Biotherapy 3: 345-349, 1991. © 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Intrapleural application of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer A multi-institutional cooperative study Kosei Yasumoto ~ & Takeshi Ogura 2
~Respiratory Disease Center, Matsuyama Red Cross Hospital, Bunkyo-cho I, Matsuyama 790; 2Third Department of Internal Medicine, School of Medicine, Tokushima University, Kuramoto-cho 3-18-15, Tokushima 770, Japan Received 14 November 1990; accepted 21 December 1990
Key words: intrapleural RIL-2, lung cancer, malignant pleurisy, recombinant interleukin-2 (RIL-2) Abstract
Forty-three patients with malignant pleurisy due to lung cancer were entered into the trial to evaluate clinical efficacy of intrapleural instillation of recombinant interleukin-2 (RIL-2). Among 35 evaluable patients, serial cytological examinations of pleural effusion following the start of the treatment revealed disappearance of malignant cells in 26 (74%). Malignant cells were detected again in 7 of the 26, however, cytology remained negative in the other 19 patients for longer than 4 weeks. Pleural effusion disappeared roentogenographically in 13 of 35 evaluable patients. Additional 8 patients demonstrated marked decrease of pleural effusion. Complete response (CR) which means disappearance of both malignant cells and pleural effusion for longer than 4 weeks was obtained in 13 of the 35 patients (37%). No serious side effects were experienced in this trial. These results indicate that intrapleural RIL-2 is one of candidates to control intractable malignant pleurisy due to lung cancer.
Introduction
The adoptive transfer of LAK cells generated from peripheral blood lymphocytes (PBL) has provided a therapeutic benefit in the treatment of advanced cancer as reported by Rosenberg et at. [1-3] and West et al. [4]. This success has encouraged the development of a more effective LAK or IL-2 treatment. However, when injected intravenously, the serum half-life in mice and humans is quite short. A large proportion of this clearance appears to be related to renal clearance [5, 6]. Because of this short half-life administration
of large amount of IL-2 is required to activate in vivo antitumor effector mechanisms [2, 3, 7]. Clinical trials have shown that antitumor responses can be attained in patients with disseminated malignancies by infusion of in vitro activated LAK cells plus IL-2, or high doses of IL-2 alone. However, severe toxicities are expressed at the dose of IL-2 used in most of these studies. While these toxic effects are rapidly reversible after the discontinuation of the therapy, intensive care unit support has often proved necessary. This level of toxicity has led some investigators to question the applicability of this approach [1-4].
346 Table I. List of the institutes and responsible doctors.
Table 2. Clinical backgrounds of evaluable patients.
Institute
Background factor
Second Department of Surgery, School of Medicine, Akita University Department of Clinical Pathology, Nippon Medical College National Cancer Center Hospital Kinki Central Hospital Osaka Prefectural Habikino Hospital Second Department of Surgery, School of Medicine, Tottori University Third Department of Internal Medicine, School of Medicine, Tokushima University Tokushima Prefectural Central Hospital Takamatsu Red Cross Hospital Matsuyama Red Cross Hospital Shikoku Cancer Center Hospital Second Department of Surgery, School of Medicine, Kyushu University Minami-Fukuoka National Hospital Omuta National Hospital
Responsible doctor
Number of patients
Sex
Schichisaburo Abo Hisanobu Niitani Nagahiro Saijo Masami Ito Masahiro Fukuoka
Toru Mori
Takeshi Ogura Yoshihiro Takeshita Masaki Kobayashi Kosei Yasumoto Narimitsu Takashima
Teruyoshi Ishida Nobuo Hirota Tsuneo Ishibashi
Recently, we have described that IL-2 in pleural effusion is maintained in relatively high level for long time even after infusion of relatively small amount of IL-2 [8]. Therefore, we have investigated the effect of intrapleural administration of IL-2 in patients with malignant pleurisy due to lung cancer.
