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Immunotherapy and lung cancer: current developments and novel targeted therapies
Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician’s therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. Keywords: checkpoint inhibitors • immunotherapies • lung cancer • nivolumab • tremelimumab • tumor vaccines
Background Lung cancer is the most commonly diagnosed malignancy in less developed regions of the world, and the second in the most developed nations, with 1.8 million new cases in 2012, corresponding to a 12.9% of the global cancer burden. Due to its high lethality, lung cancer is, at the same time, the most common cause of death from cancer [1] . The two main histological subtypes of lung cancer are small-cell lung cancer (SCLC) and non-SCLC (NSCLC), the latter accounting for approximately 85% of all cases [2] and being diagnosed in the locally advanced or metastatic stage at presentation in 70% of patients [3] . Overall, only 16.6% of lung cancer patients survive 5 years or more (3.9% in the metastatic setting) [4] . For patients with advanced-stage NSCLC, chemo t herapy with a platinumdoublet yields a median overall survival (OS) of approximately 10 months [5] . Cis-
10.2217/IMT.14.82 © 2014 Future Medicine Ltd
platin-based chemotherapy in the adjuvant setting showed an absolute survival benefit of 5% [6] . Recent introduction of molecular targeted therapies in the metastatic setting resulted in clinically meaningful OS improvements, but only in selected patients with tumors harboring specific genetic profiles, such as activating mutations of the EGF receptor (EGFR) and the ALK translocations [7] . Therefore, even with the latest advances, lung cancer prognosis remains dismal, mandating research for novel therapies with new mechanisms of action. Immunotherapy represents a broad class of treatment modalities designed to elicit immune-mediated destruction of tumor cells [8] . Immunotherapy’s encouraging results in other human malignancies hold promise that it may be applied to lung neoplasms [9] . This paper’s main purpose is to provide a comprehensive review about current understanding of immunotherapy for lung cancer.
Immunotherapy (2014) 6(11), 1221–1235
Duarte Domingues1,2, Alice Turner3, Maria Dília Silva2, Dânia Sofia Marques1, Juan Carlos Mellidez2, Luciano Wannesson4, Giannis Mountzios5 & Ramon Andrade de Mello*,1,6 Department of Medical Oncology, Portuguese Oncology Institute (IPO PORTO), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal 2 Department of Medical Oncology, Hospital Infante Dom Pedro, Aveiro, Portugal 3 School of Medicine, University of Otago, 2 Riccarton Ave, Christchurch Central, 8011, Christchurch, New Zealand 4 Oncology Institute of Southern Switzerland (IOSI), CH6500 Bellinzona, Switzerland 5 Department of Medical Oncology, University of Athens School of Medicine, Athens, Greece 6 Department of Biomedical Sciences & Medicine, School of Medicine, University of Algarve, 8005-139, Faro, Portugal *Author for correspondence: Tel.: +351 225 084 000 ext. 7323 Fax: +351 225 084 010 ramello@ ualg.pt 1
part of
ISSN 1750-743X
1221
Review Domingues, Turner, Silva et al. Lung cancer immunology A brief description of lung cancer immunology is provided, in order to better understand immunotherapies’ mechanisms of action. Innate immunity
Innate immunity is a nonspecific first line of defense, involving macrophages and neutrophils [10] . A chronic inflammation state induced by smoking, occupational exposures and other environmental factors activates the innate immunity with subsequent release of cytokines. These cytokines may promote tumor destruction, but can also lead to oncogenesis by stimulating tumor proliferation, angiogenesis and metastatic potential [11] . Tumor cells can activate M2 macrophages by releasing IL-10 [12] . Sentinel cells from the innate branch of immunity may recognize relatively nonspecific structurally preserved molecules, distinguishable from the host molecules through Toll-like receptors in their surface. Immunosurveillance
