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Figure S8 from Virus-Like Particle–Drug Conjugates Induce Protective, Long-lasting Adaptive Antitumor Immunity in the Absence of Specifically Targeted Tumor Antigens
journal contributionposted on 2023-04-04, 01:02 authored by Rhonda C. Kines, Cynthia D. Thompson, Sean Spring, Zhenyu Li, Elisabet de los Pinos, Stephen Monks, John T. Schiller
Gating examples for MHC Class I H-2Db-E749-57 tetramer staining (A) and intracellular cytokine staining after PBMC re-stimulation (B) shown in Figure 6. C) Unstained and Isotype controls for each data set.
ARTICLE ABSTRACTThis 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 antitumor immunity in the TC-1 syngeneic murine tumor model. Upon in vitro activation with near-infrared light (NIR), AU-011–mediated cell killing was proimmunogenic in nature, resulting in the release of damage-associated molecular patterns such as DNA, ATP, and HMGB-1, activation of caspase-1, and surface relocalization 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% to 100% complete response rate that was durable 100 days after treatment, with 50% to 80% of those animals displaying protection from secondary tumor rechallenge. Depletion of CD4+ or CD8+ T cells, either at the time of AU-011 treatment or secondary tumor rechallenge of tumor-free mice, indicated that both cell populations are vital to AU-011′s ability to eradicate primary tumors and induce long-lasting antitumor protection. Tumor-specific CD8+ T-cell responses could be observed in circulating peripheral blood mononuclear cells within 3 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 antitumor immunity, and this activity is enhanced when combined with checkpoint inhibitor antibodies.