Abstract
With the emergence of immune checkpoint inhibitors and adoptive T-cell therapies, there is a considerable interest in using personalized autologous dendritic cell (DC) vaccines in combination with T cell-targeting immunotherapies to potentially maximize the therapeutic impact of DC vaccines. Here, we describe the development and optimization of a Good Manufacturing Practice (GMP)-compliant manufacturing process based on tumor lysate as a tumor antigen source for the production of an oxidized tumor cell lysate loaded DC (OC-DC) vaccine. The manufacturing process required one day for lysate preparation and six days for OC-DC vaccine production. Tumor lysate production was standardized based on an optimal tumor digestion protocol and the immunogenicity was improved through oxidation using hypochloric acid prior to freeze-thaw cycles resulting in the oxidized tumor cell lysate (OC-L). Next, monocytes were selected using the CliniMACS prodigy closed system and were placed in culture in cell factories in the presence of IL-4 and GM-CSF. Immature DCs were loaded with OC-L and matured using MPLA-IFNγ. After assessing the functionality of the OC-DC cells (IL12p70 secretion and COSTIM assay), the OC-DC vaccine was cryopreserved in multiple doses for single use. Finally, the stability of the formulated doses was tested and validated. We believe this GMP-compliant DC vaccine manufacturing process will facilitate access of patients to personalized DC vaccines, and allow for multi-center clinical trials.
Highlights
Often referred to as the most potent antigen presenting cells (APC), dendritic cells (DC) have been used since the mid-1990s in clinical trials for therapeutic vaccination of cancer patients [1]
We present the results from the process development work performed to optimize this Good Manufacturing Practice (GMP)-compliant oxidized tumor cell lysate loaded DC (OC-DC) vaccine production process
The oxidized tumor cell lysate (OC-L) manufacturing process was adapted from the method described by Chiang et al [12] in order to render it GMP-compliant for Swiss regulatory requirements
Summary
Often referred to as the most potent antigen presenting cells (APC), dendritic cells (DC) have been used since the mid-1990s in clinical trials for therapeutic vaccination of cancer patients [1]. The proven immunogenicity of DC-based vaccines and their safety profile were very promising, but objective clinical responses were not as positive as initially expected [2,3]. The use of personalized autologous DC vaccines in combination with T-cell-targeting immunotherapies appears as an appealing opportunity for vaccines to reach their full therapeutic potential. To this date, one of the major challenges for DC vaccination remains a cost-effective GMP-compliant process standardized in the EU, in Switzerland, and in the United States.
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