The immunosurveillance hypothesis postulates that malignant cells express antigens that are recognized by the immune system as foreign, eliciting immune responses against the tumor [13] . Antigens are internalized, processed and displayed by APCs, particularly dendritic cells (DCs). The DCs then migrate to the lymph nodes, where they activate T lymphocytes via interaction of the specific T-cell receptors (TCRs) with the processed antigenic determinants bound to the MHC proteins in the DCs surface (Figure 1) . CD8 + T cells recognize antigen-MHC class I complexes and, once activated, turn into cytotoxic lymphocytes (CTLs). CD4 + T-helper cells (of the Th1 kind), on the other hand, identify antigen-MHC class II complexes and secrete cytokines, such as IL-2 and IFN-γ, which in turn ease CD8 + T-cell activation [13] . Activated CTLs are able to identify these tumor cells via interaction with their complementary TCR, and then induce apoptotic cell death. Finally, a subpopulation of CD4 + CD25 + T lymphocytes, named Tregs, have a fundamental role in maintaining homeostasis by inhibiting excessive immune reactions [14] . Historically, lung cancer was considered as a non immune-sensitive neoplasia [13,15] . However, this notion is beginning to change, since there is increasing evidence that lung tumors can evoke antitumor immune responses (both humoral and cellular-mediated) [15] . SCLC patients with clinical features of the immunemediated Lambert–Eaton paraneoplastic syndrome appeared to have better progression-free survival [16] . Increased stromal infiltration of CD8 + T cells is an independent favorable prognostic indicator in NSCLC
1222
Immunotherapy (2014) 6(11)
[9,13] .
On the other hand, high tumor Treg infiltration is associated with disease recurrence [9,13] . Actually, the first description of Tregs in the neoplastic setting was made in human lung cancer [17,18] . Neoplastic cells may evade immunosurveillance by modulating their tumor-associated antigens, losing MHC expression, escaping apoptosis, inducing T-cell death, increasing Treg or decreasing CD4 +/CD8 + ratios [11,12] . Lung tumors can also produce a dense stroma, which can thwart infiltration by T cells or therapies [19] . Cigarette smoke exposure may also play a part in this immunosuppressive effect [20] . Immune checkpoints
Besides the antigen-MHC-TCR interaction, additional co-activation signals must also be present (Figure 2) , namely interaction of T cell’s CD28 with the APC’s/tumor cell’s B7 surface molecules (CD80 or CD86). In order to prevent autoimmunity phenomena, immune checkpoints are set in place. Activated CD8 + T cells express a protein receptor named CTLA-4, which also binds B7 with high affinity, limiting further T-cell activation by CD28 [12,13] . PD1 is another T-cell surface receptor that, upon binding its cognate ligand PD-L1 in the APC/tumor cell, inhibits the immune response (Figure 2) . While CTLA-4’s action focuses on limiting the initiation of T-cell activation in the lymph nodes, PD1 acts later by limiting T-cell activity in the tumor microenvironment [12] . Immunologic effects of irradiation & chemotherapy Interesting observations from selected case-reports suggest that immunological antitumor effects can be triggered by tumor-cell destruction by means of various treatment modalities [10] . Ionizing radiation induces cell death with consequent release of tumoral antigens. These, in turn, stimulate an inflammatory response that may have antineoplastic activity. In animal studies, radiotherapy is more effective in immunocompetent mice than in their immunodeficient counterparts [10] . Radiotherapy has also been shown to activate innate immunity’s Toll-like receptors. Significant responses have been observed at distant tumor sites after both radiation and administration of Toll-like receptor agonists [10] . Many chemotherapeutic agents induce cell death mainly by direct necrosis, with spill-over of the intracellular content to the extracellular milieu. This produces an inflammatory response against these unknown components, which can be magnified by immunotherapies [10] . The antigens released during chemotherapy have been used to prime the immune
future science group
Immunotherapy & lung cancer
Secretes cytotoxic molecules
Inhibits
Activated CTL
Tumor cells
Review
Treg cell
Turns into
Naive CD8+ T cell Tumor antigen
Internalized and processed by
TCR Class I MHC
Activates IL-2, IFN-γ
APC
Class II MHC
Secretes
TCR
CD4+ Th1 cell Antitumoral vaccine
Figure 1. The immunosurveillance mechanism. Antigens derived from the tumor are processed by APCs and displayed to specific T cells. Activated Th1 cells secrete immunostimulatory cytokines. Activated CD8 + T cells exert cytotoxicity against the tumor. This process is inhibited by Treg cells. Antitumoral vaccines act through this pathway by supplying tumor antigens (and also immunostimulatory adjuvants) to the APCs. CTL: Cytotoxic lymphocyte; IFN: Interferon; TCR: T-cell receptor.
