutaneous injections of 50 mg thymopentin 3 times a week for 6 weeks: 2 complained of pain at the injection site, 1 presented with headache, 1 with insomnia, 1 with decreased insulin demand in diabetes mellitus, 1 with mild rash and 1 with collapse after intravenous injection (15c). Subcutaneous thymopentin in a single dose of 50 mg was used as an adjuvant to hepatitis B vaccination: none of the 29 hemodialyzed
lmmunomodulating agents Chapter39 patients developed side effects (16c). Zaruba et al (17c) noted 1 case of pruritus after the second subcutaneous injection of 50 mg thymopentin in a series of 13 hemodialyzed patients receiving 3 injections a week for 3 weeks after hepatitis B vaccination. No side effects were observed in 8 patients with lepromatous leprosy after receiving 50 mg thymopentin subcutaneously 3 times a week for 16 weeks, then 100 mg thymopentin for 6-7 weeks (18c). Sixteen patients with rheumatoid arthritis were treated with 50 mg thymopentin intravenously 3 times a week for 3 consecutive weeks; a statistically significant decrease in white blood cell count was noted and 1 patient developed marked leukopenia (2,800). Additionally, 6 patients complained of hypersomnia and 1 of nausea (19c). However, the same group of investigators did not confirm the decrease in white blood cell count in a larger series of 41 patients (20c). Reviewing the manufacturers' data on thymopentin safety from 196 European patients included in various clinical trials, Weiss and Stocker (21 R) found mild gastrointestinal side effects in 18.6% of cases, central nervous system symptoms, mainly sleep disorders and fatigue, in 30.5%, skin reactions in 18.6% and 3 patients with transient increase in, liver enzymes. Similar results were given by Friedman (22R) when reviewing all the manufacturers' safety data on thymopentin; interestingly, no evidence of drug interaction was noted in 290 patients taking concomitant medications. However, further studies are warranted to confirm all these findings. SYNTHETIC I M M U N O M O D U L A T I N G AGENTS (SEDA-9, 320; SEDA-IO, 332)
Forphenicinol Forphenicinol is a derivative of forphenicine isolated from culture filtrates of actinomycetes. In a Phase I trial, oral single doses ranging from 10-600mg were given to 55 cancer patients. No evidence of adverse effects was observed (23c).
Levamisole ( S E D- I O, 713; S E D A -8, 341; SEDA-9, 320; SEDA-IO, 332) Arora et al (24c) noted mild side effects in 50% of their 30 leprosy patients treated with 150 mg levamisole per day on 3 consecutive
329 days every fortnight for 3 months: nausea was observed in 9 patients, vomiting in 5, insomnia in 5, giddiness in 3, nervousness in 2 and abdominatpain in 1. Plengvanit et al (25 c) observed only 3 cases of nausea and vomiting among 51 patients with primary liver cancer treated with levamisole 150 mg per day, 3 times a week every other week. Veys et al (26 c) compared long-term treatment with levamisole, penicillamine and gold salts in rheumatoid arthritis. Of 220 patients treated with 150 mg levamisole once a week, 31 (14.1%) developed decreased white blood cell counts necessitating interruption of treatment, 29 (13.2%) presented with aflu-like syndrome, 16 (7.3%) with dermatitis, vasculitis or itching, 2 with central nerve excitation, 2 with dyspepsia, and 1 with thrombocytopenia.
Polynucleotides ( S ED A-9 , 320) Double-stranded RNA No clinical or laboratory evidence of toxicity was noted in 13 patients with solid tumors after receiving cumulative doses of up to 4 g of mismatched double-stranded RNA. Furthermore, no specific antibody could be detected (27c). Poly A:U (SEDA-9, 320) Lacour (28 c) observed no symptom of toxicity except a slight pyrogenic effect in a few patients among more than 400 patients with breast cancer receiving 30 or 60mg poly A:U per week for 6 consecutive weeks. Poly (ICLC) (SEDA-8, 342) Eighteen patients with multiple sclerosis were included in a Phase I trial of poly (ICLC). Doses of 20-100 I~g/kg were slowly infused intravenously every week for 10 weeks. Headache, nausea, chills, myalgias, and arthralgia associated with fever were noted in nearly all patients. Transient elevations of serum transaminases occurred in 84% of cases and lactic dehydrogenase or alkaline phosphatase was elevated in about 50%. Abnormalities of liver function persisted for more than 3 days in 3 patients (29c). All 28 leukemic children treated with incremented doses of intravenous poly (ICLC) developed fever over 39~ Hypotension was also commonly observed. Major side effects included convulsions (3 cases), coma (2 cases), thrombocytopenia (3 cases) and liver function abnormalities (6 cases) (30c).
