First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients

Abstract

BackgroundDepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907.MethodsA phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol.ResultsDPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines.ConclusionsThe novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent.Trial RegistrationClinicalTrials.gov NCT01095848

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis

“…Observations from preclinical tumor models and from human vaccination studies show that polyfunctional type 1 TCs simultaneously expressing TNF-α, IFN-γ, and IL-2 particularly correlated with immune protection, while TCs expressing IFN-γ alone may not correlate with improved clinical outcome (26,27). Cytokine secretion is induced by antigen-specific stimulation and, in the case of TNF-α, is mainly restricted to the first 2-4 hours after activation (28).…”

Functional impairment of infiltrating T cells in human colorectal cancer

“…The dual production of IFNg and IL-2 in T cells has previously been described as an important anticancer T cell subset. 16,30 These cells correlate strongly with immune protection against tumors in preclinical tumor models and human vaccine studies. 16,30 Dual IFNg and IL-2-producing T cells produce more IFNg on a per cell basis and are more likely to become memory cells than single IFNg producing T cells.…”

“…16,30 These cells correlate strongly with immune protection against tumors in preclinical tumor models and human vaccine studies. 16,30 Dual IFNg and IL-2-producing T cells produce more IFNg on a per cell basis and are more likely to become memory cells than single IFNg producing T cells. 16,31,32 These attributes are beneficial to T cells that destroy tumor cells.…”

Clearance of depot vaccine SPIO-labeled antigen and substrate visualized using MRI

“…By attaching superparamagnetic iron oxide (SPIO) to the antigen and formulating it in DepoVax TM , it is possible to visualize the biodistribution of the antigen at both the site of vaccination and nearby LNs over time, and to evaluate the clearance of the antigen from the depot site [11,13,14]. In this study, we were able to differentiate clearance of the antigen from clearance of the oil substrate by differential labeling of either constituent.…”

“…However, this type of depot may attract and trap antigen-specific T cells, reducing systemic immunity [15]. The DepoVax formulation generates a depot without an emulsion and has been demonstrated to induce strong and sustained systemic immune responses in pre-clinical and clinical trials [4,14]. Therefore, in this study we sought to understand the distribution patterns and kinetics of antigen release from a DepoVax vaccine depot in vivo.…”