13 The immune system and gynaecological cancer S . T . A . MALIK A . A . EPENETOS
~TRODUCTION The relationship of the immune system and cancer has traditionally been considered in terms of immune surveillance in the control of cancer and the potential for immunotherapy in cancer. There is little evidence to suggest that the frequency of gynaecological neoplasms is increased in immunosuppressed patients or in immunodeficient animals, with the possible exception of human papilloma virus (HPV) associated cervical cancer. However, the prospects for effective immunotherapy of cancer have been considerably enhanced by the availability of biological molecules such as monoclonal antibodies and recombinant cytokines. Monoclonal antibodies that recognize putative tumour associated antigens have already had an impact on the immunodiagnosis of cancer and the development of assays for tumour markers and their clinical use as antitumour agents have been addressed (Hird et al, 1990). This review discusses the use of active immunotherapy and cytokine therapy in the treatment of gynaecological cancer and breast cancer. ACTIVE IMMUNOTHERAPY IN GYNAECOLOGICAL CANCER
Non-specific active immunotherapy The earliest recorded trials of non-specific immunostimulants in patients with advanced malignancies were reported by a New York surgeon, William Coley, at the turn of the century (Coley, 1896). Coley had observed objective tumour regression in cancer patients who had intercurrent infections, particularly erysipelas. On the basis of these observations patients with advanced cancer, including gynaecological cancers, were treated with preparations of erysipelas-inducing streptococci and Serratia marcescens with remarkable results (Nauts, 1987). However, therapy with 'Coley's toxins' was largely abandoned with the advent of radiotherapy and chemotherapy, and due to the problems associated with obtaining preparations of standardized activity. Non-specific immunoadjuvants such as BCG and Corynebacterium Baillibre's Clinical Obstetrics and Gynaecology--
Vol. 6, No. 3, September1992 ISBN0-7020-1634-9
641 Copyright© 1992,byBailli~reTindall All rights of reproductionin anyformreserved
642
S. T. A . M A L I K A N D A . A . E P E N E T O S
parvum were shown to have antitumour activity in animal tumour models, and have been investigated in patients with ovarian cancer. The most notable results of BCG therapy in gynaecological cancer were reported by Alberts et al (1979) in a randomized study of 121 patients treated with chemotherapy alone (cyclophosphamide and adriamycin), or chemotherapy combined with BCG given by scarification. There was a significantly higher response rate in the BCG group (18%) compared with the control group (3%), and this was reflected in the median survival of the two groups of 22.3 months and 13.7 months respectively. However, two subsequent studies from the same group of investigators failed to confirm any additional benefit of BCG in combination with cisplatin containing regimens (Alberts et al, 1989a,b). There are two reported randomized trials of intravenous C. parvum in combination with standardized chemotherapy in ovarian cancer. Wanebo et al (1979) noted no additional benefit, but a significantly higher response rate and progression free interval was noted in the immunotherapy group in the trial reported by Gall et al (1980). However, the design of the latter study has been criticized because all of the immunotherapy patients in this multicentre study were treated at a single institution. Therapy with multiple courses of intraperitoneal C. parvum alone led to two complete and three partial responses in a group of 11 patients with ovarian cancer (Bast et al, 1983). Other immunoadjuvants such as levarnisole and the heat and penicillintreated preparation of the low virulence strain of Streptococcus pyogenes (OK-432) have been given to patients with ovarian cancer, but the value of these agents remains to be assessed in randomized clinical trials. Two randomized studies of adjuvant immunotherapy with OK-432 and the immunostimulant sizofuran have been reported (Okamura et al, 1989) in patients with cervical cancer. There was a statistically significant 3-year recurrence-free rate in the 221 patients in the OK-432 group (72%), compared with the 161 patients in the control group (58.6%). Sizofuran also led to a significantly greater 5-year survival rate in patients with stage II-III cancer, compared with the control group. A series of studies of BCG immunotherapy in conjunction with cytotoxic chemotherapy were reported in patients with stage II breast cancer (Buzdar et al, 1979). The promising results were not substantiated in randomized controlled trials (Hubay et al, 1985). There are no convincing data that the use of levamisole, or other immunoadjuvants has any therapeutic benefit in patients with breast cancer. Intralesional BCG and purified protein derivative (PPD) have both been used to treat local chest wall recurrences of breast cancer with some success (Klein et al, 1976; Pardridge et al, 1979). For example, repeated injections of BCG led to tumour regressions in 8 of 11 patients. Five of these patients had complete tumour regressions that lasted from 12 to 33 months (Pardridge et al, 1979).
