A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients

Abstract

Despite the promising therapeutic effects of immune checkpoint blockade (ICB), most patients with solid tumors treated with anti-PD-1/PD-L1 monotherapy do not achieve objective responses, with most tumor regressions being partial rather than complete. It is hypothesized that the absence of pre-existing antitumor immunity and/or the presence of additional tumor immune suppressive factors at the tumor microenvironment are responsible for such therapeutic failures. It is therefore clear that in order to fully exploit the potential of PD-1 blockade therapy, antitumor immune response should be amplified, while tumor immune suppression should be further attenuated. Cancer vaccines may prime patients for treatments with ICB by inducing effective anti-tumor immunity, especially in patients lacking tumor-infiltrating T-cells. These “non-inflamed” non-permissive tumors that are resistant to ICB could be rendered sensitive and transformed into “inflamed” tumor by vaccination. In this article we describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade. We incorporate into the schedule of standard of care (SOC) chemotherapy adjuvant setting a vaccine platform comprised of autologous dendritic cells loaded with personalized neoantigen peptides (PEP-DC) identified through our own proteo-genomics antigen discovery pipeline. Furthermore, we add nivolumab, an antibody against PD-1, to boost and maintain the vaccine's effect. We also demonstrate the feasibility of identifying personalized neoantigens in three pancreatic ductal adenocarcinoma (PDAC) patients, and we describe their optimal incorporation into long peptides for manufacturing into vaccine products. We finally discuss the advantages as well as the scientific and logistic challenges of such an exploratory vaccine clinical trial, and we highlight its novelty.

Development and Optimization of a GMP-Compliant Manufacturing Process for a Personalized Tumor Lysate Dendritic Cell Vaccine

“…Importantly, we are the first group to describe the production of a DC-based vaccine using the CliniMACS Prodigy in combination with culture in cell factories and an MPLA and IFNγ-based maturation. The OC-DC production process was approved by Swissmedic and we conducted two clinical trials utilizing the two types of personalized DC vaccines in two different indications (ovarian and pancreatic cancer) [27,28].…”

Biogenesis of HLA Ligand Presentation in Immune Cells Upon Activation Reveals Changes in Peptide Length Preference

“…In this study, we aimed to characterize the repertoire of naturally presented HLA-I and -II ligands in CD14 + precursors cells, as well as ImmDCs and MaDCs, leveraging our recently developed improved sample preparation method ( 23 ). Specifically, we searched for properties that would allow, in the future, improved prediction of immunogenic HLA ligands for clinical applications, such as for the development of personalized vaccines using DCs loaded with long peptides ( 48 ).…”

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

“…This circumvents the inhibition of activated, proliferating vaccine-induced T cells, and can dramatically foster T-cell responses by depletion of unwanted myeloid cells [133]. Gemcitabine has been explored in mice and humans in combination DC and other cancer vaccines with promising results [137][138][139][140][141]. Reassuringly, gemcitabine also synergizes with two other types of immune therapy, namely oncolytic virotherapy and ICB [142][143][144].…”