330 Similar findings were reported by Durie et al (31 c) and Hawkins et al (32c): Fever was noted in all patients; hypotension, nausea and vomiting were quite common; thrombocytopenia
Chapter 39 J. Descotes and liver enzyme abnormalities were also reported. Finally, Hess (33 c) warned on possible elevations of liver enzymes after poly (ICLC) infusions.
REFERENCES 1. Chirigos MA, Talmadge JE (1985) Immunotherapeutic agents: their role in cellular immunity and their therapeutic potential. Springer Semin. Immunopathol., 8, 327. 2. Talmadge JE, Herberman RB (1986) The preclinical screening laboratory: evaluation of immunomodulatory and therapeutic properties of biological response modifiers. Cancer Treat. Rep., 70, 171. 3. Smalley RV, Oldham RK (1986) Phase I trials of biological response modifiers. Drugs Exp. Clin. Res., 12, 31. 4. Davies L (1986) Immunological adjuvants of natural origin and their adverse effects. Adverse Drug React. Acute Poisoning Rev., 1, 1. 5. Mihich E (1985) Biological response modifiers: their potential and limitations in cancer therapeutics. Cancer Invest., 3, 71. 6. Math~ G, Gouveia J, Eriguchi M, Reizenstein P (1985) Passive, adoptive and active immunotherapy. A review of clinical trials in cancer. Int. J. Immunother., 1, 139. 7. Droller MJ (1985) Immunotherapy in genitourinary neoplasia. J. Urol. (Baltimore), 133, 1. 8. Berek JS, Knapp RC, Hacker NF et al (1985) Intraperitoneai immunotherapy of epithelial ovarian carcinoma with Corynebacterium parvum. Am. J. Obstet. Gynecol., 152, 1003. 9. Rosenberg SA, Lotze MT, Muul LM et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med., 313, 1485. 10. Pluzanska A, Stempezynska J, Szmigielski S et al (1985) Local immunotherapy with Propionibacterium granulosum KP-45 in advanced breast cancer. Anticancer Res., 5, 521. 11. Dillman RO, Beauregard JC, Halpern SE, Clutter M (1986) Toxicities and side effects associated with intravenous infusions of monoclonal antibodies. J. Biol. Response Modif., 5, 73. 12. Bouvier JB (1984) Prtvention des rtcidives dans les infections de rarbre respiratoire: inttr& de l'administration de Biostim dts le dtbut de l'episode aigu. C.R. ThOr. Pharmacol. Clin., 3, 3. 13. Sehulof RS (1985) Thymic peptide hormones: basic properties and clinical applications in cancer. CRC Oncol. Hematol., 3, 309 14. Ctumeck N, Van de Perre P, Mascart-Lemone F et al (1984) Preliminary results on clinical and immunological effects of thymopentin in AIDS. Int. J. Clin. Pharmacol. Res., 4, 459. 15. DeMaubeuge J, Haneke E, Djawari D et al (1985) Thymopentin treatment of herpex simplex
infections: an open, monitored multicenter study. Surv. lmmunol. Res., 4, Suppl 1, 30. 16. Grob PJ, Binswanger U, Blumberg A et al (1985) Thymopentin as adjuvant to hepatitis B vaccination: results from three double-blind studies. Surv. Immunol. Res., 4, Suppl 1, 107. 17. Zaruba K, Grob PJ, Bolla K (1985) Thymopentin as adjuvant therapy to hepatitis B vaccination in formerly non- or hyporesponding hemodialysis patients. Surv. lmmunol. Res., 4, Suppl 1, 102. 18. Castells A, Terencio J, Ramirez A e t al (1985) Thymopentin treatment in patients with chemotherapy-resistant lepromatous leprosy. Surv. lmmunol. Res., 4, Suppl 1, 63. 19. Franchimont P, Hauwaert C, Bolla K (1985) Thymopentin in active rheumatoid arthritis. Surv. Immunol. Res., 4, Suppl 1, 81. 20. Malaise MG, Hauwaert C, Franchimont Pet al (1985) Treatment of active rheumatoid arthritis with slow intravenous injections of thymopentin. Lancet, 1, 832. 