Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination.
We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4(+)CD25(+)CD127(low/-)FOXP3(+)) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR (low) CD14 (+) or Lin (-/lo) HLA-DR (-) CD33 (+) CD11b (+)). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNγ/IL-4 and IFNγ/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNγ/IL-10 ratios. High CD33(+) MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14(+) MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses.
Department of Immunology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.
Gaute Lund
GL
Hansen
Department of Immunology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.
Gustav
G
Gaudernack
The Clinical Trial Unit, Department of Clinical Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.
Paal Fredrik
PF
Brunsvig
National Resource Center for Late Effects, Department of Oncology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.
Milada
M
Cvancarova
Department of Immunology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway. jon.amund.kyte@rr-research.no.|Department of Oncology, Radiumhospitalet, Oslo University Hospital, Mail Box 4950, Nydalen, 0424, Oslo, Norway. jon.amund.kyte@rr-research.no.
Jon Amund
JA
Kyte
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000097:blood / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019098:Telomerase / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use
D019496:Cancer Vaccines; D016207:Cytokines; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D019098:Telomerase
Cancer vaccine; Cytokines; Lung cancer; Myeloid-derived suppressor cells; Regulatory T cells; Survival