High-dose fractionated radiotherapy to 80 Gy for stage I-II medically inoperable non-small-cell lung cancer.

INTRODUCTION: Management of medically inoperable non-small-cell lung cancer (NSCLC) has been historically challenging, with poor rates of local control and disease-specific survival. Nearly all published series of standard fractionation radiotherapy have utilised doses <70 Gy. The present investigation describes disease control and survival outcomes for a large series of patients prescribed high-dose radiotherapy for early-stage NSCLC. METHODS: Retrospective analysis of disease control and survival outcomes for stages I-II NSCLC patients prescribed ≥70 Gy at 1.8-2.5 Gy per fraction. RESULTS: Between May 1997 and August 2008, 100 primary lung tumours in 98 patients (two metachronous) were eligible for analysis. The median age was 71 years (range 49-93), and 92 patients were considered medically inoperable. Nearly all cases were clinical stage cT1N0 (51 patients) or cT2N0 (35). The median radiotherapy dose prescribed was 80.5 Gy (range 70-90). At a median follow-up of 18 months, 72 patients died (44 of/with disease) and 50 experienced recurrence. The estimated 3-year in-field control, progression-free survival, disease-specific, and overall survival rates were 50, 29, 30 and 24%, respectively. Univariate analyses demonstrated an inverse association between local control and tumour size. Medical inoperability was associated with decreased disease-specific and overall survivals. Patient age and biologically equivalent dose were also associated with overall survival. CONCLUSIONS: Disease control and survival of fractionated radiotherapy for early-stage NSCLC remain suboptimal. Medical inoperability is associated with worse overall survival; however, local control remains a predominant pattern of failure despite 80 Gy in standard fractionation, particularly in patients with larger tumour size.

Induction of cytotoxic T-cell responses against immunoglobulin V region-derived peptides modified at human leukocyte antigen-A2 binding residues.

Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.