21. Weiss P, Stocker H (1985) Safety ofthymopentin. Surv. Immunol. Res., 4, Suppl 1, 149. 22. Friedman N (1985) Thymopentin: safety overview. Surv. lmmunol. Res., 4, Suppl 1, 139. 23. Kumano N, Nakai Y, Ishikawa T et al (1985) Changes in the immunological parameters after a single dose of forphenicinol, a new small molecular immunomodifier. Tohoku J. Exp. Med., 146, 419. 24. Arora SK, Singh G, Sen PC (1985) Side effects of levamisol~. Indian J. Med. Sci., 27, 6. 25. Plengvanit U, Chearanai O, Asavanich C et al (1986) Immunotherapy of primary liver cancer: a control study of 51 patients. J. Med. Assoc. Thailand, 69, 59. 26. Veys EM, Mielants H, Verbruggen G e t al (1986) Clinical evaluation of immunomodifiers. Adv. lnflamm. Res., 11, 301. 27. Brodsky I, Strayer DR, Krueger L J, Carter WA (1985) Clinical studies with Ampligen (mismatched double-stranded RNA). J. BioL Response Modif., 4, 669. 28. Lacour J (1985) Clinical trials using polyadenylic-polyuridylic acid as an adjuvant to surgery in treating different human tumors. J. Biol. Response Modif., 4, 538. 29. McFarlin DE, Bever CT, Salazar AM, Levy HB (1985) A preliminary trial of poly(l,C)-LC in multiple sclerosis. J. Biol. Response Moth'f, 4, 544. 30. Lampkin BC, Lavine AS, Levy H et al (1985) Phase II trial of poly (I,C)-LC, an interferon inducer, in the treatment of children with acute
lmmunomodulating agents
Chapter 39
leukemia and neuroblastoma: a report from the children's cancer study group. J. Biol. Response Modif., 4, 531. 31. Durie BGM, Levy HB, Voakes J, Jett JR, Levine AS (1985) Poly(I,C)-LC as an interferon inducer in refractory multiple myeloma. J. Biol.
Response Modif., 4, 518. 32.
Hawkins MJ, Levin M, Borden EC (1985) An
331 Eastern Cooperative Oncology Group phase I-II pilot study of polyriboinosinic-polyribocytidylic acid poly-L-lysine complex in patients with metastatic malignant melanoma. J. Biol. Response
Modif., 4, 664. 33. Hess WA (1985) Liver enzymes abnormalities after poty ICLC infusions. Cancer Treat. Rep., 70, 1342.
39
Immunomodulating agents
It is now clear that immunomodulating agents are no longer in their infancy. More attention is being paid to establishing sounder criteria for the study of their mechanisms of action (IR), preclinical evaluation (2R), clinical efficacy (3R) and finally their side effects (4R), even though these drugs still have many promises to keep (5R--7R). I M M U N O M O D U L A T I N G AGENTS OF N A T U R A L O R I G I N (SEDA-9, 319;
SEDA-IO, 331) Corynebacterium parvum ( S ED A-9 , 318) When 21 patients with epithelial ovarian cancer received 9 intraperitoneal injections of Corynebacterium parvum every 2 weeks: abdominal pain occurred in 78% of cases, fever ( > 38~ in 56%, nausea in 40%, vomiting in 22% and hypotension in 8% (8c).
Monoclonal antibodies Dillman et al (11 c) reported a total of 82 patients with 10 different malignancies who received one or several courses of murine monoclonal antibodies. The most common side effects were fever, rigors and chills which occurred in 21-23% of patients. Urticaria and pruritus were noted in 15-18% of patients. There have been three severe complications: one episode of anaphylaxis and two of bronchospasm. All three episodes responded to adequate therapy. Interestingly, there was no apparent relation between dose, infusion rate and side effects. RU-41740
Nausea and gastralgia have been reported in 40 of 2997 patients with chronic respiratory infection treated with RU-41740 daily for 3 weeks, every 2 weeks. Skin eruptions were present in 10 patients (12c).