Specific active immunotherapy Specific active immunotherapy entails the injection of tumour antigens in order to generate an antitumour immune response. There is increasing
T H E I M M U N E SYSTEM A N D G Y N A E C O L O G I C A L C A N C E R
643
evidence that some human cancers express potentially highly immunogenic epitopes such as the polymorphic epithelial mucin (PEM). Ovarian cancer patients have been shown to mount an immune response to ovarian tumour cells (Levin et al, 1975). Graham and Graham (1962) reported that the injection of whole tumour homogenates, saline extracts, or unirradiated tumour cell suspensions given in conjunction with chemotherapy and radiotherapy, led to a higher survival rate. The significance of these results is dubious because the chemotherapy was not standardized and a small number of patients was studied. A novel approach has been to inject viral oncolysates from ovarian cancer cell lines infected with the influenza virus. The infected cell lines express both ovarian cancer-associated and viral antigens. Viral oncolysates were administered intraperitoneally to 31 patients with ascites. Ascites disappeared in seven patients and was accompanied by a reduction of tumour mass in three of the patients (Freedman et al, 1988). In two out of five patients with solid intraperitoneal tumours only, objective turnout regression was noted. In most patients injected with viral oncolysates, antibodies and T cell responses to turnout cell surface antigens and viral antigens were detected (Freedman et al, 1990). Further studies of this approach are awaited. CYTOKINE THERAPY Many of the antitumour effects of non-specific immunostimulants are due to the release of cytokines. For example, the antitumour effect of endotoxin was shown to be mediated by a serum factor now known to be tumour necrosis factor (TNF) (Carswell et al, 1975). Lymphotoxin (LT or TNF-I3) was identified as a soluble lymphocyte-derived mediator with antitumour effects in vitro, released in the course of delayed hypersensitivity reactions (Granger and Williams, 1968). Cytokines are peptide cell regulators, most of which were originally characterized as products of the immune system and termed lymphokines or monokines. However, it is now evident that many cytokines are produced by other cell populations and have roles that extend beyond their immunomodulatory effects. Table 1 lists some of the major cytokines that have been identified. Several cytokines are thought to have in vitro and in vivo antitumour actions (Balkwill, 1989). The direct effects of cytokines on tumour growth may be cytotoxic or cytostatic and are occasionally related to the induction of cellular differentiation (Kelly et al, 1990). The antitumour actions of cytokines may also be mediated indirectly by activation of host antitumour responses and disruption of the host-tumour relationship, e.g. by toxic effects on tumour vasculature. In addition to their use as antitumour agents, cytokines are likely to be used increasingly as adjuncts to existing standard therapies. The colony stimulating factors are already in clinical use as agents to alleviate the myelosuppressive effects of chemotherapy and bone marrow transplantation, and their use may allow further dose escalation of existing chemotherapy regimens (Peters, 1991). Experimental data suggest other potential
S. T. A. MALIKAND A. A. EPENETOS
644
Table I. List of major cytokines.
Molecular weight (kDa) Interferons Interferon-or Interferon-I~ Interferon--,/ Tumour necrosis factors TNF-ct TNF-I3 Colony stimulating factors G-CSF GM-CSF M-CSF MUlti-CSF (IL-3) Interleukins IL-1 IL-2 IL-4 IL-5 IL-6 IL-7 IL-8 IL-9 IL-10 IL-11 Transforming growth factors TGF-a TGF-I3
Normal sources
1%23 20 20
Leukocytes Fibroblasts T, NK cells
1%26 20-25
Many cells T and B cells
19 45 22 25
Many cells Many cells Many cells Many cells
17.5 17.2 20 18 26 26 8 8 8 16
Many cells T cells Many cells T cells Many cells T cells Many cells Many cells T cells T cells
15 25
Many cells Many cells
uses for cytokines in cancer therapy, e.g. modulation of oncogene expression (Marth et al, 1990), modulation of oestrogen and progesterone receptor expression (DeCicco et al, 1988), and e n h a n c e m e n t of antibody localization (Smyth et al, 1988). The following section will review the status of cytokine therapy of gynaecological cancers with cytokines that have undergone clinical trials as antitumour agents, i.e. the interferons (IFNs), t u m o u r necrosis factor, and interleukin 2 (IL-2). Interferons
