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Review
. 2023 Jan 17:e2210452.
doi: 10.1002/adma.202210452. Online ahead of print.

Biomaterial-Based In Situ Cancer Vaccines

Yang Bo  1 , Hua Wang  1   2   3   4   5   6   7
Affiliations
Review

Biomaterial-Based In Situ Cancer Vaccines

Yang Bo et al. Adv Mater. .

Abstract

Cancer immunotherapies have reshaped the paradigm for cancer treatment over the past decade. Among them, therapeutic cancer vaccines that aim to modulate antigen-presenting cells and subsequent T cell priming processes are among the first FDA-approved cancer immunotherapies. However, despite showing benign safety profiles and the capability to generate antigen-specific humoral and cellular responses, cancer vaccines have been limited by the modest therapeutic efficacy, especially for immunologically cold solid tumors. One key challenge lies in the identification of tumor-specific antigens, which involves a costly and lengthy process of tumor cell isolation, DNA/RNA extraction, sequencing, mutation analysis, epitope prediction, peptide synthesis, and antigen screening. To address these issues, in situ cancer vaccines have been actively pursued to generate endogenous antigens directly from tumors and utilize the generated tumor antigens to elicit potent cytotoxic T lymphocyte (CTL) response. Biomaterials-based in situ cancer vaccines, in particular, have achieved significant progress by taking advantage of biomaterials that can synergize antigens and adjuvants, troubleshoot delivery issues, home, and manipulate immune cells in situ. This review will provide an overview of biomaterials-based in situ cancer vaccines, either living or artificial materials, under development or in the clinic, and discuss the design criteria for in situ cancer vaccines.

