Vaccines should activate all branches of immunity, including T cells and antibody responses, for generating a strong immune response. For therapeutic cancer vaccines, it is especially important to induce strong cytotoxic T-cell responses, since cytotoxic T-cells are the most potent immune cells for killing cancer cells. While cytotoxic T-cells can often be induced with viral vector and nucleic acid-based vaccines, peptide-based vaccines often induce only weak cytotoxic T-cell responses . When peptide antigens are taken up into antigen presenting cells, they are generally located inside intracellular vesicles, leading to presentation on MHC Class II molecules. This activates helper T-cell responses but is generally inefficient for inducing cytotoxic T-cells, which are dependent on MHC Class I antigen presentation for their activation. To address this problem, a novel light-based technology, called photochemical internalization, was studied in a Phase 1 clinical trial to evaluate its safety, tolerable dosing, and immunological responses.
Photochemical internalization technology
Photochemical internalization (PCI) is a novel technology for enhancing cytosolic drug delivery via a light-activated process. PCI vaccine includes an amphiphilic photoactive molecule called fimaporfin, the antigen, an immunological adjuvant, and 652 nm laser light. Antigen presenting cells take up vaccine antigens inside intracellular vesicles, and fimaporfin localizes on the inner surface of these vesicles. Upon laser light illumination, reactive oxygen species (ROS) are locally generated, inducing photochemical reactions, leading to permeabilization of the vesicle membranes. This releases the trapped antigens from vesicles into the cell cytosol, where the antigens can interact with the MHC Class I antigen presentation machinery, leading to presentation of the antigens on MHC Class I molecules and induction of cytotoxic T-cells.
96 healthy volunteers were recruited in the study. Participants received different doses of firmaporfin (0.75-50 µg) together with HPV16 (human papilloma virus) E6 peptide antigen and Hiltonol vaccine adjuvant. Each subject received up to 3 vaccinations intradermally at separate injection sites in the upper arms and belly with 2-week intervals. 20 hours after vaccination, injection site was illuminated with Modulight’s CE certified ML7710 laser (5 mW/cm2 for 200 s, total light dose of 1 J/cm2). Subjects in the control group received only HPV antigen and adjuvant without fimaporfin or laser to compare effects without PCI treatment. Adverse reactions were monitored, and blood samples collected to study immunological responses by ELISpot immunoassay and flow cytometry.
PCI with fimaporfin doses below 17.5 µg was safe and well tolerated, while higher doses caused local tolerability problems in some subjects, like erythema at the injection site and pain during illumination. There were only a few, mild systemic adverse events and no serious adverse events were reported. Evaluation of immunological responses revealed that PCI vaccination with a fimaporfin dose of 12.5 μg led to a 10-fold increase in the percentage of subjects exhibiting a T-cell response to vaccination, as compared to a control group without PCI treatment (83 % vs. 8%). Substantial number of responses were seen after the second vaccination (day 29) and the third vaccination boosted the response rates further (day 43). Moreover, the use of PCI seemed to result in a more consistent, multifunctional, and robust CD8+ T-cell responses to vaccination.
Percentage of responders to HPV16 E7 peptide vaccination with or without PCI treatment at different doses of fimaporfin. Responders were determined based on the ELISpot assay results measuring interferon-y secretion from antigen-stimulated T cells. Graphs from the original publication reproduced under the terms of the CC BY 4.0 International License.
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