In t erfe ron , I n t er l eu ki n-2 , and Other Cytokines Elizabeth I. Buchbinder,
MD*,
David F. McDermott,
MD
KEYWORDS Melanoma Cytokines Interferon Interleukin-2 Interleukin-21 Granulocyte-macrophage colony–stimulating factor KEY POINTS Interferon-a has immune-modulating effects and when used at high dosages in the adjuvant setting has an impact in preventing recurrence in high-risk melanoma patients. Interleukin-2 plays a complex role in the immune system and when given at high dosages to patients with metastatic melanoma a subset achieve a long-term durable complete response. The use of cytokines in the treatment of melanoma continues to evolve as does their role in combination with other immune-modulating agents and targeted therapies in the future of melanoma treatment.
CYTOKINES
Cytokines are a complex group of naturally occurring glycoproteins produced when the immune system is activated by an infection, foreign antigen, or self-antigen. The antitumor effects of cytokines are likely mediated through immunomodulation, antiproliferative activity, and inhibition of angiogenesis. Melanoma has proved to be one of the most immunogenic malignancies based on documented cases of spontaneous regression and its higher prevalence in immunocompromised patients. This evidence of immunogenicity has led to the testing of numerous cytokines including interferon (IFN)-a, IFN-g, granulocyte-macrophage colony–stimulating factor (GMCSF), interleukin (IL)-2, IL-4, IL-6, IL-12, IL-18, and IL-21 in patients with advanced melanoma. INTERFERON
In 1957 Isaacs and Lindenmann1 were studying the influenza virus and discovered that incubation of heated virus with chick chorioallantoic membrane led to release
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA * Corresponding author. E-mail address: [email protected] Hematol Oncol Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.hoc.2014.02.001 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Buchbinder & McDermott
of a previously unknown factor. This factor interfered with growth of live virus in fresh pieces of membrane and was named “interferon.” In parallel, Yasuichi Nagano was discovering IFN while exploring antiviral activity that occurred after injecting inactivated vaccinia virus into rabbit skin.2 Subsequently, IFNs were found to be produced in many animal cells and tissues. Ten mammalian IFN species have been discovered. Of these eight are found in humans, six are type I (IFN-a, IFN-b, IFN-ε, IFN-k, IFN-u, and IFN-n), one is type II (IFN-g), and one is type III (IFN-l).3,4 IFN was purified from human fibroblasts and the mRNAs responsible for its production were isolated.5,6 A full length copy of the IFN sequence was found leading to the ability to produce and purify a recombinant IFN-a2 that expanded opportunities for its use in research and clinical trials. The actions of IFNs are mediated by interaction with the receptors IFNAR1 and IFNAR2.7 These receptors are multichain complexes that use several signaling pathways within the cells. One of the pathways activated through the action of IFN is the JAK-STAT pathway.8 Treatment with IFNa2b has numerous effects on the immune system. It leads to the downregulation of intercellular adhesion molecule and the upregulation of HLA-DR expression, which may modulate tumor cell-host immune response. In addition natural killer cell function, T-cell function, and subset distribution are modulated in patients treated with IFN.9 In addition it can lead to the induction and/or activation of proapoptotic genes and proteins, such as TRAIL, caspases, Bak, and Bax, and repression of antiapoptotic genes, such as Bcl-2 and IAP.10 IFN-a has multiple effects in a variety of malignancies and has been the most broadly evaluated clinically. There are three commercially available isoforms that differ by one to two amino acids: IFN-a2a (Roche), IFN-a2b (Merck), and IFN-a2c (Boehringer Ingelheim). IFN has been approved for the treatment of hairy cell leukemia, relapsing-remitting multiple sclerosis, malignant melanoma, follicular lymphoma, condylomata acuminate (genital warts), AIDS-related Kaposi sarcoma, and chronic hepatitis B and C. Initial Use in Melanoma
As with all antineoplastics the first testing of IFNs in melanoma was in the metastatic disease setting. In 1978, the American Cancer Society initiated a multicenter trial testing IFN-a in patients with metastatic melanoma. Forty-five patients were enrolled among whom there was one partial responder and minimal responses in two others.11,12 A similar study was performed by Retsas and colleagues13 in which 17 patients with melanoma were treated with IFN-a and one partial response was seen. Studies continued as more dosing information became available. Several phase I/II studies were performed with very similar results. In these trials there were 2 responses out of 15 patients, 4 responses out of 23 patients, and 3 responses out of 20 patients.12 Tumor response rates around 16% were observed with some late responders. It is unknown if there is a survival benefit for IFN in the metastatic setting because no randomized trials comparing it with cytotoxic therapy or supportive care have been performed. Most of the responders had a low tumor volume.14 This led to the hypothesis that the greatest benefit of IFN-a would be in patients with microscopic residual disease. Adjuvant Testing