system against the tumor in the ipilimumab trials. Chemotherapies may also synergize with immunotherapies by suppressing immunotolerance induced by the tumor. This occurs by increasing T-cell access to the tumor or by inhibiting immune-regulatory suppressive cells [10] . Immunotherapy for lung cancer The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. It can be further divided into two approaches: active and passive immunotherapy. Passive immunotherapy uses in vitro synthesized immunologic effectors (e.g., cytokines or immunomodulating monoclonal antibodies) [21,22] . Conversely, active immunotherapy seeks to stimulate immune cells in vivo, using immune cells or mediators capable of activating the immune system (e.g., anti tumor vaccines or cellular therapies) [14] . A list of currently investigational immunotherapies for lung cancer is provided in the following sections. Table 1 shows the most important clinical trials involving immunotherapies in lung cancer. Table 2 shows clinical trials that are still ongoing.
future science group
Cytokines The first immunotherapies developed for NSCLC were recombinant cytokines, namely those secreted by Th1 cells, such as IL-2 and IFN (Figure 1) . Phase II trials were not suggestive of clinical benefit for human recombinant IL-2 administration (with or without IFN) [44] . In fact, therapy was not welltolerated, yielding grade 3–4 cardiac and pulmonary toxicity. A Phase II trial by Correale et al. showed that addition of IL-2 to chemotherapy (gemcitabine plus docetaxel) in patients with advanced NSCLC improved response rates (58.3 vs 28.6%) with good tolerability [41,44] . However, these findings were not replicated in a Phase III randomized trial of IL-2 in combination with chemotherapy with a cisplatinum doublet [42,44] . These results were further challenged by a subsequent study reporting 20% partial response and 50% stable disease among 20 advanced NSCLC patients when IL-2 was administered with the pineal neuro-hormone melatonin [43,44] . Blood concentration of IL-2 seems to follow a circadian pattern, which must be taken into account when defining a therapeutic strategy [45] .
www.futuremedicine.com
1223
Review Domingues, Turner, Silva et al.
T cell
Favors T-cell activation
Favors T-cell inhibition
Therapeutic mAbs Antigen
Against CTLA-4 Ipilimumab, tremelimumab
B7
MHC
B7
PD-L1
Against PD-1 Nivolumab, lambrolizumab Against PD-L1 BMS-936559, MPDL3280A
APC
Figure 2. Immune checkpoints. The APC exhibits the processed tumoral antigen to a specific T cell. For the T-cell response to ensue, binding of B7 to CD28 must occur. CTLA-4 binds B7 with high affinity, hindering CD28 binding. PD1 also inhibits the T cell by binding to PD-L1. Antibodies directed against these immune checkpoints override these immune inhibitory mechanisms and allow an immune response against the tumor. CTLA: Cytotoxic T lymphocyte antigen; PD: Programmed death; PD-L1: PD ligand 1; mAb: Monoclonal antibody; TCR: T-cell receptor.