Materials and methods Patients
Forty-three patients with malignant pleurisy due to lung cancer admitted to the hospitals listed in Table 1 were entered into this trial. Table 1 also indicates the responsible doctors of each hospital. Three patients were ineligible because of prior chemotherapy against pleural effusion. Among 40 eligible patients, 5 were unevaluable because o f withdrawal (3, one respiratory distress, 2 pyothorax) and
Male Female Age 50 59 yr 60 -69 70-88 Histology Squamous cell carcinoma Adenocarcinoma Large cell carconoma Clinical Status Distant metastasis ( - ) Distant metastasis ( + ) Pleural recurrence after operation Performance status 0 1
2 3
26 9 8 15 12 6 28 1 16 18 1 2 16 12 5
dropout (2, one refusal of continuation of the therapy, one corticosteroid administration). The total number of evaluable patients was 35. Clinical backgrounds of these 35 evaluable patients are in Table 2. /L-2 Human recombinant interleukin-2 (RIL-2) was kindly donated by Takeda Chemical Industries, Ltd., Osaka, Japan. The in vitro biological activity of the purified preparation as determined by the ability to maintain NKC-3 cells was 3.5 × 104 units/mg of protein. Usually, 4 units/ml of this RIL-2 can induce LAK activity in vitro. When the Biological Response Modifiers Program standard was used, it was 1.2× 107units/mg of protein. Treatment with R I L - 2
RIL-2 (250-1000 units in 20ml of 0.9% NaC1 solution/day) was instilled into the pleural cavity for 5 to 33 days (mainly 14
347 Table 3. Disappearance of cancer cells in pleural effusion after intrapleural instillations of RIL-2.
Dose of Number Duration of disappearance Not RIL-2 of patients of malignant cells disappeared (u/day) treated > 4 weeks < 4 weeks 250 500 1000
6 3 26
4 2 13
1 0 6
1 I 7
Total
35
I9 (54%)
7 (20%)
9 (26%)
days) through a double lumen trocar catheter which had been inserted into the pleural cavity to evacuate the pleural effusion.
Evaluation of the efficacy of the treatment Effect of the treatment was evaluated by roentogenographical disappearance of pleural effusion and/or malignant cells in the effusion by serial cytological examinations. Final efficacy was expressed as complete response which means disappearance of both pleural effusion and malignant cells for longer than 4 weeks, and partial response which means disappearance of one of the two for longer than 4 weeks.
Results
I. Disappearance of cancer cells As shown in Table 3, cancer cells in pleural effusion disappeared in 26 of 35 patients Table 4. Effect of intrapleural instillations of RIL-2 on volume of pteural effusion.
Dose of Number RIL-2 of patients (u/day) treated 250 500 1000
6 3 26
Total
35
Disappeared
2 2 9 13 (37%)
Markedly decreased
Not decreased
1 0 7
3 I 10
8 (23%)
14 (40%)
Table 5. Efficacy of intrapleural instillations of RIL-2.
Dose of RIL-2 (u/day)
Number of patients treated
250 500 1000
6 3 26
Total
35
Complete response (CR) 2 2 9 13 (37%)
Partial response (PR)
No change
2 0 4
2 1 13
6 (17%)
16 (46%)
(74%). The effect lasted longer than 4 weeks in 19 patients (54%). Increase in RIL-2 dose from 250 to 1000 units did not alter the response rate. Cancer cells disappeared by 14 days after the first installation of RIL-2 in most of the cases (79%).
2. D&appearance of pleural effusion As shown in Table 4, pleural effusion disappeared in 13 of 35 patients (37%). Additional 8 patients demonstrated marked decrease of pleural effusion. Total response rate was 60% (21 of 35). Such a response rate was not changed by difference of RIL-2 dose administered. Both cancer cells and pleural effusion disappeared, and such effects persisted longer than 4 weeks in 13 of 35 patients (37%). However, despite of disappearance of both cancer cells and pleural effusion, primary tumors were not affected at all by the treatment (Table 5).
3. Prognos& Figure 1 shows survival curves of the 35 patients treated with RIL-2. Survival rate at 1 year after the treatment was 40% and median survival period was 270 days.
