REVIEW For reprint orders, please contact: [email protected]
Immunotherapy for lung cancer: ongoing clinical trials
Sarah Declerck1 & Johan Vansteenkiste*1
ABSTRACT: Modulation of a patient’s immune system so that it acts against lung cancer cells has not been successful in the past decades. Advances in our understanding of the immune response to tumors resulted in the development of different kinds of novel immunotherapeutic agents. This has resulted in the development of two major approaches. First, antigen-specific immunotherapy or cancer vaccination, with the MAGE‑A3 vaccine in resected early-stage non‑small-cell lung cancer (NSCLC), the L‑BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy and belagenpumatucel-L and the TG4010 vaccine in advanced-stage NSCLC. Second, non-antigen-specific immunotherapy or cancer immunomodulation is reviewed, including how monoclonal antibodies modulate the interaction between antigen-presenting cells, T-lymphocytes and tumor cells (e.g., antibodies against CTLA-4, or against PD-1 receptor or its ligands). Recent Phase II trials with these treatments have shown promising results of efficacy and tolerability, which has led to testing in several large Phase III trials. Some of these are fully recruited, while others are still ongoing, and important results are be expected in the near future. Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Of all lung cancer cases 85% are non-small-cell lung cancer (NSCLC). A radical therapy may be offered to patients with nonmetastatic stages, but a large number of patients still relapse and die of their cancer [2]. For patients with advanced-stage NSCLC, modern platinum doublet chemotherapy results in a median overall survival (OS) of 10 months and a 1-year survival rate of approximately 40% [3]. Recently, personalized therapy for patients with tumors with specific molecular biological characteristics, such as tyrosine kinase inhibitors for tumors with activating EGFR mutations, has resulted in better OS outcomes in these biologically selected subgroups. However, these patients represent only 10–15% of Caucasian patients [4]. Novel treatment options are clearly warranted if we hope to improve the prognosis for patients with lung cancer. Immunotherapy, such as vaccines and antibodies that modulate T-cell activity, offers an alternative treatment approach that could help improve outcomes. Improvements in OS in randomized Phase III clinical trials led to the approval of ipilimumab for melanoma [5] and sipuleucel-T for prostate cancer [6], and generated a renewed interest in immunotherapy for solid tumors. Lung cancer immunotherapy has not been successful in the past. In the last decade, however, a better understanding of the immune system and identification of relevant target antigens in combination with the technical possibility to develop more sophisticated delivery systems has made it possible to test new therapies with promising results.
KEYWORDS
• cancer vaccine • dendritic cell • immunotherapy • lung cancer • randomized
controlled trial
Respiratory Oncology Unit (Department of Pulmonology) & Leuven Lung Cancer Group, University Hospital KU Leuven, Leuven, Belgium *Author for correspondence: Tel.: +32 16 346801; Fax: +32 16 346803; [email protected] 1
10.2217/FON.13.166 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(1), 91–105
part of
ISSN 1479-6694
91
Review Declerck & Vansteenkiste
Vaccine
Tumor antigens
APC MHC class II MHC class I
CD4 B7.1 B7.2 CD8 CD28
CD4+ T cell
CD8+ T cell
IL-2 IL-12 IFN-γ Cytokines
M∅
NK cell
B cell
Plasma cell
Tumor cell
Cytotoxic T cell
Tumor cell death
Figure 1. Steps involved in tumor vaccination. APC: Antigen-presenting cell; MHC: Major histocompatibility complex; MØ: Macrophage; NK: Natural killer. Reproduced with permission from [71].