The three m a j o r classes of IFNs (or, [3, and "y) have antiproliferative effects on tumour cells in vitro and in vivo (Balkwill, 1989). There is experimental evidence to suggest that their antitumour activity can be due to a direct effect on tumour cells, mediated by activation of effector cells such as natural killer cells and macrophages, or caused by alterations of the h o s t - t u m o u r relationship. D a t a f r o m h u m a n ovarian cancer xenograft models indicate that a direct, dose-dependent cytostatic effect is their m a j o r m o d e of action (Balkwill et al, 1989; Malik et al, 1992). In general, IFN-tx was noted to be m o r e effective in the therapy of h u m a n cancer xenografts (Balkwill et al,
THE IMMUNE SYSTEM AND GYNAECOLOGICAL CANCER
645
1989), but the precise mechanism of its antitumour effect remains to be elucidated. Recent data suggest that some of the antitumour activity of IFN-~/may be mediated by modulation of tryptophan metabolism (Malik et al, 1992) and by inhibition of c-erb-f32 proto-oncogene expression in ovarian cancer cells (Marth et al, 1990). Since IFNs were originally described as virally induced proteins that inhibited the replication of viruses (Isaacs and Lindemann, 1957), their use in HPV-associated anogenital neoplasms is of potential therapeutic value. Several trials of IFN-a in patients with ovarian cancer have been reported (reviewed in Bookman and Bast, 1991). Systemic administration of IFN-et, either intramuscularly or subcutaneously, has shown minimal activity in most studies (Einhorn et al, 1982, 1988; Freedman et al, 1983; Niloff et al, 1985). Following intraperitoneal instillation of IFN-ot, 30-1000-fold higher levels of IFN-et were noted in the peritoneal fluid compared with serum. Berek et al (1985) reported complete and partial remissions in five of 11 patients treated with intraperitoneal IFN-et. An escalating dose regimen was used, starting at 5 × 106 to 50 x 106 units given weekly over a period of 16 weeks. Response was related to the residual amount of tumour prior to commencement of therapy, and none of the patients with a residual tumour mass of greater than 5 mm achieved a response. Five out of the seven patients (71%) with residual tumour less than 5 mm had surgically documented responses. The major side-effects were fever, vomiting and occasionally abdominal pain. Willemse et al (1990) treated 20 evaluable patients with minimal residual disease at second look laparotomy with IFN-a2b, administered at a dose of 50 × 106 units weekly for 8 weeks. Of the 17 patients re-evaluated at third look laparotomy, five were in complete remission, four had partial remissions, six had stabilization of disease, and in two patients there was progression of disease. Their findings confirmed those of Berek et al (1985) in that all responses were confined to patients with residual tumour less than 5 mm. The feasibility of combination therapy with IFN-ot and chemotherapy has been demonstrated in patients with ovarian cancer (Nardi et al, 1990) but randomized trials are required to assess the contribution of IFN to IFN-cytotoxic drug combination regimens. Although IFN-13 interacts with the same receptor as IFN-et, there are no studies assessing the relative antitumour effects of these cytokines in patients with solid tumours. There has been one study reporting the use of intraperitoneal IFN-f3 in patients with advanced bulky ovarian cancer. No objective responses were noted, although the reaccumulation of ascites was prevented in some patients (Rambaldi et al, 1985). Several recent clinical trials of IFN-~/in the treatment of ovarian cancer have been reported. IFN-~/ has a broader range of immunomodulatory actions compared with IFN-a and IFN-13, such as the induction of MHC class II antigens on tumour cells and the activation of antitumour macrophages. Allevana et al (1990) administered recombinant IFN-~/(rlFN-~/) to seven patients and noted the enhancement of M H C class II expression on tumour cells, and an increase in the cytotoxicity of tumour associated macrophages and lymphocytes. D'Aquisto et al (1988) conducted a phase I trial of intraperitoneal rlFN-~/in 27 patients with refractory ovarian cancer and
646
S. T. A. M A L I K A N D A. A. E P E N E T O S
noted minimal toxicity up to doses of 8 x 106 units. No responses were noted; however, most of the patients had advanced disease and only four patients were studied at each dose level. Pujade-Lauraine et al (1991) have reported the preliminary findings of a trial of intraperitoneal rIFNo-y in patients with ovarian cancer. Fifteen complete and two partial surgically documented responses were seen in 58 patients treated with intraperitoneal rIFN-~/ at a dose of 20 × 106 units, twice weekly for 2-4 months. Most responses were seen in patients with small volume disease (