Randomized phase III trials have been performed testing both high-dose IFN-a2b and pegylated (PEG) IFN-a2b in the adjuvant setting in high-risk melanoma patients (Table 1). The first trial was Eastern Cooperative Group E1684, a randomized
IFN, IL-2, and Other Cytokines
Table 1 Summary of adjuvant trials of high-dose interferon treatment of melanoma Trial
Patient Number Population
Dose
Relapse-free Overall Survival Survival
ECOG 168415 287
T4 (>4.0 mm) 20 MIU/m2 5x/wk for 1 mo, P 5 .004 and/or Nx then 10 MIU/m2 3x/wk for (regional LN 48 wk vs observation metastasis)
ECOG 169016 642
T4 and/or Nx
20 MIU/m2 5x/wk for 1 mo, P 5 .05 then 10 MIU/m2 3x/wk for P 5 .17 48 wk vs 3 MIU/m2 3x/wk for 3 y vs observation
NS NS
ECOG 169418 880
T4 and/or Nx
20 MIU/m2 5x/wk for 1 mo P 5 .0027 then 10 MIU/m2 3x/wk for 48 wk vs GM2-KLH/QS-21 vaccine
P 5 .0147
EORTC 1899122
TxNx
6 mg/kg weekly for 8 wk then 3 mg/kg weekly for 5 y vs observation
NS
1256
P 5 .01
P 5 .046
controlled study of 287 patients with T4 or N1 melanoma. Patients were given IFNa2b, 20 MU/m2/d intravenously for 1 month followed by 10 MU/m2/d three times per week subcutaneously for 48 weeks versus observation. In this study a significant prolongation of relapse-free survival (RFS) (P 5 .0023) was observed with an increase from 1.0 to 1.7 years disease-free survival. In addition a significant prolongation in overall survival (OS) (P 5 .0237) was also observed with an increase from 2.8 to 3.8 years. The benefit of therapy was greatest among patients with lymph node involvement.15 Based on the positive results from E1684 the decision was made to move forward with a comparison of high- and low-dose IFN in an Intergroup trial. E1690 was a threearm prospective, randomized trial of patients with IIB and III melanoma. A total of 642 patients were enrolled and randomized to high-dose IFN at the same doses as E1984, low-dose IFN (3 MU/m2/d three times per week subcutaneously for 2 years), or observation. This trial showed a RFS benefit for the high-dose IFN arm by Cox multivariable analysis (P 5 .03). However, there was no significant RFS benefit seen for the lowdose arm. In addition there was no OS benefit comparing either the high-dose or low-dose arm with observation. The investigators concluded that these results may have been confounded by the high proportion of patients who received IFN-a2b at progression in the observation arm.16 Vaccination is another adjuvant therapy being explored for use in melanoma treatment. The ganglioside GM2 is a serologically well-defined melanoma antigen that has shown efficacy when combined with various adjuvants.17 Intergroup E1694 compared high-dose IFN alfa-2b versus vaccination with GM2 conjugate. A total of 880 patients with stage IIB/III melanoma were randomized to each treatment arm. The trial was closed early after an interim analysis indicated inferiority of GM2 compared with IFN. IFN had a significant RFS (P 5 .0015) and OS benefit (P 5 .009) compared with the GM2 conjugate vaccine (Table 2).18 Three large meta-analyses of the published results of IFN-based trials in the adjuvant setting were performed with similarly mixed results. The first analysis by Wheatley and colleagues19 included 12 randomized controlled trials and showed a significant
3
4
Buchbinder & McDermott
Table 2 Summary of meta-analysis of adjuvant trials of high-dose interferon treatment of melanoma Meta-Analysis
Number of Trials RFS
OS
Comments
Wheatley et al,19 2003 12
P 5 .000003 P 5 .1
Wheatley et al,20 2007 13
P 5 .00006
P 5 .008 13% risk reduction in RFS; 10% risk reduction in OS
Mocellin et al,21 2010
P
MD*,
David F. McDermott,
MD
KEYWORDS Melanoma Cytokines Interferon Interleukin-2 Interleukin-21 Granulocyte-macrophage colony–stimulating factor KEY POINTS Interferon-a has immune-modulating effects and when used at high dosages in the adjuvant setting has an impact in preventing recurrence in high-risk melanoma patients. Interleukin-2 plays a complex role in the immune system and when given at high dosages to patients with metastatic melanoma a subset achieve a long-term durable complete response. The use of cytokines in the treatment of melanoma continues to evolve as does their role in combination with other immune-modulating agents and targeted therapies in the future of melanoma treatment.