Interleukin-2 (SEDA-IO, 331) Rosenberg et al (9c) treated 25 patients for metastatic cancer with a combination of autologous killer cells and recombinant interleukin-
2. Malaise, fever, nausea or vomiting, dyspnea, eosinophilia and anemia were observed in nearly all patients. Diarrhea, weight gain, pruritus, thrombocytopenia and increased serum creatinine and bilirubin were present in 50-75% of patients.
Propionibacterium granulosum KP-45 Intratumoral injection of Propionibacterium granulosum KP-45 was found to be associated with pain, redness and swelling at the site of injection while 25% of these 25 patients with advanced breast cancer developed fever and chills which disappeared spontaneously the next day (10%
Side Effects of Drugs Annual I 1 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987
Thymic hormones (SED-IO, 713; SEDA-8, 342; SEDA-9, 319; SEDA-IO, 331) An increasing number of thymic factors are now being employed therapeutically in patients with a wide variety of diseases including immunodeficiency disorders and cancer (see 13R). Thymo~ntin (SEDA-IO, 331) This thymic factor has been extensively used. Clumeck et al (14c) treated 10 African patients for AIDS with 50 mg thymopentin intravenously, 3 times a week for 2 consecutive months, and observed no side effects. Twenty-seven patients with herpes simplex infections received subcutaneous injections of 50 mg thymopentin 3 times a week for 6 weeks: 2 complained of pain at the injection site, 1 presented with headache, 1 with insomnia, 1 with decreased insulin demand in diabetes mellitus, 1 with mild rash and 1 with collapse after intravenous injection (15c). Subcutaneous thymopentin in a single dose of 50 mg was used as an adjuvant to hepatitis B vaccination: none of the 29 hemodialyzed
lmmunomodulating agents Chapter39 patients developed side effects (16c). Zaruba et al (17c) noted 1 case of pruritus after the second subcutaneous injection of 50 mg thymopentin in a series of 13 hemodialyzed patients receiving 3 injections a week for 3 weeks after hepatitis B vaccination. No side effects were observed in 8 patients with lepromatous leprosy after receiving 50 mg thymopentin subcutaneously 3 times a week for 16 weeks, then 100 mg thymopentin for 6-7 weeks (18c). Sixteen patients with rheumatoid arthritis were treated with 50 mg thymopentin intravenously 3 times a week for 3 consecutive weeks; a statistically significant decrease in white blood cell count was noted and 1 patient developed marked leukopenia (2,800). Additionally, 6 patients complained of hypersomnia and 1 of nausea (19c). However, the same group of investigators did not confirm the decrease in white blood cell count in a larger series of 41 patients (20c). Reviewing the manufacturers' data on thymopentin safety from 196 European patients included in various clinical trials, Weiss and Stocker (21 R) found mild gastrointestinal side effects in 18.6% of cases, central nervous system symptoms, mainly sleep disorders and fatigue, in 30.5%, skin reactions in 18.6% and 3 patients with transient increase in, liver enzymes. Similar results were given by Friedman (22R) when reviewing all the manufacturers' safety data on thymopentin; interestingly, no evidence of drug interaction was noted in 290 patients taking concomitant medications. However, further studies are warranted to confirm all these findings. SYNTHETIC I M M U N O M O D U L A T I N G AGENTS (SEDA-9, 320; SEDA-IO, 332)
Forphenicinol Forphenicinol is a derivative of forphenicine isolated from culture filtrates of actinomycetes. In a Phase I trial, oral single doses ranging from 10-600mg were given to 55 cancer patients. No evidence of adverse effects was observed (23c).
Levamisole ( S E D- I O, 713; S E D A -8, 341; SEDA-9, 320; SEDA-IO, 332) Arora et al (24c) noted mild side effects in 50% of their 30 leprosy patients treated with 150 mg levamisole per day on 3 consecutive
329 days every fortnight for 3 months: nausea was observed in 9 patients, vomiting in 5, insomnia in 5, giddiness in 3, nervousness in 2 and abdominatpain in 1. Plengvanit et al (25 c) observed only 3 cases of nausea and vomiting among 51 patients with primary liver cancer treated with levamisole 150 mg per day, 3 times a week every other week. Veys et al (26 c) compared long-term treatment with levamisole, penicillamine and gold salts in rheumatoid arthritis. Of 220 patients treated with 150 mg levamisole once a week, 31 (14.1%) developed decreased white blood cell counts necessitating interruption of treatment, 29 (13.2%) presented with aflu-like syndrome, 16 (7.3%) with dermatitis, vasculitis or itching, 2 with central nerve excitation, 2 with dyspepsia, and 1 with thrombocytopenia.