~TRODUCTION The relationship of the immune system and cancer has traditionally been considered in terms of immune surveillance in the control of cancer and the potential for immunotherapy in cancer. There is little evidence to suggest that the frequency of gynaecological neoplasms is increased in immunosuppressed patients or in immunodeficient animals, with the possible exception of human papilloma virus (HPV) associated cervical cancer. However, the prospects for effective immunotherapy of cancer have been considerably enhanced by the availability of biological molecules such as monoclonal antibodies and recombinant cytokines. Monoclonal antibodies that recognize putative tumour associated antigens have already had an impact on the immunodiagnosis of cancer and the development of assays for tumour markers and their clinical use as antitumour agents have been addressed (Hird et al, 1990). This review discusses the use of active immunotherapy and cytokine therapy in the treatment of gynaecological cancer and breast cancer. ACTIVE IMMUNOTHERAPY IN GYNAECOLOGICAL CANCER
Non-specific active immunotherapy The earliest recorded trials of non-specific immunostimulants in patients with advanced malignancies were reported by a New York surgeon, William Coley, at the turn of the century (Coley, 1896). Coley had observed objective tumour regression in cancer patients who had intercurrent infections, particularly erysipelas. On the basis of these observations patients with advanced cancer, including gynaecological cancers, were treated with preparations of erysipelas-inducing streptococci and Serratia marcescens with remarkable results (Nauts, 1987). However, therapy with 'Coley's toxins' was largely abandoned with the advent of radiotherapy and chemotherapy, and due to the problems associated with obtaining preparations of standardized activity. Non-specific immunoadjuvants such as BCG and Corynebacterium Baillibre's Clinical Obstetrics and Gynaecology--
Vol. 6, No. 3, September1992 ISBN0-7020-1634-9
641 Copyright© 1992,byBailli~reTindall All rights of reproductionin anyformreserved
642
S. T. A . M A L I K A N D A . A . E P E N E T O S
parvum were shown to have antitumour activity in animal tumour models, and have been investigated in patients with ovarian cancer. The most notable results of BCG therapy in gynaecological cancer were reported by Alberts et al (1979) in a randomized study of 121 patients treated with chemotherapy alone (cyclophosphamide and adriamycin), or chemotherapy combined with BCG given by scarification. There was a significantly higher response rate in the BCG group (18%) compared with the control group (3%), and this was reflected in the median survival of the two groups of 22.3 months and 13.7 months respectively. However, two subsequent studies from the same group of investigators failed to confirm any additional benefit of BCG in combination with cisplatin containing regimens (Alberts et al, 1989a,b). There are two reported randomized trials of intravenous C. parvum in combination with standardized chemotherapy in ovarian cancer. Wanebo et al (1979) noted no additional benefit, but a significantly higher response rate and progression free interval was noted in the immunotherapy group in the trial reported by Gall et al (1980). However, the design of the latter study has been criticized because all of the immunotherapy patients in this multicentre study were treated at a single institution. Therapy with multiple courses of intraperitoneal C. parvum alone led to two complete and three partial responses in a group of 11 patients with ovarian cancer (Bast et al, 1983). Other immunoadjuvants such as levarnisole and the heat and penicillintreated preparation of the low virulence strain of Streptococcus pyogenes (OK-432) have been given to patients with ovarian cancer, but the value of these agents remains to be assessed in randomized clinical trials. Two randomized studies of adjuvant immunotherapy with OK-432 and the immunostimulant sizofuran have been reported (Okamura et al, 1989) in patients with cervical cancer. There was a statistically significant 3-year recurrence-free rate in the 221 patients in the OK-432 group (72%), compared with the 161 patients in the control group (58.6%). Sizofuran also led to a significantly greater 5-year survival rate in patients with stage II-III cancer, compared with the control group. A series of studies of BCG immunotherapy in conjunction with cytotoxic chemotherapy were reported in patients with stage II breast cancer (Buzdar et al, 1979). The promising results were not substantiated in randomized controlled trials (Hubay et al, 1985). There are no convincing data that the use of levamisole, or other immunoadjuvants has any therapeutic benefit in patients with breast cancer. Intralesional BCG and purified protein derivative (PPD) have both been used to treat local chest wall recurrences of breast cancer with some success (Klein et al, 1976; Pardridge et al, 1979). For example, repeated injections of BCG led to tumour regressions in 8 of 11 patients. Five of these patients had complete tumour regressions that lasted from 12 to 33 months (Pardridge et al, 1979).
