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DR. CARBONE: Lung cancer is the most common cause of cancer death. It is also very ineffectively treated once diagnosed; only about 10% to 15% of patients with lung cancer remain alive 5 years post diagnosis. There is a real need for new therapies in lung cancer.
In addition, in the majority of cases, lung cancer has a defined environmental etiology. That leads to a large population of patients in the US with a 5- to 10-fold risk: the population of former smokers. Thus, there is a tremendous need for lung cancer prevention as well.
The 2 main approaches to lung cancer vaccines are antigen-specific and whole cell. An important concept in vaccine development is the improvement of immunity with cytokines, particularly GM-CSF. Along those lines, as Dr. Jablons will describe (see below), the GVAX vaccine uses autologous tumor cells that produce GM-CSF, which induces antigen uptake in processing by dendritic cells that then present the antigen to the local lymph nodes.
The 2 main approaches to lung cancer vaccines are antigen-specific and whole cell.
L-BLP25, or Stimuvax®, is an antigen-specific vaccine recently studied in a phase IIB trial in patients with locally advanced or metastatic NSCLC who had a response or stable disease to first-line therapy and holds some promise. Dr. Butts will describe this work in some detail following my discussion.
The Eastern Cooperative Oncology Group (ECOG) is planning a randomized phase II trial to assess the addition of the anti-vascular endothelial growth factor agent, bevacizumab (Avastin®), to L-BLP25 vaccine. It will compare the L-BLP25 vaccine plus bevacizumab to bevacizumab alone after best standard therapy for locally advanced lung cancer.
Reports of several studies of vaccines for lung cancer were presented at the June 2006 ASCO meeting. One was a Belgian multicenter, double-blind, randomized, placebo-controlled phase II study to assess the recombinant melanoma-associated antigen (MAGE)-A3 compound (a purified recombinant fusion protein) as adjuvant therapy in patients with completely resected stages IB/II MAGE-A3 positive NSCLC.14 Since about 35% of patients with stage IB-II NSCLC express MAGE-A3,15 it has been postulated that postoperative MAGE-A3 immunization might be a targeted, well tolerated, and effective treatment.
In the study, patients were randomly assigned in a double-blind fashion to postoperative MAGE-A3 vaccination or placebo. Vaccination was initiated ≥6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Randomization was stratified for stage (IB vs II), histology (squamous vs other), and lymph node procedure (sampling vs dissection). The primary endpoint was time to recurrence; other endpoints were recurrence rates at different times, and survival.
In 2 years, 182 patients were randomized (121 stage IB, 61 stage II). Overall, treatment was well tolerated, with high protocol adherence. Median follow-up was 21 months, with 62 recurrences recorded. These results are encouraging.
In another phase II study, a transforming growth factor β2 (TGF-β2) antisense gene-modified allogeneic tumor cell vaccine was studied in patients with NSCLC.16 The study assessed different dose levels of an intradermal vaccine derived from 4 lung cancer cell lines. Each patient received 1 of 3 doses (1.25, 2.5, or 5.0 × 107 cells/injection) of the vaccine to a maximum of 16 injections either monthly or every other month. Sixty-one patients (15 stage IIIB and 46 stage IV), 84% of whom had prior cytotoxic therapy, received a total of 417 vaccinations.
No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received ≥2.5 × 107 cells/injection compared with those who received ≤2.5 × 107 cells/injection (P = 0.0151). The proportion of patients surviving 1 and 2 years was 61% and 52% for the high-dose group and 40% and 13% for the low-dose group, respectively.
A partial response was noted in 15% of patients. Cytokine production (IFN-γ, IL-6, and IL-4) was induced, antibody-mediated response to vaccine HLA antigen was observed, and cell-mediated response showed a correlation trend (P = 0.086) in patients achieving stable disease or partial response (15%) compared to those with progressive disease.
This vaccine appears to be well tolerated. A survival advantage is suggested in patients who receive ≥2.5 × 107 cells/injection, and further evaluation in a phase III trial is planned.
In 2005, we published results of a 10-year study in which we determined the ability to induce tumor-specific immunity with individual mutant K-ras- or p53-derived peptides and to monitor clinical outcome.17 We sequenced the tumors from patients with advanced cancer and determined those that had mutations in these 2 genes. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and IFN-γ release from mutant peptide-primed lymphocytes. Patients’ peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-γ, IL-2, IL-5, and GM-CSF; for treatment-related toxicity; and for tumor response.
