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Immunotherapy for Non-small Cell Lung Cancer: Novel Approaches to Improve Patient Outcome

      Introduction

      Non-small cell lung cancer (NSCLC) is often diagnosed in advanced stages and is associated with poor outcomes. Existing standards of care for NSCLC result in low overall cure rates, suggesting that novel treatment approaches are needed. In this review, we provide an updated look at the clinical data on immunotherapeutic interventions, which potentiate the immune system's response to lung tumor cells.

      Methods

      We searched articles on PubMed and abstracts from recent oncology meetings for publications on immunotherapies with clinical applicability to the treatment of NSCLC.

      Results

      Results from phase 2 trials show vaccine therapies, which target either tumor cells themselves or aberrantly expressed tumor markers (mucin 1, melanoma-associated antigen 3, or epidermal growth factor), may be promising immunotherapeutics for NSCLC. Antigen-independent immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibodies, talactoferrin alfa, and toll-like receptor 9 agonists, act on a stimulated immune system regardless of the tumor antigen and may be feasible interventions for metastatic NSCLC. Several immunotherapies are undergoing phase 3 studies to assess optimal treatment settings and to determine clinical benefit compared with current standard treatments for NSCLC.

      Conclusions

      A growing body of evidence suggests that immune responses to lung tumors are present. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. Furthermore, treatments that enhance antitumor immune responses may prove to be synergistic with chemotherapy. Identification of biomarkers and further elucidation of immunotherapeutic mechanisms of action will be essential in determining which patients will experience the greatest benefit from immunotherapy.

      Key Words

      Lung cancer is the leading cause of cancer death among men worldwide and is second only to breast cancer among women. In the United States, cancers of the lung and bronchus account for almost 30% of cancer deaths.
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      Lung cancer is a heterogeneous disease, which includes two main histologic subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for approximately 85% of all cases and encompasses several subtypes.
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      Maintenance therapy for patients without disease progression after first-line chemotherapy has emerged recently as a potential new treatment paradigm for some patients.
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      Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
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      Despite the introduction of new chemotherapeutic agents and several molecularly targeted drugs in the past decade, outcomes remain poor, with overall cure rates less than 20%. Clearly, new treatment approaches are needed. This article provides an overview of antitumor immune response in NSCLC and reviews available clinical data for several immunotherapeutic approaches, with a focus placed on interventions currently in phase 3 clinical development.

      ANTITUMOR IMMUNE RESPONSES IN LUNG CANCER

      The immune system can mount an antitumor response when tumor cell fragments are internalized by antigen-presenting cells (APCs) (particularly dendritic cells), processed, and displayed on the APC extracellular surface in association with class I and II major histocompatibility complex (MHC) molecules.
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      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      After drainage and maturation in adjacent lymph nodes, these APCs can interact with naive T lymphocytes to trigger activation and proliferation of tumor-specific CD4+ helper and CD8+ cytotoxic T cells (Figure 1).
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      Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
      T-cell activation requires an interaction between the antigen-MHC complex on APCs and T-cell receptors on naive T cells, as well as a costimulatory interaction between B7.1 (CD80) or B7.2 (CD86) on APCs and CD28 on T cells. Immune tolerance develops upon failure to sufficiently activate this costimulatory pathway.
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      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
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      Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010).
      Figure thumbnail gr1
      FIGURE 1Dendritic cell–T-cell interactions leading to generation of antitumor cytotoxic T cells.
      • Kelly RJ
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      • Giaccone G
      Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
      CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.
      After T-cell activation, cytotoxic T-lymphocyte antigen-4 (CTLA-4) is expressed on the T-cell surface.
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      Anti-cytotoxic T-lymphocyte antigen-antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
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      CTLA-4 binds with high affinity to CD80/CD86 and provides an inhibitory signal to limit further T-cell activation. This mechanism helps to maintain tolerance to host antigens on normal cells and thereby prevents lymphoproliferative disease. Tumors, however, can escape the immune system by inducing tolerance or by becoming resistant to T-cell-mediated destruction.
      • Drake CG
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      Mechanisms of immune evasion by tumors.
      Tumor cells may exhibit increased expression of CD4+ CD25+ T-regulatory cells that suppress the function and proliferation of tumor-specific CD4+ and CD8+ effector cells.
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      Control of T-cell activation by CD4+ CD25+ suppressor T cells.
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      Increased production of myeloid-derived suppressor cells and tumor-associated macrophages can also suppress T-cell proliferation and effector functions and stimulate tumor growth and metastasis.
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      Myeloid-derived suppressor cells.
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      Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells.
      In addition to these mechanisms, tumors can increase or decrease expression of a variety of factors that ultimately may block the activation, proliferation, or function of antitumor immune cells.
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      Signaling defects in anti-tumor T cells.
      Examples include downregulation of tumor antigen or MHC class I molecule expression and altered secretion of immunoregulatory cytokines.
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      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      Although lung cancer is not typically thought of as an “immunogenic” malignancy, a growing body of evidence suggests that immune responses to lung tumors may be present, and their magnitude may correlate with patient outcome. Retrospective analyses of tumor specimens from lung cancer patients suggest that cellular immune responses against the tumor are associated with a favorable prognosis. Several studies have shown that higher tumor infiltration with CD4+ and/or CD8+ T cells is associated with better survival in early-stage NSCLC.
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      Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma.
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      Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer.
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      A high number of CD8+ T cells infiltrated in NSCLC tissues is associated with a favorable prognosis.
      In the largest study, high numbers of stromal CD8+ and CD4+ T cells independently were associated with better disease-specific survival in a cohort of 335 patients with resected stage I to IIIA NSCLC.
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      Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer.
      In another cohort, concomitant high-level infiltration of both CD4+ and CD8+ T cells independently was prognostic of outcome, suggesting that cooperation between CD4+ and CD8+ cells may provide a better immune response than either T-cell type alone.
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      Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma.
      High CD8+ T-cell infiltration into cancer nests was associated with squamous cell histology, whereas CD4+ infiltration was independent of histology. The density of tertiary lymphoid structures consisting of clusters of mature dendritic cells and T cells adjacent to B-cell follicles was highly associated with overall survival (OS), disease-specific OS, and disease-free survival in 74 patients with early-stage NSCLC.
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      Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures.
      Tumors with few dendritic cells also had a low density of tumor-infiltrating lymphocytes. The presence of higher numbers of tumor-infiltrating macrophages and CD8+ T cells in cancer nests, compared with the surrounding tumor stromal tissue, was independently associated with better prognosis in patients with stage IV NSCLC.
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      Predominant infiltration of macrophages and CD8+ T cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer.
      As noted above, CD4+ CD25+ T-regulatory cells reduce antitumor immunity. Several retrospective analyses have shown that high expression of tumor-infiltrating T-regulatory cells is associated with disease recurrence in early-stage NSCLC.
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      Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients.
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      Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer.
      Disease recurrence was associated with a high ratio of these T-regulatory cells to tumor-infiltrating T cells in a cohort of patients with resected stage I NSCLC.
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      Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients.
      This evidence supports the hypothesis that inducing or potentiating immune responses via immunotherapeutic manipulations may offer a viable therapeutic approach in lung cancer, including patient subpopulations with high unmet medical need. The goal of immunotherapy is to potentiate the immune system's response to lung tumor cells. For example, the mechanism of action of an immunotherapeutic agent may promote more productive immune-mediated cytotoxic effector mechanisms and/or might blunt the regulatory mechanisms that promote immune tolerance against lung tumor cells. Vaccine therapy and antigen-independent immunotherapy are strategies currently under development for the treatment of lung cancer.

