Cancer vaccines: a new therapeutic alternative for lung cancer therapy?

Abstract

ImmunotherapyVol. 1, No. 5 EditorialFree AccessCancer vaccines: a new therapeutic alternative for lung cancer therapy?Luis E Raez and Edgardo S SantosLuis E RaezUniversity of Miami/Sylvester Comprehensive Cancer Center, FL, USASearch for more papers by this author and Edgardo S Santos† Author for correspondenceUniversity of Miami/Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue, Suite 3510 (D8-4), Miami, FL 33136, USA. Search for more papers by this authorEmail the corresponding author at esantos2@med.miami.eduPublished Online:2 Sep 2009https://doi.org/10.2217/imt.09.57AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Development of vaccines for lung cancer has gained more attention in recent years. For a long time, this research area encountered many difficulties owing to the low-immunogenic or nonimmunogenic characteristics of lung cancer per se; the lack of a well-known immunodominant antigen (target); and the costs of vaccine development [1]. To date, we have enough evidence to believe that non-small-cell lung cancer (NSCLC) tumors contain regulatory T cells (Tregs), which are suppressive for cytotoxic T lymphocyte (CTL) generation [2], and hence, the potential immune response is seriously impaired. Some researchers believe that whole-cell vaccination with an autologous or allogeneic approach is more complete, because the whole-cell vaccine will include the antigens that we are looking for instead of developing a vaccine for a specific antigen. At present, NSCLC vaccines do not have clinical indication in daily medical practice, unless within the a clinical trial.There are two major Phase III multicenter clinical trials underway exploring two vaccines, MAGE-A3 and L-BLP25, based on the promising results seen in Phase I/II studies. We would like to discuss first the melanoma-associated antigen-A3 (MAGE-A3). This is a tumor-specific antigen that is not expressed on normal cells. MAGE-A3 is expressed in 35% of NSCLCs, and may be associated with a poor prognosis [3]. A vaccine initially developed to treat patients with metastatic melanoma demonstrated evidence of activity, with five responses out of 26 treated patients [4]. Later, the results of a randomized Phase II trial of MAGE-A3 vaccine in patients with completely resected MAGE-A3-expressing NSCLC were reported [5]. Only patients whose tumors expressed MAGE-A3 protein and had early-stage (IB and II)-resected NSCLC were enrolled. From a total of 1089 lung cancer resection specimens, 363 were positive for MAGE-A3 expression; 182 patients out of these 363 MAGE-A3-positive cases entered the study and were randomized to receive either placebo or vaccination. Although there were several grade 3 or 4 adverse events (n = 117), only three were considered to be related to the vaccine by the investigators. The vaccine arm showed better response than the placebo (30.6 vs 43.3%); however, none of the outcome end points (disease-free interval, disease-free survival or overall survival) reached statistical significance.Our second discussion focuses on L-BLP25 vaccine development. After being studied in a Phase I trial, L-BLP25 vaccine was shown to have minimal toxicity [6]. Two Phase II trials established the dose and schedule of L-BLP25 and showed the capability of this compound to elicit a T-cell response [7]. Notably, a large Phase IIB randomized study that enrolled 171 patients showed a trend in overall survival for those patients who were vaccinated with L-BLP25 (17.4 vs 13 months; p = 0.066) [8]. Herein, patients who had stage IIIB/IV NSCLC and who attained stable disease or any response after first-line chemotherapy were randomly assigned to either L-BLP25 vaccine or best supportive care. Interestingly, a subgroup analysis performed in patients with stage IIIB suggested that survival difference was confined to this group. At the American Society of Clinical Oncology meeting in June 2009, the authors reported the safety results for 16 patients enrolled into the Phase IIB trial [9]; these patients were treated for 2 years or more with L-BLP25. Patients received L-BLP25 for 2.0–7.7 years and ten patients were treated for more than 5 years. Compliance with therapy was good: almost all (96%) maintenance vaccinations were administered every 6 weeks according to the prolonged treatment schedule. In general, the vaccine was well tolerated and the most common prolonged treatment-emergent adverse events (TEAEs) were not relevant (cough, fatigue and dyspnea). The previous two vaccines briefly discussed are the one which have recently moved into very interesting conceptual approaches in Phase III clinical trials. First, MAGE-A3 vaccine will be studied in the adjuvant setting after completion of ‘standard’ adjuvant conventional chemotherapy (a