CYTOKINES
Cytokines are a complex group of naturally occurring glycoproteins produced when the immune system is activated by an infection, foreign antigen, or self-antigen. The antitumor effects of cytokines are likely mediated through immunomodulation, antiproliferative activity, and inhibition of angiogenesis. Melanoma has proved to be one of the most immunogenic malignancies based on documented cases of spontaneous regression and its higher prevalence in immunocompromised patients. This evidence of immunogenicity has led to the testing of numerous cytokines including interferon (IFN)-a, IFN-g, granulocyte-macrophage colony–stimulating factor (GMCSF), interleukin (IL)-2, IL-4, IL-6, IL-12, IL-18, and IL-21 in patients with advanced melanoma. INTERFERON
In 1957 Isaacs and Lindenmann1 were studying the influenza virus and discovered that incubation of heated virus with chick chorioallantoic membrane led to release
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA * Corresponding author. E-mail address: [email protected] Hematol Oncol Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.hoc.2014.02.001 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Buchbinder & McDermott
of a previously unknown factor. This factor interfered with growth of live virus in fresh pieces of membrane and was named “interferon.” In parallel, Yasuichi Nagano was discovering IFN while exploring antiviral activity that occurred after injecting inactivated vaccinia virus into rabbit skin.2 Subsequently, IFNs were found to be produced in many animal cells and tissues. Ten mammalian IFN species have been discovered. Of these eight are found in humans, six are type I (IFN-a, IFN-b, IFN-ε, IFN-k, IFN-u, and IFN-n), one is type II (IFN-g), and one is type III (IFN-l).3,4 IFN was purified from human fibroblasts and the mRNAs responsible for its production were isolated.5,6 A full length copy of the IFN sequence was found leading to the ability to produce and purify a recombinant IFN-a2 that expanded opportunities for its use in research and clinical trials. The actions of IFNs are mediated by interaction with the receptors IFNAR1 and IFNAR2.7 These receptors are multichain complexes that use several signaling pathways within the cells. One of the pathways activated through the action of IFN is the JAK-STAT pathway.8 Treatment with IFNa2b has numerous effects on the immune system. It leads to the downregulation of intercellular adhesion molecule and the upregulation of HLA-DR expression, which may modulate tumor cell-host immune response. In addition natural killer cell function, T-cell function, and subset distribution are modulated in patients treated with IFN.9 In addition it can lead to the induction and/or activation of proapoptotic genes and proteins, such as TRAIL, caspases, Bak, and Bax, and repression of antiapoptotic genes, such as Bcl-2 and IAP.10 IFN-a has multiple effects in a variety of malignancies and has been the most broadly evaluated clinically. There are three commercially available isoforms that differ by one to two amino acids: IFN-a2a (Roche), IFN-a2b (Merck), and IFN-a2c (Boehringer Ingelheim). IFN has been approved for the treatment of hairy cell leukemia, relapsing-remitting multiple sclerosis, malignant melanoma, follicular lymphoma, condylomata acuminate (genital warts), AIDS-related Kaposi sarcoma, and chronic hepatitis B and C. Initial Use in Melanoma
As with all antineoplastics the first testing of IFNs in melanoma was in the metastatic disease setting. In 1978, the American Cancer Society initiated a multicenter trial testing IFN-a in patients with metastatic melanoma. Forty-five patients were enrolled among whom there was one partial responder and minimal responses in two others.11,12 A similar study was performed by Retsas and colleagues13 in which 17 patients with melanoma were treated with IFN-a and one partial response was seen. Studies continued as more dosing information became available. Several phase I/II studies were performed with very similar results. In these trials there were 2 responses out of 15 patients, 4 responses out of 23 patients, and 3 responses out of 20 patients.12 Tumor response rates around 16% were observed with some late responders. It is unknown if there is a survival benefit for IFN in the metastatic setting because no randomized trials comparing it with cytotoxic therapy or supportive care have been performed. Most of the responders had a low tumor volume.14 This led to the hypothesis that the greatest benefit of IFN-a would be in patients with microscopic residual disease. Adjuvant Testing
