Long-Term Outcomes of a Phase I Study With UV1, a Second Generation Telomerase Based Vaccine, in Patients With Advanced Non-Small Cell Lung Cancer

Abstract

Human telomerase reverse transcriptase (hTERT) is a target antigen for cancer immunotherapy in patients with non-small cell lung cancer (NSCLC). We have tested a novel hTERT vaccine, UV1, designed to give high population coverage. UV1 is composed of three synthetic long peptides containing multiple epitopes identified by epitope spreading data from long-term survivors from previous hTERT vaccination trials. Eighteen non-HLA-typed patients with stage III/IV NSCLC with no evidence of progression after prior treatments, were enrolled in a phase I dose-escalation study of UV1 vaccination with GM-CSF as adjuvant, evaluating safety, immune response, and long-term clinical outcome. Treatment with UV1 was well tolerated with no serious adverse events observed. Seventeen patients were evaluable for tumor response; 15 patients had stable disease as best response. The median progression free survival (PFS) was 10.7 months, and the median overall survival (OS) was 28.2 months. The OS at 4 years was 39% (7/18). Five patients are alive (median survival 5.6 years), and none of these are known to have received checkpoint therapy after vaccination. UV1 induced specific T-cell responses in the majority (67%) of patients. Immune responses were dynamic and long lasting. Both immune response (IR) and OS were dose related. More patients in the highest UV1 dosage group (700 μg) developed IRs compared to the other groups, and the IRs were stronger and occurred earlier. Patients in this group had a 4-year OS of 83%. The safety and clinical outcome data favor 700 μg as the preferred UV1 dose in this patient population. These results provide a rationale for further clinical studies in NSCLC with UV1 vaccination in combination with immune checkpoint blockade.

Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT0178909.

Trial registration: ClinicalTrials.gov NCT01789099.

Keywords: clinical efficacy; dose response; human telomerase reverse transcriptase; non-small cell lung cancer; peptide; vaccine monotherapy.

Figure 1

Summary of pre- and post-vaccination UV1-specific T-cell responses. T-cell proliferation against UV1 peptides in pre- and post-vaccination blood samples from the 18 patients evaluable for immune responses. The graph shows the strongest post-vaccination T-cell responses detected against the UV1 peptide mix for each patient (A). Proliferation was measured in response to peptide-loaded PBMC by ³H-thymidine incorporation. A stimulation index (SI) of >3 is considered as an immune response. Stimulation index is plotted as mean of triplicates +/- standard deviation. Twelve of eighteen patients (12/18) had an immune response (67%). In blue: 100µg dose group, in red: 300µg dose group and in green: 700µg dose group (light: pre-vaccination, dark: post-vaccination). T-cell responses against the UV1 vaccine mix and its individual peptide components (725, 728, and 719-20) at all time points measured in patients 908, 700 µg dose (B), 909, 700µg dose (C), 911, 100µg dose (D), and 916, 300µg dose (E). Red arrows indicate when the last vaccine dose was given (B–E).

Figure 2

High UV1 dose improves immune response which correlates with improved OS. The number of patients responding to one (or only UV1 mix), two or three, or no peptides is shown in (A). In (B), the survival (weeks) is shown for patients responding to no peptides, one peptide or two or more. The time-to-response and accumulated proportion of immune responders per UV1 dose group is shown in (C). Overall survival (OS) in immune responders versus non-immune responders is shown in (D).

Figure 3

Tumor reduction and Th1 cytokine production post vaccination. Timeline for diagnosis, treatment and disease progression in patient 908 (A). Summary of pre- and post-vaccination UV1-specific T-cell responses detected, and tumor reduction measured in patient 908 (B). T-cell proliferation against UV1 peptides in blood samples pre- and post-vaccination at all time points tested from patient 908. Proliferation was measured in response to peptide-loaded PBMC by ³H-thymidine incorporation. A stimulation index (SI) of ≥3 is considered as an immune response. Dotted line is the logarithmic trend line for tumor diameter. Th1 cytokine production in T cells stimulated with UV1 peptides post vaccination is shown in (C). TNF-α and IFN-γ production was measured by intracellular cytokine staining in PBMCs pre-stimulated with UV1 peptides. T cells from indicated time points from two patients were re-stimulated with autologous APCs, either PBMCs or B-cell lines (EBV-LCLs) loaded with UV1 peptides (10 µM) for 10 h. CD4+ T-cell response is indicated by black bars and CD8+ T-cell response by hatched bars.

Figure 4

Survival versus months since first UV1 dose. Overall survival is shown in (A) and progression free survival is shown in (B).