4. Side effects Side effects of the treatment in 40 eligible patients are listed in Table 6. Main and frequent side effects were fever, transient
348 %
1\ "~ m
40
30
20 l0 00
I-G-al! evaluable i
[
patlenls 35
90
180 270 360 450 5,i0 630 720 81'0 900 Survival period (da~) Fig. 1. Survival curve of evaluable patients. Median observation period = 390 days (range, 29-1143). Kaplan-Meier method was employed.
increase of pleural effusion, and eosinophilia. Fever up to 39°C (in most patients, 38°C) was encountered in 63% of patients. Eosinophilia (6 to 37%, average 23%) was observed in 51% of patients. However, it returned to the normal level within 4 to 22 days after the end of the treatment. A transient increase of pleural effusion lasting 1 to 51 days after the start of the treatment (average, 8 days) was observed roentogenographically in 74% of the patients. Among them, 9 patients complained of respiratory distress because of the increase of pleural effusion. Discussion
Since its has been mote the [10], and
discovery [9], interleukin-2 (IL-2) widely studied as a factor to prodifferentiation of cytotoxic T-cells to activate natural killer cells [11]
and to induce lymphokine-activated killer cells [ 12, 13]. There may be two modalities of anticancer treatments using IL-2. One is an adoptive immunotherapy in which LAK cells generated in vitro by coculture with IL-2 and lymphocytes are infused intravenously in conjunction with or without intravenous injection of IL-2. The other is a passive immunotherapy in which IL-2 is administered directly to cancer patients. Rosenberg et al. reported the results of high-dose IL-2 in the treatment of 652 cancer patients [3]. Of these patients, 214 were treated with IL-2 and LAK cells. Responders were 14 of complete response (CR) and 30 of partial response (PR) among 177 evaluable patients out of the 214. The response rate was 25%. The 44 responders comprised renal cell carcinoma (25/72), malignant melanoma (10/ 48), colorectal cancer (5/30), and nonHodgkin's lymphoma (4/7). On the other hand, 155 patients were treated with intravenous administration of high dose IL-2 alone. Responders comprised 4 C R and 18 PR among 130 evaluable patients out of the 135. The response rate was 17%. The 22 responders were limited to renal cell carcinoma (12/54) and malignant melanoma (10/42). These results may indicate that malignant cells of different origins have quite different susceptibility to IL-2 therapy. Kinetic study of IL-2 after intravenous injection revealed rapid clearance of IL-2 from kidney [6]. This short half life of IL-2 in the serum necessitates administration of large
Table 6. Main side effects of intrapleural instillations of RIL-2.
Adverse reaction
Fever Nausea, vomiting Respiratory distress Eosinophilia Elevated GOT or G I ~
Total
Number of patients treated with R1L-2 250 u/day
500 u/day
1000 u/day
7
3
30
40
4 0 2 3 0
2 0 1 3 0
19 3 6 15 5
25 3 9 21 5
349
amounts of IL-2 to achieve tumor response to IL-2. Also it was accompanied with severe toxicities such as fluid retention and respiratory distress syndrome [3, 4]. Previously, we have reported that intrapleural instillation of IL-2 leads to relatively high levels for a prolonged time. When 1000 units of IL-2 was instilled into the pleural cavity, IL-2 concentration in the pleural effusion was 28 units/ml at 30 min., and gradually dropped to 4 units/ml after 24 hr. This IL-2 concentration of 4 units/ml is optimal to induce LAK cells in vitro. LAK cells were induced in the effusion in 9 of 11 patients, 4 to 10 days after the treatment. Moreover, pleural effusion and cancer cells in the effusion disappeared in the 9 patients in whom LAK cell were induced [8]. In that study, there were 6 patients in whom pleural effusion could not be detected by chest roentgenograms, however, small amount of pleural effusion (usually 100 to 200 ml) was observed when thoracotomy was performed. Such effusions were checked for malignant cells. In the 6 patients the primary lesions were resected by an usual lobectomy, and the malignant pleurisy was treated by intrapleural instillation of IL-2 postoperatively. All of the 6 patients demonstrated disappearance of effusion and cancer cells in the effusion. At this moment, prognostic impact of this response rate is not clear, however, further study should be done to evaluate the efficacy of local administration of IL-2 in conjunction with chemotherapeutic agents as one modality of treatments in patients with malignant pleurisy due to lung cancer.