Immune checkpoint inhibitors One of the most promising approaches in immuno therapy for lung cancer is to inhibit the immune checkpoints that harness an effective immune response against the tumor (Figure 2) . This is accomplished using T-cell-directed monoclonal antibodies (mAbs). Nevertheless, the same strategy has not been always successful in other tumor types, such as prostate cancer [12,13] . Ipilimumab
Ipilimumab is a fully humanized mAb directed against CTLA-4, which has shown efficacy against metastatic melanoma [46,47] . A Phase II trial for ipilimumab in lung cancer was conducted, but results for NSCLC and SCLC were reported separately. Lynch et al. [23] enrolled 204 chemotherapy-naive patients with stage IIIB/IV NSCLC and randomly assigned them (1:1:1) to receive one of the following regimens: • Paclitaxel-carboplatin chemotherapy with placebo; • The same ipilimumab;
chemotherapy
with
concurrent
• A phased schedule of 2 chemotherapy cycles followed by ipilimumab with chemotherapy for the next four cycles.
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Immunotherapy (2014) 6(11)
The phased schedule was designed to allow chemotherapy-induced antigen release before ipilimumab administration, whereas the combined schedule meant to guarantee that ipilimumab would be present when said antigen release would have started [9,23] . The study met its primary end point of improved immune-related progression free survival (irPFS) for phased ipilimumab versus the control arm (hazard ratio [HR]: 0.72; p = 0.05), but not for concurrent ipilimumab (HR: 0.81; p = 0.13) [12,23] . A subgroup analysis showed a greater improvement among NSCLC of the squamous subtype. An equally designed trial was carried out by Reck et al. for extensive-disease SCLC. It showed similar results in the sense that the phased schedule, but not the concurrent scheme, increased irPFS when compared with the placebo control (HR: 0.64; p = 0.03) [16] . However, Reck et al. used paclitaxel and carboplatin as chemotherapy, instead of the standard-ofcare etoposide-based regimens for SCLC. Preclinical models have shown that anti-CTLA-4 agents act synergistically with etoposide, so further investigation of ipilimumab in SCLC could involve this agent [16,48,49] . These promising results for ipilimumab led to two Phase III trials that are still ongoing (Table 2) .
future science group
Phase
Compound
future science group
1
1
Brahmer et al.
Herbst et al.
www.futuremedicine.com
CIM Avax + cyclophosphamide
TG4010 + cisplatin/gemcitabine
TG4010 in monotherapy (+ cisplatin double upon progression)
Tecetomide
Tecetomide
MAGE-A3
MPDL3280A (anti-PD-L1)
BMS-936559 (anti-PD-L1)
BSC
Cisplatin/ gemcitabine
TG4010 + cisplatin doublet
Placebo
BSC
Placebo
Different doses of experimental drug
Different doses of experimental drug
Different doses of experimental drug
Different doses of experimental drug
BSC
Placebo + carbo/ paclitaxel
Placebo + carbo/ paclitaxel
Comparator
80
148
65
1.514
171
182
171
75
75
122
87
130
204
n
PFS at 3 months: tremelimumab vs placebo 20.9 vs 14.3%
irPFS: concurrent vs placebo (HR: 0.75) sequential vs placebo (HR: 0.64)
irPFS: concurrent vs placebo (HR: 0.81) sequential vs placebo (HR: 0.72)
Primary end point
Stage IIIb/IV NSCLC after first-line chemo
Stage IIIb/IV NSCLC with MUC1 expression (first line)
Stage IIIb/IV NSCLC
Stage III NSCLC after chemorad
Stage IIIb/IV NSCLC (second line)
Resectable NSCLC with MAGE-A3 expression
Locally advanced or metastatic NSCLC
NSCLC progression after ≥ one line of chemo
0.123
0.112
0.254
15% achieved in 61 patients OS associated with dose level
Safety/tolerability 2) PFS: 4.4 months; OS: 7 months
OS: 9.9 months (95% CI: 8.6–11.3)
OS: BEC2/BCG vs BSC 14.3 vs 16.4 months
Primary end point
Immunotherapy and lung cancer: current developments and novel targeted therapies
Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician’s therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. Keywords: checkpoint inhibitors • immunotherapies • lung cancer • nivolumab • tremelimumab • tumor vaccines