      VACCINE THERAPY

      Several different vaccine therapy strategies have been evaluated in lung cancer (for a more comprehensive overview, please see the article by Bradbury and Shepherd).
      • Bradbury PA
      • Shepherd FA
      Immunotherapy for lung cancer.
      Most data are based on the use of antigen-specific vaccines and tumor cell vaccines, whereas only pilot study data are available for dendritic cell vaccines (Table 1).
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      • Maione P
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      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      • Butts C
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      Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.
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      Randomized phase IIb trial evaluating the therapeutic vaccine TG4010 (MVA-MUC1-IL2) as an adjunct to chemotherapy in patients with advanced non-small cell lung cancer.
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      • et al.
      Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC).
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      Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer.
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      Phase II study of belagenpumatucel-L, a transforming factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer.
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      Phase II trials of belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients.
      A nonspecific immune stimulant, known as an adjuvant, is administered in combination with vaccines to stimulate movement of APCs to the vaccination site and uptake of the vaccine antigen by the APCs.
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      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      • Bradbury PA
      • Shepherd FA
      Immunotherapy for lung cancer.
      TABLE 1Phase 2 Study Results of Vaccines Currently in Phase 3 Development
       Vaccine TypeNameTargetStudy DesignOutcomeReference
       Antigen-specificL-BLP25MUC1171 patients with stage IIIB/IV NSCLC received L-BLP25 or best supportive carePatients with IIIB disease treated with L-BLP25 had improved survival (30.6 vs. 13.3 mo; p = 0.16)35, 41
       Antigen-specificTG4010MUC1 (also contains IL-2)148 treatment-naïve patients with stage IIIB/IV NSCLC received cis/gem ± TG4010TG4010 + cis/gem improved 6-mo PFS rate (44% vs. 35%; p = 0.03); patients with normal baseline levels of NK cells had improved OS in TG4010 + cis/gem group (17.1 vs. 11.3 mo)16, 36, 44, 45
       Antigen-specificMAGE-A3MAGE-A3182 patients with completely resected MAGE-A3 + stage IB/II NSCLC received adjuvant MAGE-A3 vaccine vs. placebo 2:1Trend for extending disease-free interval compared with placebo (HR = 0.74; p = 0.107); better in patients who had gene expression signature associated with high risk of relapse37
       Antigen-specificCimaVax EGFEGF80 previously treated advanced NSCLC patients randomized 1:1 to receive the vaccine or placeboDirect correlation between antibody response and decrease in serum EGF; longer survival in all vaccinated patients compared with unvaccinated; significant difference (median OS of 11.47 vs. 5.33 mo; p = 0.0124) in the group aged <60 yr38
       Tumor cellBelagenpumatucel-LFour lung cancer cell lines + TGF-β275 NSCLC patients received 1.25, 2.5, or 5 × 107 cells/injection15% response rate in advanced disease group; longer 2-yr OS in two higher doses vs. lower dose (52% vs. 20%); 18.5-mo OS for 21 patients treated at 2.5 × 107 cells/injection monthly39, 40
      cis/gem, cisplatin/gemcitabine; NSCLC, non-small cell lung cancer; EGF, epidermal growth factor; HR, hazard ratio; IL-2, interleukin-2; L-BLP25, liposomal BLP25; MUC1, mucin 1; NK, natural killer; OS, overall survival; PFS, progression-free survival; TGF, transforming growth factor.

      Antigen-Specific Vaccines

      An antigen with potential for utilization in vaccine therapy should have an expression pattern that is tumor-specific (i.e., exclusively or aberrantly expressed in the tumor), be prevalent among tumors of that type, and be found persistently throughout disease progression (i.e., expressed in early and metastatic disease). Ideally, it should also exhibit some evidence that it promotes an immune response against the tumor.
      • Bradbury PA
      • Shepherd FA
      Immunotherapy for lung cancer.
      The liposomal BLP25 vaccine (L-BLP25), Stimuvax (Merck KGaA, Darmstadt, Germany), targets the exposed core peptide of one such antigen, mucin 1 (MUC1), which is overexpressed in many malignacies,
      • Sangha R
      • Butts C
      L-BLP25: a peptide vaccine strategy in non small cell lung cancer.
      including approximately 86% of adenocarcinomas and 74% of other NSCLCs.
      • Situ D
      • Wang J
      • Ma Y
      • et al.
      Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer.
      MUC1 normally is expressed on the apical surface of mucin-secreting epithelial cells but exhibits an aberrant glycosylation pattern in tumor cells. MUC1 expression in tumor cells is associated with impaired apoptosis, immune response suppression, chemoresistance, and poor outcome. L-BLP25 vaccine is formulated in a lipid to facilitate uptake by APCs and enhance vaccine delivery to immune cells.
      L-BLP25 was evaluated in a randomized phase 2 trial in 171 patients with stage IIIB/IV NSCLC who did not progress after first-line chemotherapy.
      • Butts C
      • Murray N
      • Maksymiuk A
      • et al.
      Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.
      Patients were randomized to receive either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single low dose of cyclophosphamide 300 mg/m2 intravenously (IV), to enhance the effect of immunotherapy, as demonstrated in preclinical models, followed by eight weekly 1000 μg subcutaneous immunizations with vaccine and maintenance immunizations every 6 weeks thereafter. OS favored the vaccine-treated group (17.4 versus 13.0 months), but the difference between treatments did not reach statistical significance (hazard ratio [HR] = 0.739; p = 0.112) likely due to the sample size. However, a post hoc analysis suggested that the benefit of L-BLP25 was confined to the subset of 65 patients with stage IIIB disease. After a median follow-up of 53 months, L-BLP25 was associated with a strong and durable trend for improved survival compared with BSC alone in stage IIIB patients (30.6 versus 13.3 months; p = 0.16).
      • Sangha R
      • Butts C
      L-BLP25: a peptide vaccine strategy in non small cell lung cancer.
      On the basis of these findings, an international, randomized, phase 3 START (Stimulating Targeted Antigenic Responses To NSCLC) trial was initiated to compare L-BLP25 vaccine therapy versus placebo in patients with unresectable stage III NSCLC who did not progress after sequential or concurrent chemoradiotherapy (clinicaltrials.gov identifier NCT00409188). Planned accrual is 1476 patients, with OS evaluated as the primary end point. Screening for accrual was completed in June 2011.
      TG4010, another vaccine that targets MUC1, is a recombinant viral vector based on the modified virus of Ankara that expresses the entire MUC1 sequence and interleukin-2 (IL-2).
      • Ramlau R
      • Quoix E
      • Rolski J
      • et al.
      A phase II study of TG4010 (MVA-Muc1-IL2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer.
      IL-2 is included to stimulate T-cell responses, and therefore, this vaccine has the potential to stimulate or augment cellular responses directed against MUC1-expressing tumor cells.
      TG4010 was evaluated in a randomized phase 2b trial in 148 previously untreated patients with stage IIIB/IV NSCLC.
      • Gridelli C
      • Rossi A
      • Maione P
      • et al.
      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      • Ramlau R
      • Westeel V
      • Papai Z
      • et al.
      Randomized phase IIb trial evaluating the therapeutic vaccine TG4010 (MVA-MUC1-IL2) as an adjunct to chemotherapy in patients with advanced non-small cell lung cancer.
      Patients were randomly allocated to receive first-line cisplatin/gemcitabine chemotherapy with or without TG4010. The vaccine was administered subcutaneously each week for the first 6 weeks and then every 3 weeks until disease progression. Addition of TG4010 significantly improved the primary end point of 6-month progression-free survival (PFS) rate compared with chemotherapy alone (44% versus 35%; p = 0.03). Median OS did not differ significantly between groups; however, in the subset of patients who had normal blood levels of activated natural killer (NK) cells at baseline (approximately 75% of the study cohort), addition of TG4010 led to an improvement in OS (17.1 versus 11.3 months).

