Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study

Abstract

Patients with inoperable pancreatic cancer have a dismal prognosis with a mean life expectancy of 3-6 months. New treatment modalities are thus urgently needed. Telomerase is expressed in 85-90% of pancreas cancer, and immunogenic telomerase peptides have been characterised. A phase I/II study was conducted to investigate the safety, tolerability, and immunogenecity of telomerase peptide vaccination. Survival of the patients was also recorded. Forty-eight patients with non-resectable pancreatic cancer received intradermal injections of the telomerase peptide GV1001 at three dose levels, in combination with granulocyte-macrophage colony-stimulating factor. The treatment period was 10 weeks. Monthly booster vaccinations were offered as follow-up treatment. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T-cell proliferation. GV1001 was well tolerated. Immune responses were observed in 24 of 38 evaluable patients, with the highest ratio (75%) in the intermediate dose group. Twenty-seven evaluable patients completed the study. Median survival for the intermediate dose-group was 8.6 months, significantly longer for the low- (P = 0.006) and high-dose groups (P = 0.05). One-year survival for the evaluable patients in the intermediate dose group was 25%. The results demonstrate that GV1001 is immunogenic and safe to use. The survival data indicate that induction of an immune response is correlated with prolonged survival, and the vaccine may offer a new treatment option for pancreatic cancer patients, encouraging further clinical studies.

Figure 1

In vitro stimulation of GV1001-specific T-cell clones from patient no 102 (clone 22) and 105 (clones 6, 35, 51). Clones were stimulated with GV1001 (25 μM) pulsed onto APCs homozygous for different HLA-class II molecules as indicated. Results are presented as c.p.m.

Figure 2

Type and percentage of immune responders in patients vaccinated with low, intermediate, and high dose GV1001 (A) and kinetics of immune responses in the three dose groups, as measured by DTH response (B). Bars show accumulated responses in each group.

Figure 3

In vitro T-cell responses against GV1001 in blood samples harvested before (week 1), during and after vaccination (weeks 2, 3, 4, 6, and 10). Responses are given as SI. Control cultures were primed and stimulated with control peptide PEP 544 or PEP 508.

Figure 4

(A) Cytokine profile generated by stimulating PBMC from patient 101 in the intermediate dose group harvested before vaccination (W0) and on week 10 (W10) and (B) patient 212 in the high-dose group. Data are given as picogram cytokine ml⁻¹ in supernatants harvested 24 h after stimulation of primed cells with APC with or without GV1001.

Figure 5

Dose response curve for T-cell clone 1 from patient no 102 stimulated with GV1001. Fifty thousand T cells were stimulated using 25 × 10³ autologous EBV-transformed B cells as APCs. Results, counted after 3 days, are presented as mean c.p.m. of triplicates±s.d.. Similar bell shaped curves were observed with other T-cell clones.

Figure 6

(A) Recognition of recombinant hTERT by GV1001-specific T-cell clone nos. 22 and 30 from patient no 102 and clone 51 from patient no 105. T cells (50 000 well⁻¹) were stimulated with 50 000 irradiated autologous EBV-transformed B cells as APC for 48 h before labelling and harvesting (see below). The APC were pulsed with either GV1001 (10 μM) or recombinant hTERT (3 μM for clones 22 and 30 and 0.5 μM for clone 51). T cells with APC alone served as negative controls. (B) Recognition of ascites cells from patient 105 by T-cell clone nos 35 and 49 derived from the same patient after vaccination. T cells (50 000 well⁻¹) were stimulated for 48 h with 50 000 irradiated, T-cell depleted (anti-CD3-coated Dynabeads) ascites cells or 50 000 irradiated autologous EBV-transformed B cells with or without GV1001 (25 μM) as positive and negative controls. After 48 h of culture, ³H-thymidine was added and the cultures harvested the next day. Results are expressed as mean c.p.m. of triplicate cultures.

Figure 7

(A) Survival (Kaplan–Meier plot) of the evaluable patients treated with different doses of GV1001. Median survival (95% conf. int.): Low-dose group (n=8); 119 days (31–190), intermediate dose group (n=16); 260 days (133–337), and high-dose group (n=14); 153 days (106–249). Intermediate vs low dose; P=0.006, intermediate vs high dose; P=0.05 (log-rank). (B) Survival (Kaplan–Meier plot) of all immune responders (n=24) vs all non-responders (n=14) in the whole evaluable study population. Median survival (95% confidene interval) was; 216 days (146–323) for the immune responders and 88 days (53–190) for the non-responders. P=0.0001 (log-rank).