References 1. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E,
2.
3.
4.
5. 6.
7.
8.
9.
I0.
l l.
12.
13.
Vetto JT, Seipp CA, Simpson CG, Reichert CM. Observation on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313: 1485-92. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. 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 1987; 316: 889-905. Rosenberg SA, Lotze ML, Yang JC, Aebersold PM, Lineban WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surgery 1989; 210:474 85. West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Okdham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 898-905. Donohue JH, Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983; 130:2203 8. Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy WH, Harris R, Hersey P. Clearance rates and systemic effects of intravenously administrated interleukin-2 (IL-2) containing preparations in human subjects. Br J Cancer 1983; 47: 123-33. Hang AE, Hyatt CL, Rosenberg SA. Systemic administration of recombinant human interleukin-2 in mice. J Biol Response Modifiers 1984; 3: 561-72. Yasumoto K, Miyazaki K, Nagashima A, Ishida T, Kuda T, Yano T, Sugimachi K, Nomoto K. Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer. Cancer Res. 1987; 47: 2184 -~7. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science (Wash DC) 1976; 193:1007 8. Baker PE, Gillis S, Ferm MM, Smith KA. The effect o f T cell growth factor on the generation of cytolytic T cells. J Immunol 1982; 121: 2168-73. Henney CS, Kuribayashi K, Kern DE, Gills S. Interleukin-2 augment natural killer cell activity. Nature (Lond.) 1981; 291: 335-8. Lotze MT, Grimm EA, Mazumder A, Strausser JL, Rosenberg SA. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res 1981; 41: 4420-5. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982; 155:1823 41.
Intrapleural application of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer A multi-institutional cooperative study Kosei Yasumoto ~ & Takeshi Ogura 2
~Respiratory Disease Center, Matsuyama Red Cross Hospital, Bunkyo-cho I, Matsuyama 790; 2Third Department of Internal Medicine, School of Medicine, Tokushima University, Kuramoto-cho 3-18-15, Tokushima 770, Japan Received 14 November 1990; accepted 21 December 1990
Key words: intrapleural RIL-2, lung cancer, malignant pleurisy, recombinant interleukin-2 (RIL-2) Abstract
Forty-three patients with malignant pleurisy due to lung cancer were entered into the trial to evaluate clinical efficacy of intrapleural instillation of recombinant interleukin-2 (RIL-2). Among 35 evaluable patients, serial cytological examinations of pleural effusion following the start of the treatment revealed disappearance of malignant cells in 26 (74%). Malignant cells were detected again in 7 of the 26, however, cytology remained negative in the other 19 patients for longer than 4 weeks. Pleural effusion disappeared roentogenographically in 13 of 35 evaluable patients. Additional 8 patients demonstrated marked decrease of pleural effusion. Complete response (CR) which means disappearance of both malignant cells and pleural effusion for longer than 4 weeks was obtained in 13 of the 35 patients (37%). No serious side effects were experienced in this trial. These results indicate that intrapleural RIL-2 is one of candidates to control intractable malignant pleurisy due to lung cancer.
Introduction
The adoptive transfer of LAK cells generated from peripheral blood lymphocytes (PBL) has provided a therapeutic benefit in the treatment of advanced cancer as reported by Rosenberg et at. [1-3] and West et al. [4]. This success has encouraged the development of a more effective LAK or IL-2 treatment. However, when injected intravenously, the serum half-life in mice and humans is quite short. A large proportion of this clearance appears to be related to renal clearance [5, 6]. Because of this short half-life administration
of large amount of IL-2 is required to activate in vivo antitumor effector mechanisms [2, 3, 7]. Clinical trials have shown that antitumor responses can be attained in patients with disseminated malignancies by infusion of in vitro activated LAK cells plus IL-2, or high doses of IL-2 alone. However, severe toxicities are expressed at the dose of IL-2 used in most of these studies. While these toxic effects are rapidly reversible after the discontinuation of the therapy, intensive care unit support has often proved necessary. This level of toxicity has led some investigators to question the applicability of this approach [1-4].