      Quoix E, Westeel V, Papai Z, et al. TG4010.09: randomized, controlled, phase IIb trial evaluating the therapeutic vaccine TG4010 (MVA-MUC1-IL2) as an adjunct to chemotherapy in patients with advanced non-small cell lung cancer. Presented at the European Society of Medical Oncology Annual Meeting, September 12–16, 2008, Stockholm, Sweden. Abstract 234PD.

      • Transgene SA
      Transgene confirms longer survival for patients treated with Tg4010 in its ongoing phase IIb non-small cell lung cancer trial [press release]. February 17, 2009.
      Side effects related to TG4010 most commonly included injection site reactions, fever, and abdominal pain. A phase 2b/3 trial is evaluating TG4010 in MUC1-positive NSCLC patients with normal baseline levels of activated NK cells (clinicaltrials.gov identifier NCT00415818).
      An epidermal growth factor (EGF)-based vaccine (CimaVax EGF) has been developed and licensed in Cuba for use in adult patients with stage IIIB/IV NSCLC. Since 1995, CimaVax EGF has undergone five phase 1/2 and one phase 2 clinical trials (reviewed in the article by Rodriguez et al.).
      • Rodríguez PC
      • Rodríguez G
      • González G
      • et al.
      Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.
      The phase 1/2 studies confirmed immunogenicity of the vaccine and helped to determine dose, injection sites, adjuvant, and combinability with chemotherapy. The phase 2 clinical trial, in which 80 advanced NSCLC patients previously treated with first-line chemotherapy randomized 1:1 to receive the vaccine, demonstrated a direct correlation between antibody response and decrease in serum EGF. Longer survival was observed in all vaccinated patients compared with randomized unvaccinated controls, and the difference was significant (p = 0.0124) in the group aged younger than 60 years (median OS of 11.47 months in those vaccinated compared with 5.33 months in controls). Side effects were of grade ≤2 in severity and occurred in less than 25% of all patients.
      • Neninger Vinageras E
      • de la Torre A
      • Osorio Rodríguez M
      • et al.
      Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer.
      A phase 3 clinical trial has been underway since June 2006 at 18 clinical research sites throughout the country. This study is planned to recruit 579 advanced-stage (IIIB/IV) NSCLC patients, with a 1:2 randomization (one control patient for each two treated patients). Results will be evaluated in two-patient strata: age older than 60 years (n = 381) and age 60 years or younger (n =198). Preliminary results from 160 patients show numerical differences in 24-month survival rates, but statistical significance of these differences has not yet been confirmed.
      • Rodríguez PC
      • Rodríguez G
      • González G
      • et al.
      Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.
      In addition, an international phase 3 clinical trial of CimaVax EGF opened to accrual in late 2010.
      Melanoma-associated antigen 3 (MAGE-A3) is the antigenic target for another vaccine that is being evaluated in the adjuvant setting after surgical resection of early-stage NSCLC. MAGE-A3, a peptide on the human leukocyte antigen-A1 molecule recognized by cytotoxic T cells, is expressed almost exclusively on tumor cells. MAGE-A3 expression occurs at higher rates in squamous cell carcinomas than in adenocarcinomas and is thought to be associated with a poor prognosis.
      • Sienel W
      • Varwerk C
      • Linder A
      • et al.
      Melanoma-associated antigen (MAGE)-A3 expression in stages I and II non-small cell lung cancer: results of a multi-center study.
      • Brichard VG
      • Lejeune D
      GSK's antigen-specific cancer immunotherapy programme: pilot results leading to phase III clinical development.
      • Grah J
      • Samija M
      • Juretic A
      • et al.
      Immunohystochemical expression of cancer/testis antigens (MAGE-A3/4, NY-ESO-1) in non-small cell lung cancer: the relationship with clinical-pathological features.
      • Vansteenkiste JF
      • Zielinski M
      • Dahabreh IJ
      • et al.
      Association of gene expression signature and clinical efficacy of MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) as adjuvant therapy in resected stage IB/II non-small cell lung cancer.
      In an international, randomized phase 2 trial, 182 patients with completely resected MAGE-A3-positive stage IB/II NSCLC were assigned in a 2:1 ratio to adjuvant therapy with a MAGE-A3 vaccine or placebo. The vaccine demonstrated a trend toward a longer disease-free interval compared with placebo (HR = 0.74; p = 0.107), with similar nonsignificant improvements in disease-free survival and OS.
      • Vansteenkiste J
      • Zielinski M
      • Linder A
      • et al.
      Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC).
      The clinical efficacy (disease-free interval) of the MAGE-A3 vaccine was nearly doubled (HR = 0.57) among patients with a gene expression signature possibly associated with a high risk of relapse.
      • Vansteenkiste JF
      • Zielinski M
      • Dahabreh IJ
      • et al.
      Association of gene expression signature and clinical efficacy of MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) as adjuvant therapy in resected stage IB/II non-small cell lung cancer.
      This signature consisted of immune-related genes relevant to the tumor microenvironment at baseline.
      • Tyagi P
      • Mirakhur B
      MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy.
      The regimen was well tolerated, and compliance with the trial protocol was high.
      • Vansteenkiste J
      • Zielinski M
      • Linder A
      • et al.
      Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC).
      The phase 3 MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell Lung Cancer Immunotherapy trial; clinicaltrials.gov identifier NCT00480025) was initiated based on these promising phase 2 data. The study plans to enroll 2270 patients with resected MAGE-A3-positive stage IB, II, or IIIA NSCLC in 33 countries, making it the largest study of adjuvant immune therapy in NSCLC conducted to date.
      • Tyagi P
      • Mirakhur B
      MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy.
      Patients are being randomized in a 2:1 ratio to the MAGE-A3 vaccine or placebo, with treatment delivered as 13 intramuscular injections over a 27-month period. Disease-free survival is the primary end point, and validation studies of the gene expression signature are planned. Study completion is expected by 2015. The signature will be validated in this trial using techniques that can be applied to formalin-fixed paraffin-embedded samples.
      Another antigen-specific vaccine strategy in development for lung cancer targets gangliosides, a broad family of structurally related glycolipids located in the outer leaflet of the cell surface that are involved in numerous biologic functions including cell-cell recognition, cell matrix attachment, and differentiation. Gangliosides are thought to be good targets for cancer immunotherapy because they are found in higher abundance in tumors when compared with the matched normal tissues. In lung cancer, this strategy was first tested in SCLC patients with a vaccine against BEC2, an anti-idiotypic antibody that mimics the ganglioside antigen GD3. In a small pilot study, prolonged survival was observed in 15 patients with SCLC vaccinated with Bec2 and given in combination with bacille Calmette-Guerin, the main toxicity being skin reaction at the injection site that are generally mild but can be quite severe.
      • Grant SC
      • Kris MG
      • Houghton AN
      • et al.
      Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin.
      Despite these promising initial results, a large phase 3 trial failed to show an improvement in OS with this therapy.
      • Giaccone G
      • Debruyne C
      • Felip E
      • et al.
      Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971–08971B; Silva Study).
      Data from preclinical studies in mice demonstrated the antitumor effect of anti-N-glycolyl (NGc) ganglioside anti-idiotype monoclonal antibody racotumomab (formerly known as 1E10) when used as a monotherapy (reviewed in the article by Fernandez et al.)
      • Fernandez LE
      • Gabri MR
      • Guthmann MD
      • et al.
      NGcGM3 ganglioside: a privileged target for cancer vaccines.
      or as a combination therapy with chemotherapy (low-dose cyclophosphamide).
      • Fuentes D
      • Avellanet J
      • Garcia A
      • et al.
      Combined therapeutic effect of a monoclonal anti-idiotype tumor vaccine against NeuGc-containing gangliosides with chemotherapy in a breast carcinoma model.
      Provided this rationale for the use of chemoimmunotherapy in solid cancers, this strategy is being evaluated in studies with NSCLC patients. First, a small study of 20 NSCLC patients was conducted, in which treatment with 1 mg of aluminum hydroxide-precipitated 1E10 monoclonal antibody resulted in a strong, specific antibody response of both immunoglobulin (Ig)M and IgG isotypes against NeuGcGM3 ganglioside; this response correlated with longer median survival times.
      • Hernández AM
      • Toledo D
      • Martínez D
      • et al.
      Characterization of the antibody response against NeuGcGM3 ganglioside elicited in non-small cell lung cancer patients immunized with an anti-idiotype antibody.
      The vaccine seems to be well tolerated. Second, a randomized phase 2 study with racotumomab versus supportive care in 30 patients with advanced NSCLC has been initiated and is expected to be completed in September 2012 (clinicaltrials.gov identifier NCT01240447). In addition, a randomized phase 3 study with racotumomab versus supportive care is underway as of January 2009 and is seeking to enroll 1082 patients with advanced NSCLC. The primary end point of this trial is OS of the entire population and of the subgroup of patients with IIIA or “dry” IIIB disease (controlled-trials.com ISRCTN47153584).