Polynucleotides ( S ED A-9 , 320) Double-stranded RNA No clinical or laboratory evidence of toxicity was noted in 13 patients with solid tumors after receiving cumulative doses of up to 4 g of mismatched double-stranded RNA. Furthermore, no specific antibody could be detected (27c). Poly A:U (SEDA-9, 320) Lacour (28 c) observed no symptom of toxicity except a slight pyrogenic effect in a few patients among more than 400 patients with breast cancer receiving 30 or 60mg poly A:U per week for 6 consecutive weeks. Poly (ICLC) (SEDA-8, 342) Eighteen patients with multiple sclerosis were included in a Phase I trial of poly (ICLC). Doses of 20-100 I~g/kg were slowly infused intravenously every week for 10 weeks. Headache, nausea, chills, myalgias, and arthralgia associated with fever were noted in nearly all patients. Transient elevations of serum transaminases occurred in 84% of cases and lactic dehydrogenase or alkaline phosphatase was elevated in about 50%. Abnormalities of liver function persisted for more than 3 days in 3 patients (29c). All 28 leukemic children treated with incremented doses of intravenous poly (ICLC) developed fever over 39~ Hypotension was also commonly observed. Major side effects included convulsions (3 cases), coma (2 cases), thrombocytopenia (3 cases) and liver function abnormalities (6 cases) (30c).
330 Similar findings were reported by Durie et al (31 c) and Hawkins et al (32c): Fever was noted in all patients; hypotension, nausea and vomiting were quite common; thrombocytopenia
Chapter 39 J. Descotes and liver enzyme abnormalities were also reported. Finally, Hess (33 c) warned on possible elevations of liver enzymes after poly (ICLC) infusions.
REFERENCES 1. Chirigos MA, Talmadge JE (1985) Immunotherapeutic agents: their role in cellular immunity and their therapeutic potential. Springer Semin. Immunopathol., 8, 327. 2. Talmadge JE, Herberman RB (1986) The preclinical screening laboratory: evaluation of immunomodulatory and therapeutic properties of biological response modifiers. Cancer Treat. Rep., 70, 171. 3. Smalley RV, Oldham RK (1986) Phase I trials of biological response modifiers. Drugs Exp. Clin. Res., 12, 31. 4. Davies L (1986) Immunological adjuvants of natural origin and their adverse effects. Adverse Drug React. Acute Poisoning Rev., 1, 1. 5. Mihich E (1985) Biological response modifiers: their potential and limitations in cancer therapeutics. Cancer Invest., 3, 71. 6. Math~ G, Gouveia J, Eriguchi M, Reizenstein P (1985) Passive, adoptive and active immunotherapy. A review of clinical trials in cancer. Int. J. Immunother., 1, 139. 7. Droller MJ (1985) Immunotherapy in genitourinary neoplasia. J. Urol. (Baltimore), 133, 1. 8. Berek JS, Knapp RC, Hacker NF et al (1985) Intraperitoneai immunotherapy of epithelial ovarian carcinoma with Corynebacterium parvum. Am. J. Obstet. Gynecol., 152, 1003. 9. Rosenberg SA, Lotze MT, Muul LM et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med., 313, 1485. 10. Pluzanska A, Stempezynska J, Szmigielski S et al (1985) Local immunotherapy with Propionibacterium granulosum KP-45 in advanced breast cancer. Anticancer Res., 5, 521. 11. Dillman RO, Beauregard JC, Halpern SE, Clutter M (1986) Toxicities and side effects associated with intravenous infusions of monoclonal antibodies. J. Biol. Response Modif., 5, 73. 12. Bouvier JB (1984) Prtvention des rtcidives dans les infections de rarbre respiratoire: inttr& de l'administration de Biostim dts le dtbut de l'episode aigu. C.R. ThOr. Pharmacol. Clin., 3, 3. 13. Sehulof RS (1985) Thymic peptide hormones: basic properties and clinical applications in cancer. CRC Oncol. Hematol., 3, 309 14. Ctumeck N, Van de Perre P, Mascart-Lemone F et al (1984) Preliminary results on clinical and immunological effects of thymopentin in AIDS. Int. J. Clin. Pharmacol. Res., 4, 459. 15. DeMaubeuge J, Haneke E, Djawari D et al (1985) Thymopentin treatment of herpex simplex