346 Table I. List of the institutes and responsible doctors.
Table 2. Clinical backgrounds of evaluable patients.
Institute
Background factor
Second Department of Surgery, School of Medicine, Akita University Department of Clinical Pathology, Nippon Medical College National Cancer Center Hospital Kinki Central Hospital Osaka Prefectural Habikino Hospital Second Department of Surgery, School of Medicine, Tottori University Third Department of Internal Medicine, School of Medicine, Tokushima University Tokushima Prefectural Central Hospital Takamatsu Red Cross Hospital Matsuyama Red Cross Hospital Shikoku Cancer Center Hospital Second Department of Surgery, School of Medicine, Kyushu University Minami-Fukuoka National Hospital Omuta National Hospital
Responsible doctor
Number of patients
Sex
Schichisaburo Abo Hisanobu Niitani Nagahiro Saijo Masami Ito Masahiro Fukuoka
Toru Mori
Takeshi Ogura Yoshihiro Takeshita Masaki Kobayashi Kosei Yasumoto Narimitsu Takashima
Teruyoshi Ishida Nobuo Hirota Tsuneo Ishibashi
Recently, we have described that IL-2 in pleural effusion is maintained in relatively high level for long time even after infusion of relatively small amount of IL-2 [8]. Therefore, we have investigated the effect of intrapleural administration of IL-2 in patients with malignant pleurisy due to lung cancer.
Materials and methods Patients
Forty-three patients with malignant pleurisy due to lung cancer admitted to the hospitals listed in Table 1 were entered into this trial. Table 1 also indicates the responsible doctors of each hospital. Three patients were ineligible because of prior chemotherapy against pleural effusion. Among 40 eligible patients, 5 were unevaluable because o f withdrawal (3, one respiratory distress, 2 pyothorax) and
Male Female Age 50 59 yr 60 -69 70-88 Histology Squamous cell carcinoma Adenocarcinoma Large cell carconoma Clinical Status Distant metastasis ( - ) Distant metastasis ( + ) Pleural recurrence after operation Performance status 0 1
2 3
26 9 8 15 12 6 28 1 16 18 1 2 16 12 5
dropout (2, one refusal of continuation of the therapy, one corticosteroid administration). The total number of evaluable patients was 35. Clinical backgrounds of these 35 evaluable patients are in Table 2. /L-2 Human recombinant interleukin-2 (RIL-2) was kindly donated by Takeda Chemical Industries, Ltd., Osaka, Japan. The in vitro biological activity of the purified preparation as determined by the ability to maintain NKC-3 cells was 3.5 × 104 units/mg of protein. Usually, 4 units/ml of this RIL-2 can induce LAK activity in vitro. When the Biological Response Modifiers Program standard was used, it was 1.2× 107units/mg of protein. Treatment with R I L - 2
RIL-2 (250-1000 units in 20ml of 0.9% NaC1 solution/day) was instilled into the pleural cavity for 5 to 33 days (mainly 14
347 Table 3. Disappearance of cancer cells in pleural effusion after intrapleural instillations of RIL-2.
Dose of Number Duration of disappearance Not RIL-2 of patients of malignant cells disappeared (u/day) treated > 4 weeks < 4 weeks 250 500 1000
6 3 26
4 2 13
1 0 6
1 I 7
Total
35
I9 (54%)
7 (20%)
9 (26%)
days) through a double lumen trocar catheter which had been inserted into the pleural cavity to evacuate the pleural effusion.