      Tumor Cell Vaccines

      Vaccines prepared from tumor cells theoretically have the potential to expose the patient's immune system to a wide range of tumor cell antigens.
      • Bradbury PA
      • Shepherd FA
      Immunotherapy for lung cancer.
      Sipuleucel-T, the only Food and Drug Administration-approved therapeutic cancer vaccine, provides proof of concept for this immunotherapeutic approach. This agent is an autologous tumor cell vaccine, which was shown to improve survival significantly in patients with castration-resistant prostate cancer.
      • Kantoff PW
      • Higano CS
      • Shore ND
      • et al.
      Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
      From a practical and logistical perspective, allogeneic vaccines prepared from cancer cell lines may be preferable to autologous vaccines prepared from the patient's own tumor cells. However, the antigens present in the allogeneic vaccines are not necessarily expressed on a given patient's tumor.
      Belagenpumatucel-L is the only tumor cell vaccine currently undergoing phase 3 testing in lung cancer. This allogeneic vaccine is derived from four lung cancer cell lines, including two adenocarcinomas, one squamous cell carcinoma, and one large cell carcinoma, which were transfected with a plasmid containing a transforming growth factor (TGF)-β2 antisense transgene.
      • Nemunaitis J
      • Dillman RO
      • Schwarzenberger PO
      • et al.
      Phase II study of belagenpumatucel-L, a transforming factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer.
      The expression of antisense mRNA against TGF-β2 is designed to reduce production of this cytokine, thereby enhancing the immunogenicity of the vaccine.
      In a phase 2 trial, 75 NSCLC patients, including 61 with previously treated stage IIIB/IV disease, received intradermal immunization with one of three doses (1.25, 2.5, or 5 × 107 cells/injection) every 1 or 2 months up to a maximum of 16 injections.
      • Nemunaitis J
      • Dillman RO
      • Schwarzenberger PO
      • et al.
      Phase II study of belagenpumatucel-L, a transforming factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer.
      Fifteen percent of patients in the advanced disease cohort had partial responses. Survival was longer in the patients receiving the two higher doses than in the low-dose group (2-year OS: 52% versus 20%). In a subsequent study, median survival was 18.5 months for a cohort of 21 stage IV NSCLC patients treated with belagenpumatucel-L at a dose of 2.5 × 107 cells/injection monthly, with no significant side effects reported.
      • Nemunaitis J
      • Dillman RO
      • Schwarzenberger PO
      • et al.
      Phase II study of belagenpumatucel-L, a transforming factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer.
      • Nemunaitis J
      • Nemunaitis M
      • Senzer N
      • et al.
      Phase II trials of belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients.
      In this latter study, longer survival with belagenpumatucel-L was associated with a low level of circulating tumor cells.
      These findings led to the ongoing phase 3 trial, in which belagenpumatucel-L is being evaluated as maintenance therapy after first-line chemotherapy/chemoradiotherapy in patients with stage III or IV NSCLC. Patients who achieve complete or partial response or stable disease and who remain stable for 1 month after stopping chemotherapy are randomized to belagenpumatucel-L or placebo once monthly for 18 months, with additional immunizations at 21 and 24 months. The primary end point is OS, with planned accrual of 700 patients. Completion of the study is expected in 2011 (clinicaltrials.gov identifier NCT00676507).