Background Lung cancer is the most commonly diagnosed malignancy in less developed regions of the world, and the second in the most developed nations, with 1.8 million new cases in 2012, corresponding to a 12.9% of the global cancer burden. Due to its high lethality, lung cancer is, at the same time, the most common cause of death from cancer [1] . The two main histological subtypes of lung cancer are small-cell lung cancer (SCLC) and non-SCLC (NSCLC), the latter accounting for approximately 85% of all cases [2] and being diagnosed in the locally advanced or metastatic stage at presentation in 70% of patients [3] . Overall, only 16.6% of lung cancer patients survive 5 years or more (3.9% in the metastatic setting) [4] . For patients with advanced-stage NSCLC, chemo t herapy with a platinumdoublet yields a median overall survival (OS) of approximately 10 months [5] . Cis-
10.2217/IMT.14.82 © 2014 Future Medicine Ltd
platin-based chemotherapy in the adjuvant setting showed an absolute survival benefit of 5% [6] . Recent introduction of molecular targeted therapies in the metastatic setting resulted in clinically meaningful OS improvements, but only in selected patients with tumors harboring specific genetic profiles, such as activating mutations of the EGF receptor (EGFR) and the ALK translocations [7] . Therefore, even with the latest advances, lung cancer prognosis remains dismal, mandating research for novel therapies with new mechanisms of action. Immunotherapy represents a broad class of treatment modalities designed to elicit immune-mediated destruction of tumor cells [8] . Immunotherapy’s encouraging results in other human malignancies hold promise that it may be applied to lung neoplasms [9] . This paper’s main purpose is to provide a comprehensive review about current understanding of immunotherapy for lung cancer.
Immunotherapy (2014) 6(11), 1221–1235
Duarte Domingues1,2, Alice Turner3, Maria Dília Silva2, Dânia Sofia Marques1, Juan Carlos Mellidez2, Luciano Wannesson4, Giannis Mountzios5 & Ramon Andrade de Mello*,1,6 Department of Medical Oncology, Portuguese Oncology Institute (IPO PORTO), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal 2 Department of Medical Oncology, Hospital Infante Dom Pedro, Aveiro, Portugal 3 School of Medicine, University of Otago, 2 Riccarton Ave, Christchurch Central, 8011, Christchurch, New Zealand 4 Oncology Institute of Southern Switzerland (IOSI), CH6500 Bellinzona, Switzerland 5 Department of Medical Oncology, University of Athens School of Medicine, Athens, Greece 6 Department of Biomedical Sciences & Medicine, School of Medicine, University of Algarve, 8005-139, Faro, Portugal *Author for correspondence: Tel.: +351 225 084 000 ext. 7323 Fax: +351 225 084 010 ramello@ ualg.pt 1
part of
ISSN 1750-743X
1221
Review Domingues, Turner, Silva et al. Lung cancer immunology A brief description of lung cancer immunology is provided, in order to better understand immunotherapies’ mechanisms of action. Innate immunity
Innate immunity is a nonspecific first line of defense, involving macrophages and neutrophils [10] . A chronic inflammation state induced by smoking, occupational exposures and other environmental factors activates the innate immunity with subsequent release of cytokines. These cytokines may promote tumor destruction, but can also lead to oncogenesis by stimulating tumor proliferation, angiogenesis and metastatic potential [11] . Tumor cells can activate M2 macrophages by releasing IL-10 [12] . Sentinel cells from the innate branch of immunity may recognize relatively nonspecific structurally preserved molecules, distinguishable from the host molecules through Toll-like receptors in their surface. Immunosurveillance
The immunosurveillance hypothesis postulates that malignant cells express antigens that are recognized by the immune system as foreign, eliciting immune responses against the tumor [13] . Antigens are internalized, processed and displayed by APCs, particularly dendritic cells (DCs). The DCs then migrate to the lymph nodes, where they activate T lymphocytes via interaction of the specific T-cell receptors (TCRs) with the processed antigenic determinants bound to the MHC proteins in the DCs surface (Figure 1) . CD8 + T cells recognize antigen-MHC class I complexes and, once activated, turn into cytotoxic lymphocytes (CTLs). CD4 + T-helper cells (of the Th1 kind), on the other hand, identify antigen-MHC class II complexes