infections: an open, monitored multicenter study. Surv. lmmunol. Res., 4, Suppl 1, 30. 16. Grob PJ, Binswanger U, Blumberg A et al (1985) Thymopentin as adjuvant to hepatitis B vaccination: results from three double-blind studies. Surv. Immunol. Res., 4, Suppl 1, 107. 17. Zaruba K, Grob PJ, Bolla K (1985) Thymopentin as adjuvant therapy to hepatitis B vaccination in formerly non- or hyporesponding hemodialysis patients. Surv. lmmunol. Res., 4, Suppl 1, 102. 18. Castells A, Terencio J, Ramirez A e t al (1985) Thymopentin treatment in patients with chemotherapy-resistant lepromatous leprosy. Surv. lmmunol. Res., 4, Suppl 1, 63. 19. Franchimont P, Hauwaert C, Bolla K (1985) Thymopentin in active rheumatoid arthritis. Surv. Immunol. Res., 4, Suppl 1, 81. 20. Malaise MG, Hauwaert C, Franchimont Pet al (1985) Treatment of active rheumatoid arthritis with slow intravenous injections of thymopentin. Lancet, 1, 832. 21. Weiss P, Stocker H (1985) Safety ofthymopentin. Surv. Immunol. Res., 4, Suppl 1, 149. 22. Friedman N (1985) Thymopentin: safety overview. Surv. lmmunol. Res., 4, Suppl 1, 139. 23. Kumano N, Nakai Y, Ishikawa T et al (1985) Changes in the immunological parameters after a single dose of forphenicinol, a new small molecular immunomodifier. Tohoku J. Exp. Med., 146, 419. 24. Arora SK, Singh G, Sen PC (1985) Side effects of levamisol~. Indian J. Med. Sci., 27, 6. 25. Plengvanit U, Chearanai O, Asavanich C et al (1986) Immunotherapy of primary liver cancer: a control study of 51 patients. J. Med. Assoc. Thailand, 69, 59. 26. Veys EM, Mielants H, Verbruggen G e t al (1986) Clinical evaluation of immunomodifiers. Adv. lnflamm. Res., 11, 301. 27. Brodsky I, Strayer DR, Krueger L J, Carter WA (1985) Clinical studies with Ampligen (mismatched double-stranded RNA). J. BioL Response Modif., 4, 669. 28. Lacour J (1985) Clinical trials using polyadenylic-polyuridylic acid as an adjuvant to surgery in treating different human tumors. J. Biol. Response Modif., 4, 538. 29. McFarlin DE, Bever CT, Salazar AM, Levy HB (1985) A preliminary trial of poly(l,C)-LC in multiple sclerosis. J. Biol. Response Moth'f, 4, 544. 30. Lampkin BC, Lavine AS, Levy H et al (1985) Phase II trial of poly (I,C)-LC, an interferon inducer, in the treatment of children with acute
lmmunomodulating agents
Chapter 39
leukemia and neuroblastoma: a report from the children's cancer study group. J. Biol. Response Modif., 4, 531. 31. Durie BGM, Levy HB, Voakes J, Jett JR, Levine AS (1985) Poly(I,C)-LC as an interferon inducer in refractory multiple myeloma. J. Biol.
Response Modif., 4, 518. 32.
Hawkins MJ, Levin M, Borden EC (1985) An
331 Eastern Cooperative Oncology Group phase I-II pilot study of polyriboinosinic-polyribocytidylic acid poly-L-lysine complex in patients with metastatic malignant melanoma. J. Biol. Response
Modif., 4, 664. 33. Hess WA (1985) Liver enzymes abnormalities after poty ICLC infusions. Cancer Treat. Rep., 70, 1342.