Virus-like particle-drug conjugates induce protective, long-lasting adaptive anti-tumor immunity in the absence of specifically targeted tumor antigens
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence l'intérêt d'un anticorps conjugué à une particule de type viral obtenue par génie génétique (protéine L2 du papillomavirus humain de type 16 associée à une protéine L1 modifiée) et à une molécule sensible aux proches infrarouges pour induire une immunité anti-tumorale adaptative et une protection de longue durée en l'absence d'antigènes tumoraux spécifiques
This study examined the ability of a papillomavirus-like particle drug-conjugate, belzupacap sarotalocan (AU-011) to eradicate subcutaneous tumors after intravenous injection and to subsequently elicit long-term anti-tumor immunity in the TC-1 syngeneic murine tumor model. Upon in vitro activation with near-infrared light (NIR), AU-011-mediated cell killing was pro-immunogenic in nature, resulting in the release of damage-associated molecular patterns such as DNA, ATP, and HMGB-1, activation of caspase-1, and surface re-localization of calreticulin and HSP70 on killed tumor cells. A single in vivo administration of AU-011 followed by NIR caused rapid cell death, leading to long-term tumor regression in ~50% of all animals. Within hours of treatment, calreticulin surface expression, caspase-1 activation, and depletion of immunosuppressive leukocytes were observed in tumors. Combination of AU-011 with immune checkpoint inhibitor antibodies, anti-CTLA-4 or anti-PD-1, improved therapeutic efficacy, resulting in 70-100% complete response rate that was durable 100 days post-treatment, with 50-80% of those animals displaying protection from secondary tumor re-challenge. Depletion of CD4+ or CD8+ T cells, either at the time of AU-011 treatment or secondary tumor re-challenge of tumor-free mice, indicated that both cell populations are vital to AU-011's ability to eradicate primary tumors and induce long-lasting anti-tumor protection. Tumor-specific CD8+ T-cell responses could be observed in circulating PBMCs within three weeks of AU-011 treatment. These data, taken together, support the conclusion that AU-011 has a direct cytotoxic effect on tumor cells and induces long-term anti-tumor immunity, and this activity is enhanced when combined with checkpoint inhibitor antibodies.