      Dendritic Cell Vaccines (DC-Vacs)

      DC-Vacs are designed to boost the immunogenicity of tumor-associated antigens. In this approach, autologous dendritic cells are cultured with necrotic lung cancer cells to allow processing of the tumor antigens, and subsequently the antigen-loaded dendritic cells were injected either intradermally or into the patient's inguinal lymph nodes. Pilot studies suggest that this approach is feasible and tolerable in patients with NSCLC,
      • Hirschowitz EA
      • Foody T
      • Kryscio R
      • et al.
      Autologous dendritic cell vaccines for non-small-cell lung cancer.
      • Hirschowitz EA
      • Foody T
      • Hidalgo GE
      • et al.
      Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells.
      • Chang GC
      • Lan HC
      • Juang SH
      • et al.
      A pilot clinical trial of vaccination with dendritic cells pulsed with autologous tumor cells derived from malignant pleural effusion in patients with late-stage carcinoma.
      and further research is ongoing (clinicaltrials.gov identifier NCT00103116). A recent small phase 1 study of a new DC-Vac, into which tumor lysate was loaded by electroporation, has been reported. Fifteen patients with inoperable stage III or IV NSCLC received 3, 6, or 12 × 106 DC-Vac intradermally three times at 2-week intervals. The maximum dose of DC-Vac was shown to be well tolerated. In five of nine patients, the vaccine resulted in increased interferon-γ production by CD8+ cells after exposure to tumor lysate. In addition, there were mixed responses that demonstrate some clinical benefit in two patients.
      • Um SJ
      • Choi YJ
      • Shin HJ
      • et al.
      Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer.
      Taken together, these data suggest that antigen-specific and tumor cell vaccines are promising immunotherapeutics for NSCLC, but phase 3 data are needed to ascertain whether these interventions improve patient outcome, and if so, in which treatment setting(s).

      ANTIGEN-INDEPENDENT IMMUNOTHERAPY

      Vaccine therapy depends on the ability of specific antigens to trigger an immune response, while other immunotherapeutic approaches act on steps after the immune system already has been stimulated. Accordingly, these latter approaches should be effective regardless of which tumor antigen actually stimulates the immune response.
      • Fong L
      • Small EJ
      Anti-cytotoxic T-lymphocyte antigen-antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.

      Anti-CTLA-4 Monoclonal Antibodies

      Monoclonal antibodies against CTLA-4 are designed to enhance and prolong the activation and proliferation of tumor-specific T cells by blocking the inhibitory signal provided by CTLA-4, thereby allowing development of an effective immune response against the tumor
      • Fong L
      • Small EJ
      Anti-cytotoxic T-lymphocyte antigen-antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
      • Tarhini AA
      • Iqbal F
      CTLA-4 blockade: therapeutic potential in cancer treatment.
      (Figure 2).
      • Fong L
      • Small EJ
      Anti-cytotoxic T-lymphocyte antigen-antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
      Because these agents target the immune system itself, they are not dependent on a specific tumor antigen or antigenic profile. Moreover, they are potentially useful across lung cancer subtypes and molecular phenotypes, including those having particularly high unmet need.
      Figure thumbnail gr2
      FIGURE 2Mechanism of action of anti-CTLA-4.
      • Fong L
      • Small EJ
      Anti-cytotoxic T-lymphocyte antigen-antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
      APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor. A, co-stimulation via CD28 ligation transduces T-cell activating signals; B, CTLA-4 ligation on activated T cells downregulates T-cell responses; and C, blocking CTLA-4 ligation enhances T-cell responses.
      Ipilimumab is a humanized IgG1 anti-CTLA-4 monoclonal antibody that is undergoing evaluation in lung cancer patients. In a recent phase 3 clinical study, ipilimumab administered with or without a glycoprotein 100 (gp100) peptide vaccine resulted in improved survival of previously treated patients with unresectable metastatic melanoma over gp100 alone, with drug-related side effects, such as diarrhea, colitis, pruritis, rash, and fatigue, which were managed by protocol-defined guidelines.
      • Hodi FS
      • O'Day SJ
      • McDermott DF
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      After approval of ipilimumab in the United States, a Risk Evaluation and Mitigation Strategy is available to further inform oncologists of serious immune-mediated adverse reactions (imARs) that may be associated with the agent.
      • Yervoy™ US Prescribing Information
      Risk Evaluation and Mitigation Strategy. Bristol-Myers Squibb 2011.
      These findings are noteworthy in that ipilimumab is the first agent to provide a statistically significant improvement in OS in this patient population, and in March 2011, the US Food and Drug Administration subsequently approved ipilimumab for this indication.
      Preclinical evidence suggests that chemotherapy may complement the activity of anti-CTLA-4 monoclonal antibodies, presumably via release of tumor antigens following chemotherapy-induced cytotoxicity.
      • Jure-Kunkel MN
      • Masters G
      • Girit E
      • et al.
      Antitumor activity of an anti-CTLA-4 monoclonal antibody (mAb) in combination with ixabepilone in preclinical tumor models.
      This observation suggests that administering an anti-CTLA-4 monoclonal antibody in combination with chemotherapy may improve antitumor responses—consistent with the approach being taken with several vaccines.
      The safety and efficacy of ipilimumab in lung cancer was demonstrated in a randomized, double-blind, phase 2 trial in which patients with stage IIIB/IV NSCLC or extensive-stage SCLC received paclitaxel/carboplatin with or without ipilimumab.

      Lynch T, Neal J, Bondarenko I, et al. Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIB/IV non-small cell lung cancer (NSCLC). Presented at the 35th European Society for Medical Oncology, October 8–12, 2010, Milan, Italy. Abstract 375PD.

      A total of 204 patients were randomized to receive one of three treatment arms: ipilimumab 10 mg/kg IV administered concurrently with the first four cycles of paclitaxel/carboplatin (concurrent schedule), ipilimumab 10 mg/kg IV administered in cycles 3–6 of paclitaxel/carboplatin (phased schedule), or paclitaxel/carboplatin alone. After completion of six cycles of paclitaxel/carboplatin, maintenance therapy with ipilimumab or placebo was administered every 12 weeks based on the initial treatment allocation. The primary end point was immune-related PFS (irPFS), which is the PFS based on assessments made using immune-related response criteria (irRC), which are novel response criteria that were developed and standardized to characterize the observed patterns of response to ipilimumab (see Table 2

      Lynch T, Neal J, Bondarenko I, et al. Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIB/IV non-small cell lung cancer (NSCLC). Presented at the 35th European Society for Medical Oncology, October 8–12, 2010, Milan, Italy. Abstract 375PD.

