Synthetic vaccine particles for durable cytolytic T lymphocyte responses and anti-tumor immunotherapy

Abstract

We previously reported that synthetic vaccine particles (SVP) encapsulating antigens and TLR agonists resulted in augmentation of immune responses with minimal production of systemic inflammatory cytokines. Here we evaluated two different polymer formulations of SVP-encapsulated antigens and tested their ability to induce cytolytic T lymphocytes (CTL) in combination with SVP-encapsulated adjuvants. One formulation led to efficient antigen processing and cross-presentation, rapid and sustained CTL activity, and expansion of CD8+ T cell effector memory cells locally and centrally, which persisted for at least 1–2 years after a single immunization. SVP therapeutic dosing resulted in suppression of tumor growth and a substantial delay in mortality in several syngeneic mouse cancer models. Treatment with checkpoint inhibitors and/or cytotoxic drugs, while suboptimal on their own, showed considerable synergy with SVP immunization. SVP encapsulation of endosomal TLR agonists provided superior CTL induction, therapeutic benefit and/or improved safety profile compared to free adjuvants. SVP vaccines encapsulating mutated HPV-16 E7 and E6/E7 recombinant proteins led to induction of broad CTL activity and strong inhibition of TC-1 tumor growth, even when administered therapeutically 13–14 days after tumor inoculation in animals bearing palpable tumors. A pilot study in non-human primates showed that SVP-encapsulated E7/E6 adjuvanted with SVP-encapsulated poly(I:C) led to robust induction of antigen-specific T and B cell responses.

Human papilloma virus E1-specific T cell immune response is associated with the prognosis of cervical cancer patients with squamous cell carcinoma

“…Several types of therapeutic vaccines, including recombinant protein vaccines, peptide vaccines, chimeric vaccines, nucleic acid vaccines, etc. are being assessed in terms of efficacy and safety [ 8 – 10 ]. However, there is not yet any such therapeutic vaccine licensed [ 11 ].…”

HPV16 E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer 

“…Epitope prediction is essential for the design and development therapeutic vaccines against HPV-related diseases. Compared with E6 peptides, E7 peptides are more frequently used in current research of peptide vaccines for HPV-induced CC [20][21][22] as the E7 protein is smaller with fewer amino acids thus more convenient for screening. However, vaccines targeting E7 might not be able to elicit T cell response indiscriminately in all CC patients.…”

Prognostic significance of negative conversion of high-risk Human Papillomavirus DNA after treatment in Cervical Cancer patients

“…This indicates not only the preventive HPV vaccination, but also therapeutic HPV vaccines, which can induce cellular immune response against HPV oncoproteins and eliminate malignant cells expressing HPV proteins are urgently needed. Currently, several therapeutic vaccines, including recombinant protein vaccines, peptide vaccines, chimeric vaccines, nucleic acid vaccines are being studied for efficacy and safety 27 - 29 . We look forward to the early clinical use of these vaccines.…”