and secrete cytokines, such as IL-2 and IFN-γ, which in turn ease CD8 + T-cell activation [13] . Activated CTLs are able to identify these tumor cells via interaction with their complementary TCR, and then induce apoptotic cell death. Finally, a subpopulation of CD4 + CD25 + T lymphocytes, named Tregs, have a fundamental role in maintaining homeostasis by inhibiting excessive immune reactions [14] . Historically, lung cancer was considered as a non immune-sensitive neoplasia [13,15] . However, this notion is beginning to change, since there is increasing evidence that lung tumors can evoke antitumor immune responses (both humoral and cellular-mediated) [15] . SCLC patients with clinical features of the immunemediated Lambert–Eaton paraneoplastic syndrome appeared to have better progression-free survival [16] . Increased stromal infiltration of CD8 + T cells is an independent favorable prognostic indicator in NSCLC
1222
Immunotherapy (2014) 6(11)
[9,13] .
On the other hand, high tumor Treg infiltration is associated with disease recurrence [9,13] . Actually, the first description of Tregs in the neoplastic setting was made in human lung cancer [17,18] . Neoplastic cells may evade immunosurveillance by modulating their tumor-associated antigens, losing MHC expression, escaping apoptosis, inducing T-cell death, increasing Treg or decreasing CD4 +/CD8 + ratios [11,12] . Lung tumors can also produce a dense stroma, which can thwart infiltration by T cells or therapies [19] . Cigarette smoke exposure may also play a part in this immunosuppressive effect [20] . Immune checkpoints
Besides the antigen-MHC-TCR interaction, additional co-activation signals must also be present (Figure 2) , namely interaction of T cell’s CD28 with the APC’s/tumor cell’s B7 surface molecules (CD80 or CD86). In order to prevent autoimmunity phenomena, immune checkpoints are set in place. Activated CD8 + T cells express a protein receptor named CTLA-4, which also binds B7 with high affinity, limiting further T-cell activation by CD28 [12,13] . PD1 is another T-cell surface receptor that, upon binding its cognate ligand PD-L1 in the APC/tumor cell, inhibits the immune response (Figure 2) . While CTLA-4’s action focuses on limiting the initiation of T-cell activation in the lymph nodes, PD1 acts later by limiting T-cell activity in the tumor microenvironment [12] . Immunologic effects of irradiation & chemotherapy Interesting observations from selected case-reports suggest that immunological antitumor effects can be triggered by tumor-cell destruction by means of various treatment modalities [10] . Ionizing radiation induces cell death with consequent release of tumoral antigens. These, in turn, stimulate an inflammatory response that may have antineoplastic activity. In animal studies, radiotherapy is more effective in immunocompetent mice than in their immunodeficient counterparts [10] . Radiotherapy has also been shown to activate innate immunity’s Toll-like receptors. Significant responses have been observed at distant tumor sites after both radiation and administration of Toll-like receptor agonists [10] . Many chemotherapeutic agents induce cell death mainly by direct necrosis, with spill-over of the intracellular content to the extracellular milieu. This produces an inflammatory response against these unknown components, which can be magnified by immunotherapies [10] . The antigens released during chemotherapy have been used to prime the immune
future science group
Immunotherapy & lung cancer
Secretes cytotoxic molecules
Inhibits
Activated CTL
Tumor cells
Review
Treg cell
Turns into
Naive CD8+ T cell Tumor antigen
Internalized and processed by
TCR Class I MHC
Activates IL-2, IFN-γ
APC
Class II MHC
Secretes
TCR
CD4+ Th1 cell Antitumoral vaccine
Figure 1. The immunosurveillance mechanism. Antigens derived from the tumor are processed by APCs and displayed to specific T cells. Activated Th1 cells secrete immunostimulatory cytokines. Activated CD8 + T cells exert cytotoxicity against the tumor. This process is inhibited by Treg cells. Antitumoral vaccines act through this pathway by supplying tumor antigens (and also immunostimulatory adjuvants) to the APCs. CTL: Cytotoxic lymphocyte; IFN: Interferon; TCR: T-cell receptor.