      • Wolchok JD
      • Hoos A
      • O'Day S
      • et al.
      Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
      for further explanation).
      TABLE 2Effect of Ipilimumab on Outcomes in Patients with Advanced NSCLC65
      Treatment Arm
      Ipilimumab + Pax/Carbo (Concurrent)Ipilimumab + Pax/Carbo (Phased)Pax/Carbo
       ir
      Immune-related response criteria include evaluation of both index lesions and measurable new lesions.66 The sum of the products of the two largest perpendicular diameters (SPD) of all index lesions are calculated at baseline, whereas the SPD of the index lesions and new measurable lesions are calculated at subsequent tumor assessments, and then summed to define the tumor burden. According to immune-related response criteria, complete response reflects the disappearance of all lesions in two consecutive assessments made ≥4 wk apart; partial response reflects a ≥50% decrease in tumor burden from baseline in two assessments made ≥4 wk apart; and stable disease reflects cases where the criteria for partial response cannot be met nor is there a 25% increase in tumor burden compared with its nadir.
      PFS (mo)
      5.55.74.6
       mWHO
      Modified World Health Organization defines complete response as disappearance of all index/nonindex lesions; partial response as ≥50% reduction in the sum of products of diameters (SOPD) of index lesions compared with the baseline SOPD, with no evidence of progression; progressive disease as ≥25% increase in SOPD of lesions compared with smallest SOPD recorded for study period or progression of any nonindex lesion/appearance of new lesion. To qualify as complete response or partial response, no new lesions could be present.
      PFS (mo)
      4.15.14.2
       Median OS (mo)9.712.28.3
      a Immune-related response criteria include evaluation of both index lesions and measurable new lesions.66 The sum of the products of the two largest perpendicular diameters (SPD) of all index lesions are calculated at baseline, whereas the SPD of the index lesions and new measurable lesions are calculated at subsequent tumor assessments, and then summed to define the tumor burden. According to immune-related response criteria, complete response reflects the disappearance of all lesions in two consecutive assessments made ≥4 wk apart; partial response reflects a ≥50% decrease in tumor burden from baseline in two assessments made ≥4 wk apart; and stable disease reflects cases where the criteria for partial response cannot be met nor is there a 25% increase in tumor burden compared with its nadir.
      b Modified World Health Organization defines complete response as disappearance of all index/nonindex lesions; partial response as ≥50% reduction in the sum of products of diameters (SOPD) of index lesions compared with the baseline SOPD, with no evidence of progression; progressive disease as ≥25% increase in SOPD of lesions compared with smallest SOPD recorded for study period or progression of any nonindex lesion/appearance of new lesion. To qualify as complete response or partial response, no new lesions could be present.
      Data for the cohort with advanced NSCLC show that ipilimumab administered in the phased schedule significantly extended irPFS compared with chemotherapy alone (5.68 versus 4.63 months; HR = 0.686; p = 0.026), whereas the concurrent schedule showed only a trend for longer irPFS (5.52 versus 4.63 months; HR = 0.775; p = 0.094).

      Lynch T, Neal J, Bondarenko I, et al. Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIB/IV non-small cell lung cancer (NSCLC). Presented at the 35th European Society for Medical Oncology, October 8–12, 2010, Milan, Italy. Abstract 375PD.

      The phased schedule also prolonged PFS when measured using modified World Health Organization criteria (Table 2). Median OS was 12.2 months with the phased schedule, 9.69 months with the concurrent schedule, and 8.28 months with chemotherapy alone. Overall response rate, whether measured by immune-related response or modified WHO criteria, favored the phased ipilimumab group.
      Patients in both ipilimumab groups received a median of 4 doses of the monoclonal antibody but tended to receive fewer cycles of chemotherapy. Paclitaxel/carboplatin was administered for a median of 6 cycles in the control group compared with 5 cycles in the phased ipilimumab group and 4 cycles in the concurrent ipilimumab group. The safety profile of ipilimumab was consistent with previous studies of the monoclonal antibody in other solid tumors, and ipilimumab did not appear to potentiate the toxicity associated with paclitaxel/carboplatin. Side effects, which occurred in 66% of patients receiving ipilimumab and 55% of those receiving chemotherapy alone, most commonly included diarrhea, colitis, pruritus, rash, and elevations in ALT/AST (alanine aminotransferase/aspartate aminotransferase) levels.

      Lynch T, Neal J, Bondarenko I, et al. Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIB/IV non-small cell lung cancer (NSCLC). Presented at the 35th European Society for Medical Oncology, October 8–12, 2010, Milan, Italy. Abstract 375PD.

      These safety results were consistent with previous results from other ipilimumab trials.

      Lynch T, Neal J, Bondarenko I, et al. Phase 2 trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIB/IV non-small cell lung cancer (NSCLC). Presented at the 35th European Society for Medical Oncology, October 8–12, 2010, Milan, Italy. Abstract 375PD.

      The clinical experience with ipilimumab in melanoma suggests that severe and fatal imARs may arise due to the drug's mechanism of action; however, side effects are generally manageable using product-specific treatment guidelines, which include criteria for early diagnosis and guidance for use of high-dose corticosteroids for severe events that may affect the gastrointestinal tract, skin, liver, and endocrine system.
      • Yervoy™ US Prescribing Information
      Risk Evaluation and Mitigation Strategy. Bristol-Myers Squibb 2011.

      Chin K, Ibrahim R, Berman D, et al. Treatment guidelines for the management of immune-related adverse events in patients treated with ipilimumab. Paper presented at the joint meeting of the 7th World Congress on Melanoma and 5th Congress of the European Association of Dermato-Oncology, May 12–16, 2009, Vienna, Austria. Abstract 787P.

      Early reporting of symptoms by patients and diligent adherence to these guidelines
      • Yervoy™ US Prescribing Information
      Risk Evaluation and Mitigation Strategy. Bristol-Myers Squibb 2011.
      by medically trained professionals have been shown to reduce the risk for life-threatening complications.

      Chin K, Ibrahim R, Berman D, et al. Treatment guidelines for the management of immune-related adverse events in patients treated with ipilimumab. Paper presented at the joint meeting of the 7th World Congress on Melanoma and 5th Congress of the European Association of Dermato-Oncology, May 12–16, 2009, Vienna, Austria. Abstract 787P.