Evaluation of the efficacy of the treatment Effect of the treatment was evaluated by roentogenographical disappearance of pleural effusion and/or malignant cells in the effusion by serial cytological examinations. Final efficacy was expressed as complete response which means disappearance of both pleural effusion and malignant cells for longer than 4 weeks, and partial response which means disappearance of one of the two for longer than 4 weeks.
Results
I. Disappearance of cancer cells As shown in Table 3, cancer cells in pleural effusion disappeared in 26 of 35 patients Table 4. Effect of intrapleural instillations of RIL-2 on volume of pteural effusion.
Dose of Number RIL-2 of patients (u/day) treated 250 500 1000
6 3 26
Total
35
Disappeared
2 2 9 13 (37%)
Markedly decreased
Not decreased
1 0 7
3 I 10
8 (23%)
14 (40%)
Table 5. Efficacy of intrapleural instillations of RIL-2.
Dose of RIL-2 (u/day)
Number of patients treated
250 500 1000
6 3 26
Total
35
Complete response (CR) 2 2 9 13 (37%)
Partial response (PR)
No change
2 0 4
2 1 13
6 (17%)
16 (46%)
(74%). The effect lasted longer than 4 weeks in 19 patients (54%). Increase in RIL-2 dose from 250 to 1000 units did not alter the response rate. Cancer cells disappeared by 14 days after the first installation of RIL-2 in most of the cases (79%).
2. D&appearance of pleural effusion As shown in Table 4, pleural effusion disappeared in 13 of 35 patients (37%). Additional 8 patients demonstrated marked decrease of pleural effusion. Total response rate was 60% (21 of 35). Such a response rate was not changed by difference of RIL-2 dose administered. Both cancer cells and pleural effusion disappeared, and such effects persisted longer than 4 weeks in 13 of 35 patients (37%). However, despite of disappearance of both cancer cells and pleural effusion, primary tumors were not affected at all by the treatment (Table 5).
3. Prognos& Figure 1 shows survival curves of the 35 patients treated with RIL-2. Survival rate at 1 year after the treatment was 40% and median survival period was 270 days.
4. Side effects Side effects of the treatment in 40 eligible patients are listed in Table 6. Main and frequent side effects were fever, transient
348 %
1\ "~ m
40
30
20 l0 00
I-G-al! evaluable i
[
patlenls 35
90
180 270 360 450 5,i0 630 720 81'0 900 Survival period (da~) Fig. 1. Survival curve of evaluable patients. Median observation period = 390 days (range, 29-1143). Kaplan-Meier method was employed.
increase of pleural effusion, and eosinophilia. Fever up to 39°C (in most patients, 38°C) was encountered in 63% of patients. Eosinophilia (6 to 37%, average 23%) was observed in 51% of patients. However, it returned to the normal level within 4 to 22 days after the end of the treatment. A transient increase of pleural effusion lasting 1 to 51 days after the start of the treatment (average, 8 days) was observed roentogenographically in 74% of the patients. Among them, 9 patients complained of respiratory distress because of the increase of pleural effusion. Discussion
Since its has been mote the [10], and
discovery [9], interleukin-2 (IL-2) widely studied as a factor to prodifferentiation of cytotoxic T-cells to activate natural killer cells [11]
and to induce lymphokine-activated killer cells [ 12, 13]. There may be two modalities of anticancer treatments using IL-2. One is an adoptive immunotherapy in which LAK cells generated in vitro by coculture with IL-2 and lymphocytes are infused intravenously in conjunction with or without intravenous injection of IL-2. The other is a passive immunotherapy in which IL-2 is administered directly to cancer patients. Rosenberg et al. reported the results of high-dose IL-2 in the treatment of 652 cancer patients [3]. Of these patients, 214 were treated with IL-2 and LAK cells. Responders were 14 of complete response (CR) and 30 of partial response (PR) among 177 evaluable patients out of the 214. The response rate was 25%. The 44 responders comprised renal cell carcinoma (25/72), malignant melanoma (10/ 48), colorectal cancer (5/30), and nonHodgkin's lymphoma (4/7). On the other hand, 155 patients were treated with intravenous administration of high dose IL-2 alone. Responders comprised 4 C R and 18 PR among 130 evaluable patients out of the 135. The response rate was 17%. The 22 responders were limited to renal cell carcinoma (12/54) and malignant melanoma (10/42). These results may indicate that malignant cells of different origins have quite different susceptibility to IL-2 therapy. Kinetic study of IL-2 after intravenous injection revealed rapid clearance of IL-2 from kidney [6]. This short half life of IL-2 in the serum necessitates administration of large
Table 6. Main side effects of intrapleural instillations of RIL-2.
