Development of a vaccine based on bacteria‐mimicking tumor cells coated with novel engineered toll‐like receptor 2 ligands

Abstract

For a successful tumor vaccine, it is necessary to develop effective immuno‐adjuvants and identify specific tumor antigens. Tumor cells obtained from surgical or biopsy tissues are a good source of tumor antigens but, unlike bacteria, they do not induce strong immune responses. Here, we designed 2 novel lipopeptides that coat tumor cell surfaces and mimic bacterial components. Tumor cells coated with these lipopeptides (called bacteria‐mimicking tumor cells [BMTC]) were prepared and their efficacy as a tumor vaccine examined. Natural bacterial lipopeptides act as ligands for toll‐like receptor 2 (TLR2) and activate dendritic cells (DC). To increase the affinity of the developed lipopeptides for the negatively charged plasma membrane, a cationic polypeptide was connected to Pam2Cys (P2C), which is the basic structure of the TLR2 ligand. This increased the non‐specific binding affinity of the peptides for the cell surface. Two such lipopeptides, P2CSK11 (containing 1 serine and 11 lysine residues) and P2CSR11 (containing 1 serine and 11 arginine residues) bound to irradiated tumor cells via the long cationic polypeptides more efficiently than the natural lipopeptide MALP2 (P2C‐GNNDESNISFKEK) or a synthetic lipopeptide P2CSK4 (a short cationic polypeptide containing 1 serine and 4 lysines). BMTC coated with P2CSR11 or P2CSK11 were efficiently phagocytosed by DC and induced antigen cross‐presentation in vitro. They also induced effective tumor‐specific cytotoxic T cell responses and inhibited tumor growth in in vivo mouse models. P2CSR11 activated DC but induced less inflammation‐inducing cytokines/interferons than other lipopeptides. Thus, P2CSR11 is a strong candidate antigen‐specific immuno‐adjuvant, with few adverse effects.

Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota

“…Thus, the conjugation of Pam 3 CSK 4 to peptide vaccines improved their anti-cancer activity in preclinical models [ 120 ], and a vaccine composed of a synthetic TLR2 ligand (called Amplivant ® ) conjugated to HPV16 E6 long peptides is currently undergoing a phase I clinical trial in patients with HPV16 positive tumors or premalignant lesions (NCT02821494). Although other vaccines exploiting TLR2 agonists as adjuvants have been recently tested in different preclinical models of solid tumors, clinical data on their safety and effectiveness have not been provided so far [ 121 , 122 ], in contrast to agonists of other TLRs that are extensively tested in the clinic [ 123 ]. Actually, TLR2 is activated by two poly-TLR agonists currently used or tested in cancer treatment, i.e., a Food and Drug Administration-approved live attenuated Mycobacterium bovis preparation of bacillus of the Calmette–Guerin strain and CADI-05, a polyantigenic vaccine containing heat-killed Mycobacterium indicus pranii currently undergoing clinical investigation.…”

Recent research progress of biologically active peptides

“…Activation of DCBUT by P2CSR11 induces less inflammatory inducer/interferon. P2CSR11 is a strong candidate antigen‐specific immunoadjuvant 132 …”

TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer

“…Wu et al found that lipo-OVA (Ovalbumin fused with the TLR2 agonist, the lipid part of the bacteria) showed a strong anti-tumor effect by activating BMDCs maturation, promoting cross-presentation of tumor antigen, inducing CTL responses, increasing the numbers of CD8+ T cells (Wu et al, 2016). A vaccine comprising bacteria-mimicking tumor cells (BMTC) and P2CSR11/P2CSK11 (TLR2 ligand) promoted antitumor immunity by stimulating DCs and enhancing antigen presentation (Akazawa et al, 2018).…”