      • Hoos A
      • Ibrahim R
      • Korman A
      • et al.
      Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.
      On the basis of these results, a randomized, multicenter, double-blind phase 3 trial (CA184-104) is planned to compare ipilimumab plus paclitaxel/carboplatin versus placebo plus paclitaxel/carboplatin in patients with stage IV or recurrent NSCLC with squamous cell histology. The phased schedule of ipilimumab, in which treatment is administered starting in cycle 3 of chemotherapy, will be used, with eligible subjects continuing to receive maintenance therapy every 12 weeks after completing chemotherapy. The primary objective of the study is to compare OS between treatments (clinicaltrials.gov identifier NCT01285609).

      Talactoferrin Alfa

      Talactoferrin alfa is a recombinant human lactoferrin that differs from the native protein purified from human breast milk by the nature of its glycosylation pattern.
      • Hayes TG
      • Falchook GF
      • Varadhachary GR
      • et al.
      Phase I trial of oral talactoferrin alfa in refractory solid tumors.
      This orally active agent has immunomodulatory properties, which can promote both innate and adaptive immunity against tumor cells.
      • de la Rosa G
      • Yang D
      • Tewary P
      • et al.
      Lactoferrin acts as an alarmin to promote recruitment and activation of APCs and antigen-specific immune responses.
      For example, talactoferrin alfa induces movement of immune cells, including dendritic cells into the gut-associated lymphoid tissue where it stimulates their maturation. This leads to increased levels of dendritic cells bearing tumor antigens. In addition, talactoferrin alfa increases production of cytokines that promote maturation and proliferation of antitumor CD8+ T cells and NK cells.
      Talactoferrin alfa was evaluated in two randomized phase 2 trials in advanced NSCLC performed in India. In the first trial, 1.5 g talactoferrin alfa or placebo was administered orally twice daily for 12 consecutive weeks of a 14-week cycle to 110 stage IIIB/IV patients who had previously failed one or two lines of chemotherapy.
      • Kelly RJ
      • Gulley JL
      • Giaccone G
      Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
      • Parikh PK
      • Wang Y
      • Ranade AA
      • et al.
      Oral talactoferrin extends survival in patients with refractory NSCLC in a randomized, placebo-controlled phase 2 trial.
      Talactoferrin alfa significantly improved median OS compared with placebo (6.0 versus 3.7 months; HR = 0.69; p < 0.05) and also showed a trend for prolonging PFS. Talactoferrin alfa was well tolerated, with the incidence of side effects and grade 3/4 side effects similar in both treatment arms.
      In the second study, talactoferrin alfa or placebo was administered orally in combination with IV paclitaxel/carboplatin to 110 previously untreated patients with stage IIIB/IV NSCLC.
      • Wang Y
      • Raghunadharao D
      • Raman G
      • et al.
      Adding oral talactoferrin to first-line NSCLC chemotherapy safely enhanced efficacy in a randomized trial.
      Talactoferrin alfa was administered at a dose of 1.5 g twice daily for 35 days, postchemotherapy in cycles 1, 3, and 5. The addition of talactoferrin to first-line paclitaxel/carboplatin showed trends for increasing the objective response rate (42% versus 27%; p = 0.08) and prolonging median OS (10.4 versus 8.5 months).
      • Kelly RJ
      • Gulley JL
      • Giaccone G
      Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
      • Wang Y
      • Raghunadharao D
      • Raman G
      • et al.
      Adding oral talactoferrin to first-line NSCLC chemotherapy safely enhanced efficacy in a randomized trial.
      Talactoferrin alfa was well tolerated, with fewer side effects and grade 3/4 side effects than seen in the control arm.
      Most patients in these studies were of Indian decent, and therefore it remains to be determined whether these findings are applicable to other races/ethnicities. To address this issue, talactoferrin alfa is currently being evaluated in two randomized, placebo-controlled phase 3 clinical trials, known as FORTIS-M and FORTIS-C. FORTIS-M compares talactoferrin alfa versus placebo in 720 patients with stage IIIB/IV NSCLC who have failed at least two prior systemic anticancer regimens for advanced disease. OS is the primary end point, with study completion expected in 2011 (clinicaltrials.gov identifier NCT00707304). FORTIS-C compares talactoferrin alfa versus placebo, each in combination with first-line paclitaxel/carboplatin in 1100 patients with advanced NSCLC. OS and PFS are being evaluated as coprimary end points, with study completion expected in 2013 (clinicaltrials.gov identifier NCT00706862). In both studies, talactoferrin alfa is being administered at a dose of 1.5 g twice daily based on the phase 2 experience.

      Toll-Like Receptor 9 Agonists

      Toll-like receptors (TLRs) are a family of receptors that recognize pathogen-associated molecular patterns to regulate antigen-specific innate immunity. TLR9 is a member of this family, which is expressed on dendritic cells, T and B lymphocytes, and plasmacytoid cells. Synthetic oligodeoxynucleotides with unmethylated cytosine-guanine motifs are capable of activating TLR9 to reduce immune tolerance and improve tumor antigen recognition and tumor cell death.
      • Gridelli C
      • Rossi A
      • Maione P
      • et al.
      Vaccines for the treatment of non-small cell lung cancer: a renewed anti-cancer strategy.
      • Kelly RJ
      • Gulley JL
      • Giaccone G
      Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
      • Murad YM
      • Clay TM
      CpG oligodeoxynucleotides as TLR9 agonists.
      The TLR9 agonist PF-3512676 administered at a dose of 0.2 mg/kg subcutaneously on days 8 and 15 in combination with first-line paclitaxel/carboplatin given every 3 weeks showed a trend for improved median OS in a randomized phase 2 trial (12.3 versus 6.8 months, HR = 0.747; p = 0.188).
      • Manegold C
      • Gravenor D
      • Woytowitz D
      • et al.
      Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer.
      Two international phase 3 trials were initiated to evaluate PF-3512676 in combination with first-line paclitaxel/carboplatin and gemcitabine/cisplatin, respectively; however, both were terminated when an interim analysis showed no added benefit relative to chemotherapy alone.
      • Manegold C
      Randomized phase III trial of gemcitabine/cisplatin with or without PF-3512676 as first line treatment of advanced non-small cell lung cancer (NSCLC).
      • Hirsh V
      • Boyer M
      • Rosell R
      • et al.
      Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 as first line treatment of advanced non-small cell lung cancer (NSCLC).
      Other TLR9 agonists, such as IMO-2055, are in early development for NSCLC.