system against the tumor in the ipilimumab trials. Chemotherapies may also synergize with immunotherapies by suppressing immunotolerance induced by the tumor. This occurs by increasing T-cell access to the tumor or by inhibiting immune-regulatory suppressive cells [10] . Immunotherapy for lung cancer The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. It can be further divided into two approaches: active and passive immunotherapy. Passive immunotherapy uses in vitro synthesized immunologic effectors (e.g., cytokines or immunomodulating monoclonal antibodies) [21,22] . Conversely, active immunotherapy seeks to stimulate immune cells in vivo, using immune cells or mediators capable of activating the immune system (e.g., anti tumor vaccines or cellular therapies) [14] . A list of currently investigational immunotherapies for lung cancer is provided in the following sections. Table 1 shows the most important clinical trials involving immunotherapies in lung cancer. Table 2 shows clinical trials that are still ongoing.
future science group
Cytokines The first immunotherapies developed for NSCLC were recombinant cytokines, namely those secreted by Th1 cells, such as IL-2 and IFN (Figure 1) . Phase II trials were not suggestive of clinical benefit for human recombinant IL-2 administration (with or without IFN) [44] . In fact, therapy was not welltolerated, yielding grade 3–4 cardiac and pulmonary toxicity. A Phase II trial by Correale et al. showed that addition of IL-2 to chemotherapy (gemcitabine plus docetaxel) in patients with advanced NSCLC improved response rates (58.3 vs 28.6%) with good tolerability [41,44] . However, these findings were not replicated in a Phase III randomized trial of IL-2 in combination with chemotherapy with a cisplatinum doublet [42,44] . These results were further challenged by a subsequent study reporting 20% partial response and 50% stable disease among 20 advanced NSCLC patients when IL-2 was administered with the pineal neuro-hormone melatonin [43,44] . Blood concentration of IL-2 seems to follow a circadian pattern, which must be taken into account when defining a therapeutic strategy [45] .
www.futuremedicine.com
1223
Review Domingues, Turner, Silva et al.
T cell
Favors T-cell activation
Favors T-cell inhibition
Therapeutic mAbs Antigen
Against CTLA-4 Ipilimumab, tremelimumab
B7
MHC
B7
PD-L1
Against PD-1 Nivolumab, lambrolizumab Against PD-L1 BMS-936559, MPDL3280A
APC
Figure 2. Immune checkpoints. The APC exhibits the processed tumoral antigen to a specific T cell. For the T-cell response to ensue, binding of B7 to CD28 must occur. CTLA-4 binds B7 with high affinity, hindering CD28 binding. PD1 also inhibits the T cell by binding to PD-L1. Antibodies directed against these immune checkpoints override these immune inhibitory mechanisms and allow an immune response against the tumor. CTLA: Cytotoxic T lymphocyte antigen; PD: Programmed death; PD-L1: PD ligand 1; mAb: Monoclonal antibody; TCR: T-cell receptor.
