Head Laboratory of Clinical and Experimental Tumor Immunology Department of Surgery Grosshadern Medical Center Ludwig-Maximilians University Munich, Germany.
Lung cancer is the deadliest cancer in the world. In 2005, in the US alone, there were an estimated 163,510 deaths in patients suffering from lung cancer, including 15,000 to 20,000 “never smokers”1. These numbers clearly demonstrate that despite progress in the treatment of this disease over the past two decades, there are still few long-term survivors: only about 10% of all patients will ever be cured of this devastating disease2.
Given the modest effect and considerable toxicity of current standard treatment (surgery, chemotherapy, radiation therapy), there is clearly a need for novel treatment options. Currently, a wide variety of immunotherapeutic agents are being tested in lung cancer.
Here, we review strategies based on the humeral and cellular immune system that are already in clinical use or well progressed in early clinical trials. Because Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 80% of all lung cancers, the focus is mainly set on immunotherapy of NSCLC.
Today, at least 12 monoclonal antibodies (mAB) have received FDA approval and over 400 others are being tested in clinical trials3. In lung cancer, a primary focus was put on mABs targeting the Epidermal Growth Factor Receptor (EGFR) and the Vascular Endothelial Growth Factor (VEGF)4. The most advanced in development are the anti-EGFR mAB cetuximab (Erbitux®) and the anti-VEGF mAB bevacizumab (Avastin®).
To block growth factors and their receptors seems an obvious strategy in fighting cancer because they are known to augment tumour cell proliferation and invasion and have been shown to be overexpressed in many solid malignancies where the overexpression has been associated with a more aggressive course of disease and poor survival5. C-erb B-1 and c-erb B-2 are the two growth receptor families that have been studied most extensively. C-erb B-1 is better known under the name HER1 or Epithelial Growth Factor Receptor (EGFR). HER2 is the more common name for c-erb B-2.
Cetuximab (Erbitux®), a chimeric human:murine form of the original mAB 225, has demonstrated safety and was well tolerated in early phase clinical trials, but low patient numbers currently do not allow for final assessment of its therapeutic efficacy in lung cancer. A 28% partial response rate and 17% of patients with stable disease were observed in a Phase II trial with combination of cetuximab and docetaxel which exceeds response rates usually seen with docetaxel alone6. In another phase II trial patients with recurrent or progressive NSCLC were treated with cetuximab after receiving at least one prior chemotherapy regimen7. The response rate for all patients (n = 66) was 4.5% and the stable disease rate was 30.3%.
The median time to progression for all patients was 2.3 months and median survival time was 8.9 months. The authors of this study concluded that, although the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, the disease control rates and overall survival seemed comparable to that of pemetrexed, docetaxel and erlotinib in similar groups of patients. More Phase I/II clinical trials have been conducted on the use of cetuximab in combination with systemic chemotherapy and / or radiation therapy confirming not only the low toxicity but also the clinical response rates8,9.
Grade 3 toxicities associated with the use of cetuximab were fatigue, infections and papulopustular rash. Development of the rash, usually located on the face and upper torso, has been related to a clinical response and has been suggested to potentially serve as a surrogate marker for cetuximab activity10. Other anti-EGFR mABs currently in development include panitumumab (ABX-EGF), matuzumab (EMD 72000), pertuzumab (2C4) and MDX21411. Early phase clinical trials with these agents in patients with lung cancer are currently ongoing with results pending.
Trastuzumab (Herceptin®), a humanised monoclonal antibody that targets the HER2 receptor, has been approved for metastatic breast cancer. However, to date, it failed to demonstrate clinical efficacy in patients suffering from lung cancer12,13. Only few authors suggest further investigation of trastuzumab in HER2-positive lung cancer14. In contrast, pertuzumab (2C4), a mAB designed to inhibit the dimerisation of HER2 with EGFR and other HER tyrosine kinases and, therefore, being independent of HER2 overexpression is currently under evaluation in NSCLC in early phase clinical trials11.