      Antibody-Dependent Cellular Cytotoxicity

      Antibody-dependent cellular cytotoxicity (ADCC) is a process by which IgG1 antibodies bind to and coat the surface of cells expressing a corresponding antigen, which recruits NK cells to mediate lysis of the antibody-coated cell.
      • Abbas AK
      • Lichtman AH
      • Pober JS
      Several tactics thought to employ ADCC are currently used in many tumor types. There is some evidence to suggest that the anti-EGFR IgG1 monoclonal antibody cetuximab, approved for squamous cell carcinoma of the head and neck and colorectal cancer and under investigation in lung cancer, may operate at least in part through ADCC.
      • Kurai J
      • Chikumi H
      • Hashimoto K
      • et al.
      Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.
      • López-Albaitero A
      • Lee SC
      • Morgan S
      • et al.
      Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells.
      It is important to note that ADCC has yet to be proven in vivo; therefore, the extent to which ADCC contributes to clinical tumor immunogenicity is not understood completely. Within cancer patients, particularly those receiving chemotherapy, there exists an immunosuppressive environment characterized by T cells and NK cells that may be impaired in both number and function, in which ADCC activity may be compromised.
      • Ottaiano A
      • Scala S
      • Iaffaioli VR
      Cetuximab-dependent ADCC in cancer: dream or reality?.
      • Kono K
      • Takahashi A
      • Ichihara F
      • et al.
      Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer.
      However, additional preclinical study has called this idea into question.
      • Kurai J
      • Chikumi H
      • Hashimoto K
      • et al.
      Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.
      Some preclinical data suggest that ADCC-mediated and chemotherapy-mediated tumor cell death may even be immunogenic, i.e., they “release” tumor antigens for presentation to T cells, thereby enhancing antigen-specific immune responses to the tumor.
      • Ménard C
      • Martin F
      • Apetoh L
      • et al.
      Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity.
      • Moschella F
      • Proietti E
      • Capone I
      • et al.
      Combination strategies for enhancing the efficacy of immunotherapy in cancer patients.
      • Palena C
      • Schlom J
      Vaccines against human carcinomas: strategies to improve antitumor immune responses.

      Schettini J, Tinder T, Subramani D, et al. Antitumor activity of NK cells is locally enhanced by CpG conjugated to a tumor specific monoclonal antibody. Presented at the 99th Annual American Association of Cancer Research Meeting, April 12–16, 2008, San Diego, CA. Abstract 3805.

      Therefore, through the process of ADCC, it is possible that therapies such as cetuximab may act to prime the immune system even though they do not have a direct immune-related mechanism of action.

      CONCLUSIONS

      Although lung cancer generally is not considered to be an immunogenic malignancy, accumulating evidence suggests that enhancing antitumor immune responses may be important for improving patient outcome, including survival in subsets with high unmet medical need, such as squamous cell carcinomas and extensive-stage SCLC. Two general immunotherapy approaches have been taken, namely vaccine therapy designed to enhance antigen-stimulated immune responses and antigen-independent immunomodulatory approaches designed to reduce tumor tolerance and augment activated antitumor immune responses.
      Both approaches have satisfied initial hurdles of efficacy and safety in randomized phase 2 trials and are now being evaluated in ongoing phase 3 trials designed to document improved outcomes relative to existing standards of care (Table 3). As results of these phase 3 trials become available, immunotherapy will likely be integrated into existing treatment guidelines regardless of tumor histology and be applicable to a large percentage of the lung cancer population regardless of molecular marker status.
      TABLE 3Summary of Ongoing Phase 3 Immunotherapy Trials in NSCLC
       IdentifierTreatment ArmsStudy DesignPlanned AccrualPrimary End PointEstimated Completion
       NCT00409188L-BLP25 vs. placeboRandomized phase 3 trial in patients with unresectable stage III NSCLC1476OS2011
       NCT00415818TG4010Phase 2b/3 trial in MUC1 + NSCLC patients with normal baseline NK levelsN/AN/AN/A
      • NCT00480025
      • (MAGRIT)
      MAGE-A3 vs. placeboPhase 3 trial in patients with resected MAGE-A3 + stage IB, II, or IIIA NSCLC randomized 2:1 (vaccine:control)2270Disease-free survival2015
       N/ACimaVax EGF vs. placeboPhase 2 trial in patients with advanced stage (IIIB/IV) NSCLC patients randomized 2.1 (vaccine: control)579Survival evaluated in two-patient strata: aged >60 yr (n = 381) and aged ≤60 yr (n = 198)N/A
      Racotumomab vs. support treatmentPhase 3 study in patients with advanced NSCLC30Safety and immunogenicity2012
       NCT00676507Belagenpumatucel-L vs. placeboRandomized phase 3 trial in patients with stage III/IV NSCLC as maintenance following first-line chemotherapy/chemoradiotherapy700OS2011
       NCT01285609Ipilimumab + pax/carbo vs. pax/carboRandomized phase 3 trial in patients with stage IV or recurrent NSCLC with squamous cell histologyN/AOSN/A
      • NCT00707304
      • (FORTIS-M)
      Talactoferrin alfa vs. placeboRandomized phase 3 trial in patients with stage IIIB/IV NSCLC who had failed ≥2 prior systemic anticancer regimens for advanced disease720OS2011
      • NCT00706862
      • (FORTIS-C)
      Talactoferrin alfa vs. placebo each in combination with first-line pax/carboRandomized phase 3 trial in patients with advanced NSCLC1100OS and PFS2013
      EGF, epidermal growth factor; MAGRIT, MAGE-A3 as Adjuvant Non-Small Cell Lung Cancer Immunotherapy; MUC1, mucin 1; N/A, not available; NK, natural killer; NSCLC, non-small cell lung cancer; OS, overall survival; pax/carbo, paclitaxel/carboplatin; PFS, progression-free survival.
      To maximize the effect on immunotherapy in patients with lung cancer, it will be crucial to determine the patient population that will benefit from each type of therapy. Identifying biomarkers and further elucidating the mechanisms of these treatment strategies will contribute to our understanding and help with patient selection.
      Another important question to address is the timing of immunotherapy and whether to combine immunotherapy with other treatments, such as chemotherapy and radiation. It likely will be more beneficial to use immunotherapy as an early adjuvant treatment before the tumor develops ways to evade the immune system. Although chemotherapy alone has traditionally resulted in poor outcomes for lung cancer patients, the combination of chemotherapy and immunotherapy may have a synergistic effect. Finding the right doses, regimens, and sequences that maximize efficacy while minimizing toxicity will require careful research.
      Clinical trials need to be designed to measure immune response reliably and to correlate it with the outcome. Unlike chemotherapy, immunotherapy requires time for the immune system to mount a response to the tumor, and trials need to allow for immune response before measuring antitumor response. While extensive work has produced irRC to define the unique patterns of response to immunotherapy, these criteria have yet to be tested fully in lung cancer studies. Further work to define surrogate end points for immunotherapeutic agents for the treatment of lung cancer is necessary.

      ACKNOWLEDGMENTS

      The authors acknowledge StemScientific, funded by Bristol-Myers Squibb, for writing and editing support.

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