Specific active immunotherapy Specific active immunotherapy entails the injection of tumour antigens in order to generate an antitumour immune response. There is increasing
T H E I M M U N E SYSTEM A N D G Y N A E C O L O G I C A L C A N C E R
643
evidence that some human cancers express potentially highly immunogenic epitopes such as the polymorphic epithelial mucin (PEM). Ovarian cancer patients have been shown to mount an immune response to ovarian tumour cells (Levin et al, 1975). Graham and Graham (1962) reported that the injection of whole tumour homogenates, saline extracts, or unirradiated tumour cell suspensions given in conjunction with chemotherapy and radiotherapy, led to a higher survival rate. The significance of these results is dubious because the chemotherapy was not standardized and a small number of patients was studied. A novel approach has been to inject viral oncolysates from ovarian cancer cell lines infected with the influenza virus. The infected cell lines express both ovarian cancer-associated and viral antigens. Viral oncolysates were administered intraperitoneally to 31 patients with ascites. Ascites disappeared in seven patients and was accompanied by a reduction of tumour mass in three of the patients (Freedman et al, 1988). In two out of five patients with solid intraperitoneal tumours only, objective turnout regression was noted. In most patients injected with viral oncolysates, antibodies and T cell responses to turnout cell surface antigens and viral antigens were detected (Freedman et al, 1990). Further studies of this approach are awaited. CYTOKINE THERAPY Many of the antitumour effects of non-specific immunostimulants are due to the release of cytokines. For example, the antitumour effect of endotoxin was shown to be mediated by a serum factor now known to be tumour necrosis factor (TNF) (Carswell et al, 1975). Lymphotoxin (LT or TNF-I3) was identified as a soluble lymphocyte-derived mediator with antitumour effects in vitro, released in the course of delayed hypersensitivity reactions (Granger and Williams, 1968). Cytokines are peptide cell regulators, most of which were originally characterized as products of the immune system and termed lymphokines or monokines. However, it is now evident that many cytokines are produced by other cell populations and have roles that extend beyond their immunomodulatory effects. Table 1 lists some of the major cytokines that have been identified. Several cytokines are thought to have in vitro and in vivo antitumour actions (Balkwill, 1989). The direct effects of cytokines on tumour growth may be cytotoxic or cytostatic and are occasionally related to the induction of cellular differentiation (Kelly et al, 1990). The antitumour actions of cytokines may also be mediated indirectly by activation of host antitumour responses and disruption of the host-tumour relationship, e.g. by toxic effects on tumour vasculature. In addition to their use as antitumour agents, cytokines are likely to be used increasingly as adjuncts to existing standard therapies. The colony stimulating factors are already in clinical use as agents to alleviate the myelosuppressive effects of chemotherapy and bone marrow transplantation, and their use may allow further dose escalation of existing chemotherapy regimens (Peters, 1991). Experimental data suggest other potential
S. T. A. MALIKAND A. A. EPENETOS
644
Table I. List of major cytokines.
Molecular weight (kDa) Interferons Interferon-or Interferon-I~ Interferon--,/ Tumour necrosis factors TNF-ct TNF-I3 Colony stimulating factors G-CSF GM-CSF M-CSF MUlti-CSF (IL-3) Interleukins IL-1 IL-2 IL-4 IL-5 IL-6 IL-7 IL-8 IL-9 IL-10 IL-11 Transforming growth factors TGF-a TGF-I3
Normal sources
1%23 20 20
Leukocytes Fibroblasts T, NK cells
1%26 20-25
Many cells T and B cells
19 45 22 25
Many cells Many cells Many cells Many cells
17.5 17.2 20 18 26 26 8 8 8 16
Many cells T cells Many cells T cells Many cells T cells Many cells Many cells T cells T cells
15 25
Many cells Many cells
uses for cytokines in cancer therapy, e.g. modulation of oncogene expression (Marth et al, 1990), modulation of oestrogen and progesterone receptor expression (DeCicco et al, 1988), and e n h a n c e m e n t of antibody localization (Smyth et al, 1988). The following section will review the status of cytokine therapy of gynaecological cancers with cytokines that have undergone clinical trials as antitumour agents, i.e. the interferons (IFNs), t u m o u r necrosis factor, and interleukin 2 (IL-2). Interferons