Table 1: Lists Antibodies and Tyrosine
Kinase Inhibitors Currently under Clinical Investigation for Lung Cancer. Other factors relevant for tumour cell proliferation, such as the intercellular adhesion molecule-1 (ICAM-1)15, have been identified as targets for mABs. Of these, bevacizumab (Avastin®), which targets the Vascular Endothelial Growth Factor (VEGF) recently gained approval for the treatment of colorectal cancer. A phase II clinical trial using bevacizumab alone or in combination with chemotherapy in patients with metastatic NSCLC revealed promising results16. Other studies investigated the use of bevacizumab, for e.g., in combination with the EGFR-tyrosine kinase inhibitor erlotinib (Tarceva®) or as combination therapy with paclitaxel and carboplatin in the neoadjuvant setting17,18. In the largest trial evaluating bevacizumab, 878 patients with recurrent or advanced NSCLC (stages IIIB and IV) were included19. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group. The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively, with corresponding response rates of 35% and 15%. Rates of clinically significant bleeding were 4.4% and 0.7%, respectively.
In Small-Cell Lung Cancer (SCLC), an anti-idiotype vaccine targeting the ganglioside GD3 (BEC2) has been evaluated20. The European Organization for Research and Treatment of Cancer (EORTC) recently published data from a phase III trial using BEC2 in combination with induction chemoradiotherapy in limited stage SCLC21. A total of 515 patients were randomly assigned to receive five vaccinations of BEC2 (2.5 mg)/BCG vaccine or follow-up. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Among vaccinated patients, a trend toward prolonged survival was observed in those who developed a humeral response.
To increase their cytocidal potency, mABs are being linked to cytocidal agents, such as toxins, chemotherapeutic drugs or radionuclides. Approved for clinical use are, for e.g., gemtuzumab ozogamicin (Mylotarg®), which links the toxin calicheamicin to a CD33-specific antibody for use in the treatment of myelogenous leukemia and ibritumomab tiuxetan (Zevalin®), which links 90Y to a CD20-specific mAB. To date, the available data on comparable antibodies for the treatment of lung cancer is, however, very limited and very few reports on clinical applications are available22-24.
In contrast to the prophylactic vaccination against infectious disease or cancers associated with viral infection (cervical cancer, hepatocellular carcinoma), for cancer patients the only relevant vaccination strategy must be therapeutic. Generally speaking, cancer vaccines incorporate a source of tumour antigens combined with some type of “adjuvant” to make these tumour antigens visible to the immune system. Sources of tumour-associated antigens include whole autologous or allogeneic tumour cells, defined proteins, or specific peptide epitopes (see Figure 1). Most likely due to the heterogeneous histology of lung cancers, the relevant immunologically dominant antigens remain unknown. Therefore, the use of autologous tumour cells might be especially suitable for vaccination strategies in lung cancer, because no prior knowledge of specific tumour antigens is necessary and the induced immunity may not be confined to a single, specific antigen that could be downregulated by the tumour.
The genetic modification of autologous tumour cells to secrete immunomodulatory cytokines has been shown to induce antitumour immunity in a number of preclinical models. Of these cytokines, GM-CSF has demonstrated the greatest induction of antitumour immunity25. Two early-phase clinical trials using GM-CSF-secreting, autologous tumour cells (GVAX®) in patients with NSCLC have revealed encouraging preliminary results. Salgia and coworkers reported on safety and feasibility of this approach in 33 advanced NSCLC patients with the most common toxicities being local injection site reactions and flu-like symptoms. A mixed response in one patient and long recurrence-free intervals in two other patients following isolated metasectomy were observed26. In another phase I/II trial using the GVAX® platform, autologous tumour cells were transduced with GM-CSF through an adenoviral vector (Ad-GM) and administered as a vaccine27. 78% of patients developed antibody reactivity against allogeneic NSCLC cell lines. Three durable complete responses were observed.
