Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

Abstract

Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund’s adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.

Trial watch: Peptide-based vaccines in anticancer therapy

“…Among recent preclinical studies dealing with peptide-based anticancer vaccines, we found of particular interest the works of: (1) Zhu and colleagues (from the National Institutes of Health, Bethesda, MD, USA), who developed self-assembling albumin-vaccine nanocomplexes that reportedly enable superior delivery and mediated robust therapeutic effect against transplantable tumors growing in immunocompetent mice, especially when combined with immune checkpoint blockers and chemotherapy; 94 (2) Gall et al (from the MD Anderson Cancer Center, Houston, TX, USA), who unveiled a Fc receptor-mediated mechanism whereby the FDA-approved HER2-targeting mAB trastuzumab favors the uptake of a HER2-targeting vaccine by DCs, resulting in efficient cross-presentation of its immunodominant epitope in vivo and robust therapeutic effects against breast carcinoma; 171 (3) Tsuruta et al (from Kumamoto University, Kumamoto, Japan), who developed DEP domain containing 1 (DEPDC1)- and M-phase phosphoprotein 1 (MPHOSPH1)-derived synthetic long peptides (SLPs) that efficiently induce both helper T (T H ) cells and CTLs in vitro and in vivo ; 172 (4) Petrizzu and collaborators (from the Istituto Nazionale per lo Studio e la Cura dei Tumori, Naples, Italy), who showed that metronomic chemotherapy plus a PD-1-targeting immune checkpoint blocker are highly efficient in potentiating the antitumor effects of a multi-peptide vaccine in a mouse model of melanoma; 173 and (5) Tanaka and co-workers (from the Yamaguchi University, Ube, Japan), who demonstrated that miR-125b-1 and miR-378a expression levels may be harnessed to predict the efficacy of peptide-based vaccination against colorectal carcinoma. 174 …”

Non‐viral gene delivery for cancer immunotherapy

“…Moreover, NP‐based delivery systems can effectively target tumors via enhanced permeability and a retention effect or overexpressing receptors . Therefore, the accumulation, permeation and cellular uptake efficiency can be improved greatly by tumor microenvironment‐responsive nanovectors …”

“…45 Therefore, the accumulation, permeation and cellular uptake efficiency can be improved greatly by tumor microenvironment-responsive nanovectors. [46][47][48] NP-based approaches have been demonstrated as an effective strategy for stimulating a targeted and tumor microenvironmentsensitive immune response. [48][49][50][51][52] Researchers have designed versatile nanoformulations for the tumor-targeted and stimulusspecific delivery of immune modulators to the tumor tissues/cells (Table 1).…”

“…[46][47][48] NP-based approaches have been demonstrated as an effective strategy for stimulating a targeted and tumor microenvironmentsensitive immune response. [48][49][50][51][52] Researchers have designed versatile nanoformulations for the tumor-targeted and stimulusspecific delivery of immune modulators to the tumor tissues/cells (Table 1). 47,[53][54][55][56][57] For example, glutathione is abundant in the tumor cells compared to normal cells.…”

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

“…125−129 Researchers recently reported a cancer vaccine using albumin as a carrier showing great promise in in vivo trials. 130 Many more albumin-based approaches are currently in clinical trials. Taking advantage of natural protein aggregation processes may indeed provide a key to avoiding the challenges of heterogeneous distributions in synthetic and natural drug delivery materials.…”