The three m a j o r classes of IFNs (or, [3, and "y) have antiproliferative effects on tumour cells in vitro and in vivo (Balkwill, 1989). There is experimental evidence to suggest that their antitumour activity can be due to a direct effect on tumour cells, mediated by activation of effector cells such as natural killer cells and macrophages, or caused by alterations of the h o s t - t u m o u r relationship. D a t a f r o m h u m a n ovarian cancer xenograft models indicate that a direct, dose-dependent cytostatic effect is their m a j o r m o d e of action (Balkwill et al, 1989; Malik et al, 1992). In general, IFN-tx was noted to be m o r e effective in the therapy of h u m a n cancer xenografts (Balkwill et al,
THE IMMUNE SYSTEM AND GYNAECOLOGICAL CANCER
645
1989), but the precise mechanism of its antitumour effect remains to be elucidated. Recent data suggest that some of the antitumour activity of IFN-~/may be mediated by modulation of tryptophan metabolism (Malik et al, 1992) and by inhibition of c-erb-f32 proto-oncogene expression in ovarian cancer cells (Marth et al, 1990). Since IFNs were originally described as virally induced proteins that inhibited the replication of viruses (Isaacs and Lindemann, 1957), their use in HPV-associated anogenital neoplasms is of potential therapeutic value. Several trials of IFN-a in patients with ovarian cancer have been reported (reviewed in Bookman and Bast, 1991). Systemic administration of IFN-et, either intramuscularly or subcutaneously, has shown minimal activity in most studies (Einhorn et al, 1982, 1988; Freedman et al, 1983; Niloff et al, 1985). Following intraperitoneal instillation of IFN-ot, 30-1000-fold higher levels of IFN-et were noted in the peritoneal fluid compared with serum. Berek et al (1985) reported complete and partial remissions in five of 11 patients treated with intraperitoneal IFN-et. An escalating dose regimen was used, starting at 5 × 106 to 50 x 106 units given weekly over a period of 16 weeks. Response was related to the residual amount of tumour prior to commencement of therapy, and none of the patients with a residual tumour mass of greater than 5 mm achieved a response. Five out of the seven patients (71%) with residual tumour less than 5 mm had surgically documented responses. The major side-effects were fever, vomiting and occasionally abdominal pain. Willemse et al (1990) treated 20 evaluable patients with minimal residual disease at second look laparotomy with IFN-a2b, administered at a dose of 50 × 106 units weekly for 8 weeks. Of the 17 patients re-evaluated at third look laparotomy, five were in complete remission, four had partial remissions, six had stabilization of disease, and in two patients there was progression of disease. Their findings confirmed those of Berek et al (1985) in that all responses were confined to patients with residual tumour less than 5 mm. The feasibility of combination therapy with IFN-ot and chemotherapy has been demonstrated in patients with ovarian cancer (Nardi et al, 1990) but randomized trials are required to assess the contribution of IFN to IFN-cytotoxic drug combination regimens. Although IFN-13 interacts with the same receptor as IFN-et, there are no studies assessing the relative antitumour effects of these cytokines in patients with solid tumours. There has been one study reporting the use of intraperitoneal IFN-f3 in patients with advanced bulky ovarian cancer. No objective responses were noted, although the reaccumulation of ascites was prevented in some patients (Rambaldi et al, 1985). Several recent clinical trials of IFN-~/in the treatment of ovarian cancer have been reported. IFN-~/ has a broader range of immunomodulatory actions compared with IFN-a and IFN-13, such as the induction of MHC class II antigens on tumour cells and the activation of antitumour macrophages. Allevana et al (1990) administered recombinant IFN-~/(rlFN-~/) to seven patients and noted the enhancement of M H C class II expression on tumour cells, and an increase in the cytotoxicity of tumour associated macrophages and lymphocytes. D'Aquisto et al (1988) conducted a phase I trial of intraperitoneal rlFN-~/in 27 patients with refractory ovarian cancer and
646
S. T. A. M A L I K A N D A. A. E P E N E T O S
noted minimal toxicity up to doses of 8 x 106 units. No responses were noted; however, most of the patients had advanced disease and only four patients were studied at each dose level. Pujade-Lauraine et al (1991) have reported the preliminary findings of a trial of intraperitoneal rIFNo-y in patients with ovarian cancer. Fifteen complete and two partial surgically documented responses were seen in 58 patients treated with intraperitoneal rIFN-~/ at a dose of 20 × 106 units, twice weekly for 2-4 months. Most responses were seen in patients with small volume disease (