Cancer immunology Whether tumors express antigens that can be the recognized by the immune system was unclear in the past. The immunosurveillance hypothesis posits that the immune system does recognize malignant cells as foreign, with the possibility to eliminate them [7]. A normal cellular anti-tumor immune response begins with the uptake of tumor antigens by antigen-presenting cells (APCs), particularly dendritic cells (Figure 1). These antigens are internalized and processed into small peptide sequences and subsequently displayed on the extracellular surface of the APC in association
92
Future Oncol. (2014) 10(1)
with class I and II major histocompatibility complex (MHC) proteins. The dendritic cell with the antigenic peptide presented on its surface circulates to the draining lymph nodes. After maturation, it interacts with naive T lymphocytes [8] to trigger activation of the appropriate CD4+ T-helper lymphocytes. Activation of these CD4+ T-helper cells augments the immune response by the secretion of cytokines such as IL-2 (Th1 cells), IL-12 (dendritic cells) and INF-g (Th1 cells). This, in turn, facilitates the activation of CD8+ T cells into cytotoxic T-lymphocytes [9]. Several signals are required for T-cell activation. There has to be an interaction
future science group
Immunotherapy for lung cancer: ongoing clinical trials between the specific T-cell receptor on naive T cells and the antigen presented by the APC on a MHC molecule. This must take place in combination with the required co-stimulatory interaction between B7.1 (CD80) and B7.2 (CD86) on the APCs and CD28 present on the T cells [10]. Activated cytotoxic T-lymphocytes will then recognize tumor cells that display the complementary peptide–MHC class 1 complex on their cell surface and induce apoptotic cell death [7,11]. After activation, CD8+ T cells express cytotoxic T-lymphocyte antigen-4 (CTLA-4) on their cell surface. CTLA-4 binds with high affinity to CD80/CD86 and provides an inhibitory signal to limit further T-cell activation. This mechanism prevents autoimmunity and damage to normal host tissue, but may also be responsible for tolerance of tumor antigens [12]. Tumors have different mechanisms to evade the immune system, which leads to immuno tolerance. Tumor cells can downregulate antigens, and decrease the expression of MHC class I molecules and costimulatory molecules, which results in a failure of T-cell recognition and activation. In addition, local secretion of cytokines such as TGF-b and IDO interferes with maturation of dendritic cells, and favors myeloid-derived suppressor cells and regulatory T cells, which create a strong immunosuppressive environment. The PD-1 receptor may interact with PD-L1, resulting in downregulation of the action of activated T cells on the tumor. Finally, tumor cells can become resistant to the effect of cytotoxic T lymphocytes by failing to activate apoptosis [13]. Cancer immunotherapy Immunotherapy uses the immune system to control and potentially eradicate tumors. Older immunotherapies such as IL-2, interferon and first-generation vaccines had limited success. More recently, treatment with newer immunotherapeutic agents resulted in improved OS in Phase III trials of patients with melanoma and prostate cancer [5,6]. Although lung cancer is not typically believed to be an immunogenic malignancy, more and more evidence suggests that immune responses to lung cancer may be important. Retrospective analyses of tumor specimens from lung cancer patients have suggested that cellular immune responses against the tumor are associated with a more favorable prognosis. Increased stromal infiltration of CD4+/CD8+ T cells has been
future science group
Review
shown to be an independent positive prognostic indicator in early-stage NSCLC [14,15]. In patients with stage IV NSCLC, the presence of higher numbers of macrophages and CD8+ T-cells in tumor nests, compared with the surrounding stroma, was independently associated with favorable prognosis [16]. High expression of tumor-infiltrating regulatory T cells on the other hand reduces anti-tumor immunity and is associated with disease recurrence [17,18]. All of these findings support the hypothesis that using or manipulating the immune system to generate anti-tumor effects may be a viable therapeutic approach in lung cancer. Different strategies have been developed to elicit immune responses against tumor cells. Overall, three different approaches can be distinguished. First, there is the passive supply of antibodies targeting specific tumor-associated receptor proteins such as cetuximab. This is more often quoted as targeted therapy with monoclonal antibodies (mAbs) [19], and it is not fully understood how much of the activity may be related to antibody-dependent cellular cytotoxicity. Discussion of these agents is beyond the scope of this review. Second, therapeutic cancer vaccination is an antigen-specific immunotherapy that primes the immune system to produce antigen-specific antibodies, CD4+ T-helper cells and CD8+ cytotoxic T-lymphocytes against relevant tumor‑associated antigens. The third principle is nonantigen-specific modulation of the immune system, based on immunomodulatory agents such as mAbs that modulate T-cell activity. Antigen-specific immunotherapy: therapeutic cancer vaccines A vaccine consists of immunogenic tumorassociated antigens, shaped as peptides, recombinant proteins, gangliosides or whole tumor cells, always in combination with an adjuvant needed to potentiate the immune response [20]. The immunoadjuvant can be a phospholipid, aluminium formulation, viral vector, dendritic cell or liposome presentation. Different vaccination strategies have been evaluated in lung cancer. We review those in late-stage development. ●●Full protein vaccines
MAGE‑A3 vaccine
MAGE‑A3 is a promising target for immuno therapy because it is almost exclusively
www.futuremedicine.com
93
94
Stage IIIB or IV NSCLC after conventional first-line chemotherapy Cyclophosphamide plus 438 EGF vaccine plus BSC vs BSC alone
BSC: Best supportive care; DFI: Disease-free interval; DFS: Disease-free survival; HR: Hazard ratio; NSCLC: Non-small-cell lung cancer; OS: Overall survival; PFS: Progression-free survival.