Adverse reaction
Fever Nausea, vomiting Respiratory distress Eosinophilia Elevated GOT or G I ~
Total
Number of patients treated with R1L-2 250 u/day
500 u/day
1000 u/day
7
3
30
40
4 0 2 3 0
2 0 1 3 0
19 3 6 15 5
25 3 9 21 5
349
amounts of IL-2 to achieve tumor response to IL-2. Also it was accompanied with severe toxicities such as fluid retention and respiratory distress syndrome [3, 4]. Previously, we have reported that intrapleural instillation of IL-2 leads to relatively high levels for a prolonged time. When 1000 units of IL-2 was instilled into the pleural cavity, IL-2 concentration in the pleural effusion was 28 units/ml at 30 min., and gradually dropped to 4 units/ml after 24 hr. This IL-2 concentration of 4 units/ml is optimal to induce LAK cells in vitro. LAK cells were induced in the effusion in 9 of 11 patients, 4 to 10 days after the treatment. Moreover, pleural effusion and cancer cells in the effusion disappeared in the 9 patients in whom LAK cell were induced [8]. In that study, there were 6 patients in whom pleural effusion could not be detected by chest roentgenograms, however, small amount of pleural effusion (usually 100 to 200 ml) was observed when thoracotomy was performed. Such effusions were checked for malignant cells. In the 6 patients the primary lesions were resected by an usual lobectomy, and the malignant pleurisy was treated by intrapleural instillation of IL-2 postoperatively. All of the 6 patients demonstrated disappearance of effusion and cancer cells in the effusion. At this moment, prognostic impact of this response rate is not clear, however, further study should be done to evaluate the efficacy of local administration of IL-2 in conjunction with chemotherapeutic agents as one modality of treatments in patients with malignant pleurisy due to lung cancer.
References 1. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E,
2.
3.
4.
5. 6.
7.
8.
9.
I0.
l l.
12.
13.
Vetto JT, Seipp CA, Simpson CG, Reichert CM. Observation on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313: 1485-92. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. 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 1987; 316: 889-905. Rosenberg SA, Lotze ML, Yang JC, Aebersold PM, Lineban WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surgery 1989; 210:474 85. West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Okdham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 898-905. Donohue JH, Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983; 130:2203 8. Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy WH, Harris R, Hersey P. Clearance rates and systemic effects of intravenously administrated interleukin-2 (IL-2) containing preparations in human subjects. Br J Cancer 1983; 47: 123-33. Hang AE, Hyatt CL, Rosenberg SA. Systemic administration of recombinant human interleukin-2 in mice. J Biol Response Modifiers 1984; 3: 561-72. Yasumoto K, Miyazaki K, Nagashima A, Ishida T, Kuda T, Yano T, Sugimachi K, Nomoto K. Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer. Cancer Res. 1987; 47: 2184 -~7. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science (Wash DC) 1976; 193:1007 8. Baker PE, Gillis S, Ferm MM, Smith KA. The effect o f T cell growth factor on the generation of cytolytic T cells. J Immunol 1982; 121: 2168-73. Henney CS, Kuribayashi K, Kern DE, Gills S. Interleukin-2 augment natural killer cell activity. Nature (Lond.) 1981; 291: 335-8. Lotze MT, Grimm EA, Mazumder A, Strausser JL, Rosenberg SA. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res 1981; 41: 4420-5. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982; 155:1823 41.