sequential/maintenance approach). Second, L-BLP25 is entering into an international Phase III trial in which L-BLP25 will be compared against placebo in patients with stage III NSCLC. If MAGE-A3 and/or L-BLP25 are positive, we may have the first approved vaccines for NSCLC.Other vaccines are also in development in this field, such as belagenpumatucel-l and GVAX. The first has been created from an allogeneic NSCLC cell line genetically modified to secrete an antisense oligonucleotide to TGF-β2. TGF-β2 is immunosuppressive, suppressing NK cells, activated killer cells and dendritic cell activity, and is a poor prognostic factor in NSCLC. Preclinical and early-phase studies showed that inhibition of TGF-β2 increased the immunogenicity of tumor vaccines. The vaccine has the advantage that does not require for individual patient tumor tissue or long preparation time. In a Phase II trial, belagenpumatucel-l showed minor toxicities with only one grade 3 adverse event attributed to the vaccine in 75 patients treated [10]. There was a 16% response rate, and those who received the lowest dose level had inferior survival compared with the other two doses combined. In addition, no statistical significance difference was found between biomarkers of immune system stimulation and response rate, albeit a trend in favor for stable disease or responders. This vaccine is also entering into a Phase III study. In the case of GVAX, an autologous NSCLC vaccine transfected with adenovirus containing GM-CSF DNA, clinical activity has also been observed in early-phase studies [11,12]. An interesting observation has been the fact that bronchoalveolar carcinoma (BAC) cases have attained prolonged remissions with GVAX. It has been hypothesized that BAC may have a viral origin, and may be susceptible to GM-CSF manipulation. Thus, a Phase II trial is testing this vaccine in stage IIIB/IV BACs.In general, vaccinations in NSCLC have always shown a great immune response and some clinical activity. We are still searching for the right immunodominant antigen(s), and these new vaccines are bringing hope in that regard. Owing to their relative low toxicity profile, cancer vaccines represent an interesting alternative to be studied in early stages (adjuvant setting), as well as for maintenance treatment after definitive first-line therapy for lung cancer.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Salgaller ML: The development of immunotherapies for non-small cell lung cancer. Expert Opin. Biol. Ther.2(3),265–278 (2002).Crossref, Medline, CAS, Google Scholar2 Woo EY, Yeh H, Chu CS et al.: Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J. Immunol.168(9),4272–4276 (2002).Crossref, Medline, CAS, Google Scholar3 Gure AO, Chua R, Williamson B et al.: Cancer-testis genes are co-ordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin. Cancer Res.11(22),8055–8062 (2005).Crossref, Medline, CAS, Google Scholar4 Kruit WH, van Ojik HH, Brichard VG et al.: Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma. Int. J. Cancer17(4),596–604, (2005).Crossref, Google Scholar5 Vansteenkiste J, Zielinski M, Linder A et al.: Final results of a multicenter, 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). J. Clin. Oncol.25,18S (2007).Crossref, Google Scholar6 Palmer M, Parker J, Modi S et al.: Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non small-cell lung cancer. Clin. Lung Cancer3(1),49–57 (2001).Crossref, Medline, CAS, Google Scholar7 North S, Butts C: Vaccination with BLP25 liposome vaccine to treat non-small cell lung and prostate cancers. Expert Rev. Vaccines4(3),249–257 (2005).Crossref, Medline, CAS, Google Scholar8 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. J. Clin. Oncol.23(27),6674–6681 (2005).Crossref, Medline, CAS, Google Scholar9 Butts C, Anderson H, Maksymiuk A et al.: Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC). J. Clin. Oncol.27(Suppl.), Abstract 3055 (2009).Crossref, Google Scholar10 Nemunaitis J, Dillman RO, Schwarzenberger PO et al.: Phase II study of belagenpumatucel-l, a transforming growth factor β-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J. Clin. Oncol.24(29),4721–4730 (2006).Crossref, Medline, CAS, Google Scholar11 Salgia R, Lynch T, Skarin A et al.: Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte–macrophage colonystimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J. Clin. Oncol.21(4),624–630 (2003).Crossref, Medline, Google Scholar12 Nemunaitis J, Sterman D, Jablons D et al.: Granulocyte–macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J. Natl Cancer Inst.96(4),326–331 (2004).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 1, No. 5 Follow us on social media for the latest updates Metrics History Published online 2 September 2009 Published in print September 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download