In Situ Nanoadjuvant-Assembled Tumor Vaccine for Preventing Long-Term Recurrence

Abstract

Although immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy, a monotherapy approach is not sufficient. Here, we report an immune checkpoint inhibitor-modified nanoparticle for an in situ-assembled tumor vaccine that can activate immune systems in the tumor microenvironment and prevent the long-term recurrence of tumors. Adjuvant-loaded nanoparticles were prepared by entrapping imiquimod (IQ) in photoresponsive polydopamine nanoparticles (IQ/PNs). The surfaces of IQ/PNs were then modified with anti-PDL1 antibody (PDL1Ab-IQ/PNs) for in situ assembly with inactivated tumor cells and immune checkpoint blocking of PDL1 (programmed cell death 1 ligand 1). The presence of anti-PDL1 antibodies on IQ/PNs increased the binding of nanoparticles to CT26 cancer cells overexpressing PDL1. Subsequent near-infrared (NIR) irradiation induced a greater photothermal anticancer effect against cells treated with PDL1Ab-IQ/PNs than cells treated with plain PNs or unmodified IQ/PNs. To mimic the tumor microenvironment, we cocultured bone marrow-derived dendritic cells with CT26 cells treated with various nanoparticle formulations and NIR irradiated. This coculture study revealed that NIR-inactivated, PDL1Ab-IQ/PN-bound CT26 cells induced maturation of dendritic cells to the greatest extent. Following a single intravenous administration of different nanoparticle formulations in CT26 tumor-bearing mice, PDL1Ab-IQ/PNs showed greater tumor tissue accumulation than unmodified nanoparticles. Subsequent NIR irradiation of mice treated with PDL1Ab-IQ/PNs resulted in tumor ablation. In addition to primary tumor ablation, PDL1Ab-IQ/PNs completely prevented the growth of a secondarily challenged CT26 tumor at a distant site, producing 100% survival for up to 150 days. A long-term protection study revealed that treatment with PDL1Ab-IQ/PNs followed by NIR irradiation inhibited the growth of distant, secondarily challenged CT26 tumors 150 days after the first tumor inoculation. Moreover, increased infiltration of T cells was observed in tumor tissues treated with PDL1Ab-IQ/PNs and NIR-irradiated, and T cells isolated from splenocytes of mice in which tumor recurrence was prevented showed active killing of CT26 cells. These results suggest that PDL1Ab-IQ/PNs in conjunction with NIR irradiation induce a potent, in situ-assembled, all-in-one tumor vaccine with adjuvant-containing nanoparticle-bound, inactivated tumor cells. Such in situ nanoadjuvant-assembled tumor vaccines can be further developed for long-term prevention of tumor recurrence without the need for chemotherapy.

High Molecular Weight Chitosan-Complexed RNA Nanoadjuvant for Effective Cancer Immunotherapy

“…Our studies of the protective efficacy of vaccination in mice challenged twice with B16-OVA tumor cells showed that suppression of challenged tumor growth was attributable to the increased infiltration of both CD4(+) and CD8(+) T lymphocytes into the tumor tissues. The long-term tumor-preventive effect observed in OVA and RA/CTS polyplex-vaccinated mice could be explained by the increase in effector memory T cells [13,37].…”

“…BMDCs were isolated and differentiated from monocytes as previously described, with minor modifications [13]. Briefly, femurs and tibiae from 6-week-old C57BL/6 mice (Raon Bio, Yongin, Kyonggi-do, Korea) were isolated and flushed with complete RPMI media to collect bone marrow.…”

“…Five days after the last treatment with RA/CTS polyplexes, B16-OVA cells (3 × 10 5 ) were injected subcutaneously into the right flank. Tumors were measured with calipers, and volumes were calculated according to the equation, a × b 2 × 0.5, where a is the longest and b is the shortest dimension [13]. Long-term protection against tumors afforded by vaccination was confirmed by re-challenging cured mice with B16-OVA cells, injected in the left flank.…”

Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective

“…In a separate study, Le et al demonstrated that coating the surface of nanoparticles containing imiquimod and photosensitizer with anti‐PD‐L1 antibody can significantly increase nanoparticle accumulation in tumors overexpressing PD‐L1. [ 29 ] They represented a sequence of transmission electron microscopy (TEM) images that demonstrated the presence of nanoparticles on tumor cell surface sensitizes tumor cells to irradiation‐induced ICD and generates antitumor immunity (Figure 1B). This in situ‐generated tumor vaccine, when combined with additional anti‐PD‐L1 antibodies, successfully prevented long‐term recurrence for up to 150 d after the primary tumor was discovered.…”

Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials

“…Yang et al [52] reported the use of a lipid (DSPE-PEG-mannose) modified cancer cell membrane that was coated onto a polymeric NP loaded with adjuvant TLR 7 for an anticancer effect [52]. Recently, Le et al [92] suggested an in situ nanoadjuvant as a tumor vaccine to prevent the long-term recurrence of tumors. In their study, polydopamine NPs were loaded with imiquimod, and then the NP surface was modified with programmed death-ligand 1 (PDL1) antibodies for the co-delivery of both antigen and adjuvants to the same antigen-presenting cells.…”