[28] Difference significant in patients
Immunotherapy for lung cancer: ongoing clinical trials
Sarah Declerck1 & Johan Vansteenkiste*1
ABSTRACT: Modulation of a patient’s immune system so that it acts against lung cancer cells has not been successful in the past decades. Advances in our understanding of the immune response to tumors resulted in the development of different kinds of novel immunotherapeutic agents. This has resulted in the development of two major approaches. First, antigen-specific immunotherapy or cancer vaccination, with the MAGE‑A3 vaccine in resected early-stage non‑small-cell lung cancer (NSCLC), the L‑BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy and belagenpumatucel-L and the TG4010 vaccine in advanced-stage NSCLC. Second, non-antigen-specific immunotherapy or cancer immunomodulation is reviewed, including how monoclonal antibodies modulate the interaction between antigen-presenting cells, T-lymphocytes and tumor cells (e.g., antibodies against CTLA-4, or against PD-1 receptor or its ligands). Recent Phase II trials with these treatments have shown promising results of efficacy and tolerability, which has led to testing in several large Phase III trials. Some of these are fully recruited, while others are still ongoing, and important results are be expected in the near future. Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Of all lung cancer cases 85% are non-small-cell lung cancer (NSCLC). A radical therapy may be offered to patients with nonmetastatic stages, but a large number of patients still relapse and die of their cancer [2]. For patients with advanced-stage NSCLC, modern platinum doublet chemotherapy results in a median overall survival (OS) of 10 months and a 1-year survival rate of approximately 40% [3]. Recently, personalized therapy for patients with tumors with specific molecular biological characteristics, such as tyrosine kinase inhibitors for tumors with activating EGFR mutations, has resulted in better OS outcomes in these biologically selected subgroups. However, these patients represent only 10–15% of Caucasian patients [4]. Novel treatment options are clearly warranted if we hope to improve the prognosis for patients with lung cancer. Immunotherapy, such as vaccines and antibodies that modulate T-cell activity, offers an alternative treatment approach that could help improve outcomes. Improvements in OS in randomized Phase III clinical trials led to the approval of ipilimumab for melanoma [5] and sipuleucel-T for prostate cancer [6], and generated a renewed interest in immunotherapy for solid tumors. Lung cancer immunotherapy has not been successful in the past. In the last decade, however, a better understanding of the immune system and identification of relevant target antigens in combination with the technical possibility to develop more sophisticated delivery systems has made it possible to test new therapies with promising results.
KEYWORDS
• cancer vaccine • dendritic cell • immunotherapy • lung cancer • randomized
controlled trial
Respiratory Oncology Unit (Department of Pulmonology) & Leuven Lung Cancer Group, University Hospital KU Leuven, Leuven, Belgium *Author for correspondence: Tel.: +32 16 346801; Fax: +32 16 346803; [email protected] 1
10.2217/FON.13.166 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(1), 91–105
part of
ISSN 1479-6694
91
Review Declerck & Vansteenkiste
Vaccine
Tumor antigens
APC MHC class II MHC class I
CD4 B7.1 B7.2 CD8 CD28
CD4+ T cell
CD8+ T cell
IL-2 IL-12 IFN-γ Cytokines
M∅
NK cell
B cell
Plasma cell
Tumor cell
Cytotoxic T cell
Tumor cell death
Figure 1. Steps involved in tumor vaccination. APC: Antigen-presenting cell; MHC: Major histocompatibility complex; MØ: Macrophage; NK: Natural killer. Reproduced with permission from [71].