Keywords: Immunotherapy; biomaterials; cancer vaccines; in situ vaccines; neoantigens; tumor antigens.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Comparison of conventional cancer vaccines and in situ cancer vaccines. a) Conventional cancer vaccines are composed of preselected tumor antigens and immunostimulatory adjuvants, and aim to deliver antigens and adjuvants to antigen presenting cells (e.g., dendritic cells) in the lymph nodes for antigen presentation and subsequent priming of antigen-specific CD8+ T cells. The cytotoxic T lymphocytes (CTLs) can then recognize and kill tumor cells expressing the specific type of antigen. b) In situ cancer vaccines, instead, aim to generate endogenous tumor antigens directly from tumor cells and further utilize the generated antigens to elicit potent CTL response. Common strategies to induce the release of antigens from tumor cells include radiation therapy, chemotherapy, and oncolytic viruses or bacteria. The processing and presentation of the generated tumor antigens by dendritic cells, together with the subsequent T cell priming processes, is facilitated via the incorporation of immunostimulatory agents including adjuvants and proinflammatory cytokines.
Figure 2.
Figure 2.
Materials-based in situ cancer vaccines. Living materials (oncolytic virus or bacteria), nanomaterials, and biomaterial-scaffold-based in situ cancer vaccines can amplify the CTL response and antitumor efficacy against various types of tumors including immunologically cold solid tumors. a) The release of endogenous antigens from tumor cells can be facilitated with the assistance from chemotherapy, radiation, photodynamic therapy (PDT), or photothermal therapy (PTT). b) In-situ-generated tumor antigens are captured, shuttled into DCs, and processed and presented by DCs, while DCs are properly activated by the provided danger signal. c) Antigen-presenting and properly activated DCs induce the expansion of tumor-specific CD8+ T cells and CD4+ T helper cells. d) Meanwhile the immunosuppressive tumor microenvironment can be reprogrammed by repolarizing of M2-type macrophages to proinflammatory M1-phenotype, overcoming the immunosuppression from myeloid-derived suppressor cells (MDSCs) and increasing the CD8+/Treg ratio. e) In addition to inhibiting the primary tumors, in situ cancer vaccines can also exert abscopal effects and prevent tumor recurrence and the growth of metastatic cancers, by inducing memory T cell responses.
Figure 3.
Figure 3.
T-vec (Talimogene laherparepvec)-based in situ cancer vaccine. a) T-vec is engineered to lack ICP34.5 which enables selective infection of cancer cells, lack ICP47 which downregulates MHCI expression and thus prevents the recognition of T-Vec by effector CD8+ T cells, and secrete GM-CSF in infected cancer cells. Upon the lysis of cancer cells, GM-CSF is released to the tumor microenvironment and attract numerous DCs to the tumor site, which can take up, process, and present the released tumor antigens for elicitation of tumor-specific CTL response. In a phase 1b clinical trial, the combination therapy of T-vec and anti-PD-1 resulted in 62% overall response rate and 33% complete response rate in patients with metastatic melanoma. b) Changes in the expression of PD-L1, PD-1, CD8, CD4, CD56, CD20, CD45RO, and Foxp3 at week 6 between noninjected (left) and injected (right) samples. Median change for each subset is shown with a horizontal line. c) Example of the combination of S100 (blue), CD8 (green), and PD-L1 (red) staining of biopsy from a patient with a partial response (week 1), week 6 after injection of T-Vec, and at week 30 after long-term treatment with the combination of T-Vec and pembrolizumab. Reproduced with permission.[54] Copyright 2017, Elsevier.
Figure 4.
Figure 4.
Living-bacterial-based in situ cancer vaccine. a) VNP20009, an attenuated salmonella strain, was designed to adsorb tumor antigens released by tumor cells and transport them to DCs, for subsequent antigen presentation and T cell priming processes. b) Schematics for studying bacterial-induced DC modulation. c,d) Antigen-capturing bacteria could increase antigen presentation ability (c) and activation status (d) of DCs. e) Schematics for therapeutic tumor study. Primary CT26 tumors (1°) were irradiated, followed by bacteria treatment. Mice were rechallenged with the secondary tumors (2°). f,g) Average tumor growth curves of primary (f) and secondary (g) CT26 tumors post treatment. h) Survival of CT26-bearing mice. i) Tumor growth curves for successively rechallenged mice treated with radiation and antigen-capturing bacteria. Mice were rechallenged at the tumor on the opposite flank at days 152 and 208. a–i) Reproduced with permission.[63] Copyright 2022, Springer Nature.
Figure 5.
Figure 5.
Lipid-nanoparticle-based in situ cancer vaccines. a,b) Schematics of doxorubicin-loaded synthetic high-density lipoprotein-like nanodiscs (sHDL-DOX). sHDL-DOX can kill tumor cells and induce ICD, upregulating the expression of calreticulin and HMGB1 in tumor cells to enhance DC activation and T cell priming. CT26 colon tumor volumes for each treatment group are shown. c) Schematic illustration of in situ cancer vaccine. Low dose of DOX induced immunogenic cancer cell death to facilitate the release of TAAs. The released TAAs were then captured by lipid nanoparticles (LNPs) encapsulating cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and delivered into APCs via endocytosis. TAAs and cGAMP eventually escaped from endosomes/lysosomes for further cross-presentation and STING activation. d) Schematics for therapeutic tumor study. e) Tumor volume curves of B16F10 melanoma after the treatment with different formulations. n = 7, ***P ≤ 0.001. a,b) Reproduced with permission.[74] Copyright 2018, American Association for the Advancement of Science. c–e) Reproduced with permission.[77] Copyright 2021, American Association for the Advancement of Science.
Figure 6.
Figure 6.
Antigen-capturing or macrophage-modulating nanoparticles for in situ cancer vaccines. a,b) Numbers of proteins bound to antigen-capturing PLGA nanoparticles with different surface chemistries. c,d) Antigen-capturing nanoparticles improve the presentation of tumor antigens by dendritic cells and amplify the overall antitumor efficacy. e) Schematics for E64-DNA-mediated reprogramming of tumor-associated macrophages. E64-DNA can inhibit cysteine protease-mediated degradation of proteins in lysosomes, resulting in the preservation and improved presentation of tumor antigens. f) Experimental design (top) and effect of E64-DNA (25 μg) and cyclophosphamide (CTX; 50 mg per kg), alone or in combination, on E0771 tumor growth (bottom). VEH, vehicle (PBS). a–d) Reproduced with permission.[98] Copyright 2017, Springer Nature. e,f) Reproduced with permission.[105] Copyright 2021, Springer Nature.
Figure 7.
Figure 7.
Biomaterial-scaffold-based in situ cancer vaccine to treat poorly immunogenic tumors. a) The biomaterial is injected peritumorally, and Dox-iRGD is released to penetrate tumors and induce immunogenic death of tumor cells, whereas released chemokines can accumulate large numbers of immature dendritic cells (DCs) at the scaffold site. Accumulated DCs can take up and process tumor antigens while being activated with adjuvants to prime tumor-specific T cells for tumor cell killing. b,c) 4T1 cells were injected subcutaneously on day 0. Mice were untreated or treated with gels containing Dox-iRGD (100 μg) and CpG (50 μg) or Dox-iRGD (100 μg) alone or CpG (50 μg) alone on day 5. GM-CSF was incorporated in all groups. b) Average 4T1 tumor volume of each group over the course of the efficacy study. c) Kaplan–Meier plots for all groups. d–f) In situ gel vaccine combined with anti-PD-1 therapy for tumor control. d) Time frame of efficacy study. Following 4T1 tumor inoculation on day 0, gels containing Dox-iRGD (200 μg) and CpG (100 μg) were injected next to tumors on day 5, and anti-PD-1 was intraperitoneally injected on days 6, 9, 12, 15, and 18, respectively. e) Average 4T1 tumor volume of each group over the course of the efficacy study. f) Kaplan–Meier plots for all groups. g–j) Following surgical resection of luciferase-expressing 4T1 (luc-4T1) tumors, gels containing GM-CSF, Dox-iRGD (200 μg) and CpG (100 μg) or bolus vaccines (solution of same quantities of GM-CSF, Dox-iRGD, and CpG) were injected at surgical site. g) Outline of study. h) Luminescence signals of mice at different times. i) Kaplan–Meier plots for tumor-free survival of all groups. j) Kaplan–Meier plots for overall survival of all groups. a–j) Reproduced with permission.[135] Copyright 2020, Springer Nature.
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References

    1. WHO Report on Cancer: Setting Priorities, Investing Wisely and Providing Care for All, World Health Organization, 2020, available from https://www.who.int/publications/i/item/9789240001299.
    1. Darvin P, Toor SM, Sasidharan Nair V, Elkord E, Exp. Mol. Med 2018, 50, 1. - PMC - PubMed
    1. Seidel JA, Otsuka A, Kabashima K, Front. Oncol 2018, 8, 86. - PMC - PubMed
    1. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Car-bonnel F, Izzeddine H, Marabelle A, Champiat S, Berdelou A, Lanoy E, Texier M, Libenciuc C, Eggermont AMM, Soria J-C, Mateus C, Robert C, Nat. Rev. Clin. Oncol 2016, 13, 473. - PubMed
    1. Ramos CA, Heslop HE, Brenner MK, Annu. Rev. Med 2016, 67, 165. - PMC - PubMed

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