Immune checkpoint inhibitors One of the most promising approaches in immuno therapy for lung cancer is to inhibit the immune checkpoints that harness an effective immune response against the tumor (Figure 2) . This is accomplished using T-cell-directed monoclonal antibodies (mAbs). Nevertheless, the same strategy has not been always successful in other tumor types, such as prostate cancer [12,13] . Ipilimumab
Ipilimumab is a fully humanized mAb directed against CTLA-4, which has shown efficacy against metastatic melanoma [46,47] . A Phase II trial for ipilimumab in lung cancer was conducted, but results for NSCLC and SCLC were reported separately. Lynch et al. [23] enrolled 204 chemotherapy-naive patients with stage IIIB/IV NSCLC and randomly assigned them (1:1:1) to receive one of the following regimens: • Paclitaxel-carboplatin chemotherapy with placebo; • The same ipilimumab;
chemotherapy
with
concurrent
• A phased schedule of 2 chemotherapy cycles followed by ipilimumab with chemotherapy for the next four cycles.
1224
Immunotherapy (2014) 6(11)
The phased schedule was designed to allow chemotherapy-induced antigen release before ipilimumab administration, whereas the combined schedule meant to guarantee that ipilimumab would be present when said antigen release would have started [9,23] . The study met its primary end point of improved immune-related progression free survival (irPFS) for phased ipilimumab versus the control arm (hazard ratio [HR]: 0.72; p = 0.05), but not for concurrent ipilimumab (HR: 0.81; p = 0.13) [12,23] . A subgroup analysis showed a greater improvement among NSCLC of the squamous subtype. An equally designed trial was carried out by Reck et al. for extensive-disease SCLC. It showed similar results in the sense that the phased schedule, but not the concurrent scheme, increased irPFS when compared with the placebo control (HR: 0.64; p = 0.03) [16] . However, Reck et al. used paclitaxel and carboplatin as chemotherapy, instead of the standard-ofcare etoposide-based regimens for SCLC. Preclinical models have shown that anti-CTLA-4 agents act synergistically with etoposide, so further investigation of ipilimumab in SCLC could involve this agent [16,48,49] . These promising results for ipilimumab led to two Phase III trials that are still ongoing (Table 2) .
future science group
Phase
Compound
future science group
1
1
Brahmer et al.
Herbst et al.
www.futuremedicine.com
CIM Avax + cyclophosphamide
TG4010 + cisplatin/gemcitabine
TG4010 in monotherapy (+ cisplatin double upon progression)
Tecetomide
Tecetomide
MAGE-A3
MPDL3280A (anti-PD-L1)
BMS-936559 (anti-PD-L1)
BSC
Cisplatin/ gemcitabine
TG4010 + cisplatin doublet
Placebo
BSC
Placebo
Different doses of experimental drug
Different doses of experimental drug
Different doses of experimental drug
Different doses of experimental drug
BSC
Placebo + carbo/ paclitaxel
Placebo + carbo/ paclitaxel
Comparator
80
148
65
1.514
171
182
171
75
75
122
87
130
204
n
PFS at 3 months: tremelimumab vs placebo 20.9 vs 14.3%
irPFS: concurrent vs placebo (HR: 0.75) sequential vs placebo (HR: 0.64)
irPFS: concurrent vs placebo (HR: 0.81) sequential vs placebo (HR: 0.72)
Primary end point
Stage IIIb/IV NSCLC after first-line chemo
Stage IIIb/IV NSCLC with MUC1 expression (first line)
Stage IIIb/IV NSCLC
Stage III NSCLC after chemorad
Stage IIIb/IV NSCLC (second line)
Resectable NSCLC with MAGE-A3 expression
Locally advanced or metastatic NSCLC
NSCLC progression after ≥ one line of chemo
0.123
0.112
0.254
15% achieved in 61 patients OS associated with dose level
Safety/tolerability 2) PFS: 4.4 months; OS: 7 months
OS: 9.9 months (95% CI: 8.6–11.3)
OS: BEC2/BCG vs BSC 14.3 vs 16.4 months
Primary end point