Cancer immunology Whether tumors express antigens that can be the recognized by the immune system was unclear in the past. The immunosurveillance hypothesis posits that the immune system does recognize malignant cells as foreign, with the possibility to eliminate them [7]. A normal cellular anti-tumor immune response begins with the uptake of tumor antigens by antigen-presenting cells (APCs), particularly dendritic cells (Figure 1). These antigens are internalized and processed into small peptide sequences and subsequently displayed on the extracellular surface of the APC in association
92
Future Oncol. (2014) 10(1)
with class I and II major histocompatibility complex (MHC) proteins. The dendritic cell with the antigenic peptide presented on its surface circulates to the draining lymph nodes. After maturation, it interacts with naive T lymphocytes [8] to trigger activation of the appropriate CD4+ T-helper lymphocytes. Activation of these CD4+ T-helper cells augments the immune response by the secretion of cytokines such as IL-2 (Th1 cells), IL-12 (dendritic cells) and INF-g (Th1 cells). This, in turn, facilitates the activation of CD8+ T cells into cytotoxic T-lymphocytes [9]. Several signals are required for T-cell activation. There has to be an interaction
future science group
Immunotherapy for lung cancer: ongoing clinical trials between the specific T-cell receptor on naive T cells and the antigen presented by the APC on a MHC molecule. This must take place in combination with the required co-stimulatory interaction between B7.1 (CD80) and B7.2 (CD86) on the APCs and CD28 present on the T cells [10]. Activated cytotoxic T-lymphocytes will then recognize tumor cells that display the complementary peptide–MHC class 1 complex on their cell surface and induce apoptotic cell death [7,11]. After activation, CD8+ T cells express cytotoxic T-lymphocyte antigen-4 (CTLA-4) on their cell surface. CTLA-4 binds with high affinity to CD80/CD86 and provides an inhibitory signal to limit further T-cell activation. This mechanism prevents autoimmunity and damage to normal host tissue, but may also be responsible for tolerance of tumor antigens [12]. Tumors have different mechanisms to evade the immune system, which leads to immuno tolerance. Tumor cells can downregulate antigens, and decrease the expression of MHC class I molecules and costimulatory molecules, which results in a failure of T-cell recognition and activation. In addition, local secretion of cytokines such as TGF-b and IDO interferes with maturation of dendritic cells, and favors myeloid-derived suppressor cells and regulatory T cells, which create a strong immunosuppressive environment. The PD-1 receptor may interact with PD-L1, resulting in downregulation of the action of activated T cells on the tumor. Finally, tumor cells can become resistant to the effect of cytotoxic T lymphocytes by failing to activate apoptosis [13]. Cancer immunotherapy Immunotherapy uses the immune system to control and potentially eradicate tumors. Older immunotherapies such as IL-2, interferon and first-generation vaccines had limited success. More recently, treatment with newer immunotherapeutic agents resulted in improved OS in Phase III trials of patients with melanoma and prostate cancer [5,6]. Although lung cancer is not typically believed to be an immunogenic malignancy, more and more evidence suggests that immune responses to lung cancer may be important. Retrospective analyses of tumor specimens from lung cancer patients have suggested that cellular immune responses against the tumor are associated with a more favorable prognosis. Increased stromal infiltration of CD4+/CD8+ T cells has been
future science group
Review
shown to be an independent positive prognostic indicator in early-stage NSCLC [14,15]. In patients with stage IV NSCLC, the presence of higher numbers of macrophages and CD8+ T-cells in tumor nests, compared with the surrounding stroma, was independently associated with favorable prognosis [16]. High expression of tumor-infiltrating regulatory T cells on the other hand reduces anti-tumor immunity and is associated with disease recurrence [17,18]. All of these findings support the hypothesis that using or manipulating the immune system to generate anti-tumor effects may be a viable therapeutic approach in lung cancer. Different strategies have been developed to elicit immune responses against tumor cells. Overall, three different approaches can be distinguished. First, there is the passive supply of antibodies targeting specific tumor-associated receptor proteins such as cetuximab. This is more often quoted as targeted therapy with monoclonal antibodies (mAbs) [19], and it is not fully understood how much of the activity may be related to antibody-dependent cellular cytotoxicity. Discussion of these agents is beyond the scope of this review. Second, therapeutic cancer vaccination is an antigen-specific immunotherapy that primes the immune system to produce antigen-specific antibodies, CD4+ T-helper cells and CD8+ cytotoxic T-lymphocytes against relevant tumor‑associated antigens. The third principle is nonantigen-specific modulation of the immune system, based on immunomodulatory agents such as mAbs that modulate T-cell activity. Antigen-specific immunotherapy: therapeutic cancer vaccines A vaccine consists of immunogenic tumorassociated antigens, shaped as peptides, recombinant proteins, gangliosides or whole tumor cells, always in combination with an adjuvant needed to potentiate the immune response [20]. The immunoadjuvant can be a phospholipid, aluminium formulation, viral vector, dendritic cell or liposome presentation. Different vaccination strategies have been evaluated in lung cancer. We review those in late-stage development. ●●Full protein vaccines
MAGE‑A3 vaccine
MAGE‑A3 is a promising target for immuno therapy because it is almost exclusively
www.futuremedicine.com
93
94
Stage IIIB or IV NSCLC after conventional first-line chemotherapy Cyclophosphamide plus 438 EGF vaccine plus BSC vs BSC alone
BSC: Best supportive care; DFI: Disease-free interval; DFS: Disease-free survival; HR: Hazard ratio; NSCLC: Non-small-cell lung cancer; OS: Overall survival; PFS: Progression-free survival.
[28] Difference significant in patients