Randomized phase III trials have been performed testing both high-dose IFN-a2b and pegylated (PEG) IFN-a2b in the adjuvant setting in high-risk melanoma patients (Table 1). The first trial was Eastern Cooperative Group E1684, a randomized
IFN, IL-2, and Other Cytokines
Table 1 Summary of adjuvant trials of high-dose interferon treatment of melanoma Trial
Patient Number Population
Dose
Relapse-free Overall Survival Survival
ECOG 168415 287
T4 (>4.0 mm) 20 MIU/m2 5x/wk for 1 mo, P 5 .004 and/or Nx then 10 MIU/m2 3x/wk for (regional LN 48 wk vs observation metastasis)
ECOG 169016 642
T4 and/or Nx
20 MIU/m2 5x/wk for 1 mo, P 5 .05 then 10 MIU/m2 3x/wk for P 5 .17 48 wk vs 3 MIU/m2 3x/wk for 3 y vs observation
NS NS
ECOG 169418 880
T4 and/or Nx
20 MIU/m2 5x/wk for 1 mo P 5 .0027 then 10 MIU/m2 3x/wk for 48 wk vs GM2-KLH/QS-21 vaccine
P 5 .0147
EORTC 1899122
TxNx
6 mg/kg weekly for 8 wk then 3 mg/kg weekly for 5 y vs observation
NS
1256
P 5 .01
P 5 .046
controlled study of 287 patients with T4 or N1 melanoma. Patients were given IFNa2b, 20 MU/m2/d intravenously for 1 month followed by 10 MU/m2/d three times per week subcutaneously for 48 weeks versus observation. In this study a significant prolongation of relapse-free survival (RFS) (P 5 .0023) was observed with an increase from 1.0 to 1.7 years disease-free survival. In addition a significant prolongation in overall survival (OS) (P 5 .0237) was also observed with an increase from 2.8 to 3.8 years. The benefit of therapy was greatest among patients with lymph node involvement.15 Based on the positive results from E1684 the decision was made to move forward with a comparison of high- and low-dose IFN in an Intergroup trial. E1690 was a threearm prospective, randomized trial of patients with IIB and III melanoma. A total of 642 patients were enrolled and randomized to high-dose IFN at the same doses as E1984, low-dose IFN (3 MU/m2/d three times per week subcutaneously for 2 years), or observation. This trial showed a RFS benefit for the high-dose IFN arm by Cox multivariable analysis (P 5 .03). However, there was no significant RFS benefit seen for the lowdose arm. In addition there was no OS benefit comparing either the high-dose or low-dose arm with observation. The investigators concluded that these results may have been confounded by the high proportion of patients who received IFN-a2b at progression in the observation arm.16 Vaccination is another adjuvant therapy being explored for use in melanoma treatment. The ganglioside GM2 is a serologically well-defined melanoma antigen that has shown efficacy when combined with various adjuvants.17 Intergroup E1694 compared high-dose IFN alfa-2b versus vaccination with GM2 conjugate. A total of 880 patients with stage IIB/III melanoma were randomized to each treatment arm. The trial was closed early after an interim analysis indicated inferiority of GM2 compared with IFN. IFN had a significant RFS (P 5 .0015) and OS benefit (P 5 .009) compared with the GM2 conjugate vaccine (Table 2).18 Three large meta-analyses of the published results of IFN-based trials in the adjuvant setting were performed with similarly mixed results. The first analysis by Wheatley and colleagues19 included 12 randomized controlled trials and showed a significant
3
4
Buchbinder & McDermott
Table 2 Summary of meta-analysis of adjuvant trials of high-dose interferon treatment of melanoma Meta-Analysis
Number of Trials RFS
OS
Comments
Wheatley et al,19 2003 12
P 5 .000003 P 5 .1
Wheatley et al,20 2007 13
P 5 .00006
P 5 .008 13% risk reduction in RFS; 10% risk reduction in OS
Mocellin et al,21 2010
P