No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and 2 patients were positive for CTL at baseline. Positive IFN-γ responses occurred in 16 patients (42%) after vaccination, whereas 4 patients had positive IFN-γ reaction before vaccination. Of 29 patients with evident disease, 5 had a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-γ reaction, but not IL-5 release. Median survival times of 393 vs 98 days for a positive vs negative CTL response (P = 0.04), respectively, and of 470 vs 88 days for a positive vs negative IFN-γ response (P = 0.02), respectively, were detected (Figure 2).17 Although this is not a very practical approach, it appears to be associated with modest efficacy.
Survivin-2B is specifically expressed in various cancers and might be a novel vaccine target in lung cancer. In a Japanese study, surgical specimens were obtained from patients with lung cancer who underwent surgical resection, and differences in survivin-2B expression were determined between lung cancer and normal tissues as well as the relationship between survivin-2B expression and clinicopathologic features.18
Survivin-2B was expressed in 17 (40%) of 42 lung cancer patients; histologically, survivin-2B was expressed significantly more frequently in squamous cell carcinoma than in adenocarcinoma (P = 0.014). The frequency of precursor CTL in lymph node lymphocytes was approximately 1 in 2.0 × 107 in patients with survivin-2B expression-negative lung cancer, compared with 1 in 5.0 × 106 to 6.0 × 106 in those with survivin-2B expression-positive lung cancer.
All but 1 patient had a measurable CD8 response after 3 immunizations.
Another recent study focused on allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced NSCLC.19 Nineteen patients were treated with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 × 107 cells once every 2 weeks. Three vaccinations represented 1 course of treatment. If patients had a complete or partial response, or stable disease, the vaccine was continued for up to 3 courses (9 vaccinations).
All but 1 patient had a measurable CD8 response after 3 immunizations. In 6 surviving, clinically responding patients, CD8 titers were elevated up to 150 weeks, even after cessation of vaccination. Overall, 1 patient had a partial response, and 5 had stable disease. Median survival for all patients was 18 months (90% confidence interval, 7 to 23 months).
Autologous dendritic cell (DC) vaccines for NSCLC also are under study.20 A recent trial included individuals with histologically confirmed stage I to IIIB NSCLC who had completed definitive medical, surgical, or multimodality therapy and had stable clinical disease at screening. Autologous DC vaccines were generated from CD14+ precursors, pulsed with apoptotic bodies of an allogeneic NSCLC cell line that overexpressed Her2/neu, CEA, WT1, MAGE-2, and survivin. The DCs were partially matured with a factor that induced surface molecule expression but minimal cytokine production. Individuals were immunized intradermally twice, 1 month apart.
The vaccine was well tolerated; 3 distinct patterns of response were noted: (1) 5 of 16 (31%) patients showed no clear immunologic response, (2) 5 of 16 (31%) patients showed a tumor-antigen independent response, and (3) 6 of 16 (38%) showed an antigen-specific response.
In a phase III European study, patients with unresectable NSCLC were randomized to receive either standard chemotherapy alone or chemotherapy plus SRL172 (killed Mycobacterium vaccae suspension).21 There was no statistically significant difference between the 2 groups in overall survival (primary efficacy endpoint) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65), but a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%) compared with the chemotherapy-alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group.
The safety, feasibility, and efficacy of autologous DC-derived exosomes (DEX) loaded with the MAGE tumor antigens have been studied in patients with NSCLC in a phase I trial.22 Enrolled were HLA A2+ patients with pre-treated stage IIIb (n = 4) and IV (n = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals.
Of 9 patients who completed therapy, survival after the first DEX dose was 52 to 665+ days. DTH reactivity against MAGE peptides was detected in 3 of 9 patients. MAGE-specific T- cell responses were noted in 1 of 3 patients; increased NK lytic activity was seen in 2 of 4 patients. Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC.
There are about a dozen ongoing studies of vaccine therapy for lung cancer, focusing on a variety of formulations.
Professor of Medicine and
Cancer Biology
Vanderbilt University Medical Center
Nashville, Tennessee
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Pedro Romero, MD
Håkan Mellstedt, MD, PhD
David Carbone, MD, PhD
David Jablons, MD
Charles A. Butts, MD
Philip Bonomi, MD
Survival after vaccination with mutant oncogene peptides.
CTL: 0 = no cellular immunity; 1 = positive cellular immunity; IFN-γ: 0 = no IFN-γ release after in vitro stimulation; 1 = positive IFN-γ release.
Adapted with permission from Carbone DP, et al.17 Reprinted with permission from the American Society of Clinical Oncology.
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Vaccine Trials in NSCLCDavid Carbone, MD, PhD |
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