Telomerase Peptide Vaccination in NSCLC: A Phase II Trial in Stage III Patients Vaccinated after Chemoradiotherapy and an 8-Year Update on a Phase I/II Trial

Abstract

Purpose: We report two clinical trials in non–small cell lung cancer (NSCLC) patients evaluating immune response, toxicity, and clinical outcome after vaccination with the telomerase peptide GV1001: a phase II trial (CTN-2006) in patients vaccinated after chemoradiotherapy and an 8-year update on a previously reported phase I/II trial (CTN-2000). Experimental Design: CTN-2006: 23 inoperable stage III patients received radiotherapy (2 Gy × 30) and weekly docetaxel (20 mg/m2), followed by GV1001 vaccination. CTN-2000: 26 patients were vaccinated with two telomerase peptides (GV1001 and I540). The immune responses were evaluated by T-cell proliferation and cytokine assays. Results: CTN-2006 trial: a GV1001-specific immune response developed in 16/20 evaluable patients. Long-term immunomonitoring showed persisting responses in 13 subjects. Serious adverse events were not observed. Immune responders recorded a median PFS of 371 days, compared with 182 days for nonresponders (P = 0.20). CTN-2000 trial update: 13/24 evaluable subjects developed a GV1001 response. The immune responders achieved increased survival compared with nonresponders (median 19 months vs. 3.5 months; P < 0.001). Follow-up of four long-time survivors showed that they all harbored durable GV1001-specific T-cell memory responses and IFNγhigh/IL-10low/IL-4low cytokine profiles. Two patients are free of disease after 108 and 93 months, respectively. Conclusions: Vaccination with GV1001 is well tolerated, immunizes the majority of NSCLC patients and establishes durable T-cell memory. The considerable immune response rate and low toxicity in the phase II trial support the concept of combining chemoradiotherapy with vaccination. The survival advantage observed for immune responders warrants a randomized trial. Clin Cancer Res; 17(21); 6847–57. ©2011 AACR.

Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

“…This purpose will be evaluated in future study. They also support the synergy between CT and therapeutic vaccination targeting TERT that has been recently reported in lung cancer (25,45). For technical reasons, there are very few studies that address the frequency of tumor-specific effector or memory T cells or antibody titers before and after CT. During the past years, different groups have focused on the identification of CD4 T-cell epitopes from TAA that could be used to improve anticancer immunotherapy and for the monitoring of antitumor CD4 T-cell responses (18).…”

“…Another promiscuous TERT-derived CD4 epitope called GV1001 was reported by Gaudernack and colleagues (48). This peptide has been used in clinical trials with encouraging results when combining to CT in melanoma and NSCLC (25,26). Nevertheless, the impact of spontaneous GV1001-specific immune response on vaccination efficiency and clinical outcome has not been investigated yet.…”

“…Therefore TERT activity has been observed in all studied cancer forms, including stem cell-like tumor cells (23) and is therefore a hallmark of cancer cells (24). Furthermore, recent clinical studies using a TERT-derived CD4 epitope vaccine called GV1001 was able to increase survival of cancer patients when combined with radio or CT (25,26). These results suggested the interplay between anti-TERT-CD4 T-cell immunity and conventional anticancer therapy.…”

Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one

“…When the rate of telomerase-specific immunological responses was evaluated as an outcome of telomerase immunization, conflicting results were observed among clinical trials. [12][13][14][15][16][17][18][19] This raised concerns on the actual immunogenicity of telomerase, an issue further sustained by the fact that it is an endogenous antigen, as well as by the very low frequency of circulating telomerase-specific CD8C T cells in cancer patients and by the inability of telomerase-specific CTL to kill tumor cells, as reported by some groups. 18,20,21 Taken together, these concerns, impacted negatively on telomerase ranking in the prioritization list of tumor associated antigens that had been generated to identify the best candidates as immunogens for cancer vaccines.…”

Generation of more effective cancer vaccines

“…Telomerase-based vaccines are examples demonstrating feasibility and efficacy of this approach. [15][16][17][18][19][20][21] But are the two strategies really alternatives to each other?…”