Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1: long-term follow-up of three phase I clinical trials

Abstract

BackgroundTherapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years.Methods52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses.ResultsIn total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen.ConclusionLong-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.

Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination

“…These findings support the concept that the long UV1 vaccine peptides contain multiple epitopes eliciting a diverse T cell response in each patient, rather than single vaccine-specific clonotypes. This hypothesis is further supported by previously published data on diversity among immune responder HLA genotypes and the various HLA restrictions and epitope specificities of vaccine-specific T cell clones [ 29 ]. Nevertheless, we identified TCR clonotypes that were significantly enriched after in vitro stimulation and subsequently detected them in unstimulated PBMCs and tumor tissue.…”

“…Therapeutic cancer vaccines aiming to mount anti-hTERT immune responses have been evaluated with several platforms, including peptide, mRNA, and DNA-based approaches [ 28 ]. UV1 is a multipeptide therapeutic vaccine that has demonstrated HLA-independent induction of vaccine-specific T cell responses in patients treated across three completed phase I/IIa clinical trials [ 29 ]. Effective induction of robust T cell responses is a prerequisite for the potential clinical activity of a TCV.…”

“…Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples (50 ml in acid dextrose tubes) at baseline and at frequent intervals during the treatment and long-term follow-up periods, as previously described [ 29 ]. Briefly, vaccine-specific T cell immune responses were assessed using a standard proliferation assay ( 3 H-Thymidine incorporation).…”

“…UV1 is a TCV composed of three synthetic long peptides derived from the active site of hTERT and has been proven to establish robust, long-lasting T cell responses across an HLA-unselected population in three completed phase I clinical trials [ 29 ]. Immune responses induced by UV1 have been identified as CD4 Th1-polarized effector memory cells with inflammatory cytokine profiles (tumor necrosis factor-α and IFN-γ).…”

The Role of Telomerase in Breast Cancer’s Response to Therapy

“…Other studies on hTERT-based immunotherapy (three phase I/IIa clinical trials covering malignant melanoma, non-small-cell lung cancer, and prostate cancer) showed that UV1, a second-generation telomerase-targeting therapeutic cancer vaccine, triggered highly dynamic and persistent telomerase-peptide-specific immune responses that lasted up to 7.5 years after the initial vaccination. The superior immune response kinetics were observed in the melanoma study [ 97 ].…”