A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer

Abstract

Neoantigen vaccines have been enthusiastically pursued for personalized cancer immunotherapy while vast majority of neoantigens have no or low immunogenicity. Here, a bi-adjuvant neoantigen nanovaccine (banNV) that codelivered a peptide neoantigen (Adpgk) with two adjuvants [Toll-like receptor (TLR) 7/8 agonist R848 and TLR9 agonist CpG] was developed for potent cancer immunotherapy. Specifically, banNVs were prepared by a nanotemplated synthesis of concatemer CpG, nanocondensation with cationic polypeptides, and then physical loading with hydrophobic R848 and Adpgk. The immunogenicity of the neoantigen was profoundly potentiated by efficient codelivery of neoantigen and dual synergistic adjuvants, which is accompanied by reduced acute systemic toxicity. BanNVs sensitized immune checkpoint programmed death receptor 1 (PD-1) on T cells, therefore, a combination of banNVs with aPD-1 conspicuously induced the therapy response and led to complete regression of 70% neoantigenspecific tumors without recurrence. We conclude that banNVs are promising to optimize personalized therapeutic neoantigen vaccines for cancer immunotherapy. A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer. Sci. Adv. 6, eaaw6071 (2020).

PD-1/PD-L1 Based Combinational Cancer Therapy: Icing on the Cake

“…Therefore, exploration of the efficacy and mechanism of co-blockade of PD-L1 and CTLA-4 is promising (Sugiura et al, 2019;Zhao et al, 2019). The emerging nanovaccine was reported to profoundly potentiate the immunogenicity of the neoantigen, enhancing responsiveness (Ni et al, 2020). Furthermore, some studies reveal that angiotensinconverting enzyme 2 (ACE2) expression is increased after interleukin (IL)-1b treatment (Clarke et al, 2014), blockade of IL-1b synergized with blockade of PD-1 can inhibit tumor growth (Tian et al, 2020).…”

Main Strategies for the Identification of Neoantigens

“…Unfortunately, this class of tools is at the initial stage of development, and their prediction power suffers from insufficient training data on TCR–epitope interactions. Meanwhile, in the present time, other strategies are being successfully implemented to improve the immunogenicity of neoantigens [ 131 , 132 ]. Thus, in [ 131 ] the weak B16F10 neoantigens described in [ 118 ] were fused to the transmembrane domain of diphtheria toxin (DTT), significantly enhancing their ability to elicit CD8 + T cell response and inhibit tumor growth.…”

“…Thus, in [ 131 ] the weak B16F10 neoantigens described in [ 118 ] were fused to the transmembrane domain of diphtheria toxin (DTT), significantly enhancing their ability to elicit CD8 + T cell response and inhibit tumor growth. A bi-adjuvant vaccine containing a neoantigen supplemented with two adjuvants such as the Toll-like receptor (TLR) 7/8 agonist R848 and the TLR9 agonist CpG, boosted the immunogenicity of the neoantigen due to efficient co-delivery and synergism of adjuvants [ 132 ].…”

Combination therapies utilizing neoepitope-targeted vaccines

“…Additionally, it is important to rationally select agents for combination and to ensure that agents do not antagonize each other. Due to promising results from monotherapy vaccine studies targeting neoepitopes, recent preclinical studies investigated combining neoepitope vaccines with other cancer therapies, including checkpoint inhibitors [18,20,28,[30][31][32][33], other immunooncology agents [18,34], and "non-immune" therapies [35] to improve their efficacies. Additionally, numerous clinical trials, summarized in Table 1, have been proposed to investigate neoepitope vaccination in combination with checkpoint inhibitors, other immuno-oncology agents, and "non-immune" cancer therapies.…”