Mucin-1 (MUC1) is expressed on the cell surface of many common adenocarcinomas, including lung cancer. Because of its involvement in cell-cell interaction between malignant and endothelial cells, anti-MUC1 strategies may be useful in preventing metastatic spread of tumour cells in addition to their direct anti-tumour effect. A phase I study using a modified vaccinia virus (Ankara) expressing human MUC1, which also contains a coding sequence for human IL-2 (TG4010), revealed a safe toxicity profile and some clinical activity28. The phase II trial is currently underway as a multicentre study.
MUC1 has also been targeted in another trial of patients with NSCLC using the vaccine L-BLP25 (Stimuvax®). A multicentre phase IIB study investigating the vaccine in NSCLC patients' stages IIIB and IV has recently been updated with promising results for safety and clinical effectiveness in the first publication29,30. All patients had shown stable disease or a clinical response following standard first-line chemotherapy and were then vaccinated with Stimuvax or received best supportive care alone. Although the overall survival did not reach statistical significance, the survival in patients with stage IIIB (locoregional disease) improved at three years compared to stage IIIB patients with malignant pleural effusion and stage IV patients with 48.6% and 26.7%, respectively. An international, randomised, multicentre phase III trial for unresectable stage III NSCLC patients with stable disease or better following first-line chemoradiation has been initiated and the first patient has entered the trial in the US.
Table 2 : Lists Therapeutic Lung Cancer Vaccines Currently in Clinical Development.
Another protein vaccination strategy aims at the melanoma-associated antigen E-3 (MAGE-3), which is expressed in about 30% - 50% of lung cancers depending on stage and histological subtype and may be associated with poor prognosis31. First results reporting the successful induction of humeral and cellular immune responses in patients with NSCLC following vaccination with MAGE-3 with and without adjuvant chemotherapy have been published in 200432. Seventeen patients were enrolled following surgical resection with no evidence of disease. Nine patients received 300µg of the MAGE-3 protein alone, whereas 8 patients were treated with MAGE-3 combined with the adjuvant AS02B. In the first cohort (no adjuvant), only one patient showed a CD4+ T cell response. In contrast, 4 patients out of the second cohort (MAGE-3 plus adjuvant) developed a CD4+ T cell responses against the MAGE-3.DP4-peptide. Based on these results, a multinational phase II trial investigating the therapeutic efficacy of the MAGE-3 vaccine in patients with resected MAGE-3-positive stage IB/II NSCLC was initiated and recently completed. In this placebo-controlled study, 122 early-stage patients (MAGE-3-positive NSCLC) where vaccinated five times at three-week intervals. Preliminary analyses presented at the 2006 ASCO meeting33 revealed a 33% disease-free survival improvement for the resected and vaccinated patients. No significant toxicities were observed. A large multicentre phase III study is currently being initiated based on these results.
More lung cancer vaccines are currently being tested37,38, but review of all strategies in clinical development would go beyond the scope.
For long, lung cancer was not considered an immune-sensitive malignancy. With insufficient knowledge of relevant tumour antigens, lung cancer immunotherapy lags behind similar efforts in melanoma, renal cell and prostate cancer. However, there is increasing evidence that NSCLC and SCLC can evoke specific humeral and cellular anti-tumour immune responses. With increasing knowledge about the link between the induced immune response and a resulting objective clinical response, targeted agents may hold great promise in sequence with other (adjuvant) anti-tumour therapeutics. Obviously, not all of the immunotherapeutic approaches in the treatment of lung cancer can be mentioned in this review, e.g. adoptive cell transfer, immuno-gene therapy, inducers of apoptosis, certain signal transduction inhibitors and others47-50 have not found their way into later clinical development and, therefore, weren’t the focus of this review.
This work was supported by the Chiles Foundation, Portland, Oregon, USA, and the Walter-Schulz-Foundation, Munich, Germany.
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