Engineering Targeting Materials for Therapeutic Cancer Vaccines

Abstract

Therapeutic cancer vaccines constitute a valuable tool to educate the immune system to fight tumors and prevent cancer relapse. Nevertheless, the number of cancer vaccines in the clinic remains very limited to date, highlighting the need for further technology development. Recently, cancer vaccines have been improved by the use of materials, which can strongly enhance their intrinsic properties and biodistribution profile. Moreover, vaccine efficacy and safety can be substantially modulated through selection of the site at which they are delivered, which fosters the engineering of materials capable of targeting cancer vaccines to specific relevant sites, such as within the tumor or within lymphoid organs, to further optimize their immunotherapeutic effects. In this review, we aim to give the reader an overview of principles and current strategies to engineer therapeutic cancer vaccines, with a particular focus on the use of site-specific targeting materials. We will first recall the goal of therapeutic cancer vaccination and the type of immune responses sought upon vaccination, before detailing key components of cancer vaccines. We will then present how materials can be engineered to enhance the vaccine's pharmacokinetic and pharmacodynamic properties. Finally, we will discuss the rationale for site-specific targeting of cancer vaccines and provide examples of current targeting technologies.

Keywords: cancer; immunoengineering; immunotherapy; material engineering; targeting strategies; vaccines.

FIGURE 1

Cell- and antibody-mediated cytotoxic mechanisms of anti-tumor immunity. The immune system uses multiple mechanisms to efficiently kill tumor cells, via cytotoxic CD8⁺ T cells (CTLs), NK cells, or antibody-mediated mechanisms. (A) To be activated, T cells need 3 signals from antigen-presenting cells (APCs; e.g., dendritic cell): signal (1) is the presentation of cancer antigens (black squares) via MHC complexes; signal (2) is the signaling induced by co-stimulatory receptors (e.g., CD80/86), which are expressed by the APCs in the presence of adjuvants (e.g., MAMPs/DAMPs); and signal (3) is the stimulation by pro-inflammatory cytokines. Such cytokines are produced by APCs as well as by CD4⁺ Th1 helper cells that further enhance activation of CTLs. Upon activation and recognition of tumor cells, CTLs can induce their death via various pathways, including perforin (PRF)/granzyme B (GZMB), FasL-Fas, TRAIL or inflammatory cytokines. Using similar pathways, NK cells can kill cancer cells that have downregulated their MHCI expression and fail to signal through the inhibitory killer immunoglobulin-like receptor (iKIR), or that overstimulate NK activating receptors (AR). (B) Tumors cells can also be targeted by antibodies that induce direct killing via the activation of the complement cascade, through a mechanism called complement-dependent cytotoxicity (CDC), which leads to the formation of membrane attack complexes (MAC) perforating the tumor cell membrane. In addition, antibodies can signal via Fc receptors (FcR) on innate immune cells, to induce antibody-dependent cell phagocytosis (ADCP) of tumor cells by macrophages, or antibody-dependent cell cytotoxicity (ADCC) by NK cells or neutrophils.

FIGURE 2

Site-specific targeting of therapeutic cancer vaccines. Cancer vaccines can be designed to specifically target sites that are potent for inducing anti-tumor immunity, including the tumor and lymphoid tissues. (A) Interactions between the tumor and immune infiltrates in the inflamed tumor microenvironment. Upon cancer cell death (e.g., T cell-mediated), cancer antigens are released in the local environment (1) and can be taken up by dendritic cells (DCs) to induce in situ activation of cancer-specific T cells (2). In addition, cancer antigens are either passively drained by lymphatic vessels or actively transported by immune cells trafficking to the draining lymph node (3), where potent immune responses can be induced. Then, T cells activated in the lymph nodes can home into the tumor to kill tumor cells (4). In addition, humoral immune responses may be triggered in the lymph node and can lead to the production of cancer-targeting antibodies that enter the tumor bed to induce antibody-mediated cytotoxic mechanisms (4). It is important to note here that the depicted tumor-immune interactions do not take place in tumors that are known as immune deserts (i.e., non-inflamed). CSC: cancer stem cells, Mφ: macrophage, LEC/BEC: lymphatic/blood endothelial cell, MSC: mesenchymal stem cells, ECM extracellular matrix. (B) Lymph nodes are relevant to target by therapeutic cancer vaccines as they are naturally optimized to induce strong immune responses, due to their high content in immature DCs, and naive T and B cells. Naive lymphocytes enter the lymph node via the high endothelial venules (HEV). Antigens and adjuvants can enter lymph nodes in soluble form and be further transported by subcapsular macrophages to follicular DCs to induce B cell responses (1). In addition, migratory DCs loaded with cancer antigens can go into the paracortical zone (2), where they activate antigen-specific CD4⁺ and CD8⁺ T cells. Activated T cells exit the lymph node via the medulla (3). FDC: follicular dendritic cell, imDC: immature dendritic cell, FRC: fibroblastic reticular cells. (C) Overview of the tumor circulatory system and tumor antigen biodistribution. Tumors are connected to the blood circulatory system by blood vessels (arterial system in red, venous system in blue) and lymphatic routes (in green). The tumor is a relevant site to target by cancer vaccines as it has the highest concentration of tumor antigens (high exposure: T+++), although its high immunosuppression (IS+++) might impair vaccine efficacy. Alternative sites to target can be the tumor-draining lymph node (TdLN) also relatively highly exposed to tumor antigens. As they are less immunosuppressed, targeting non-tumor-draining lymph nodes (nTdLN) and the spleen might lead to better immune activation upon vaccination, yet their poor exposure to tumor antigens might require the use of exogenous cancer antigens.

FIGURE 3

Examples of materials for the development of therapeutic cancer vaccines. Materials can be engineered to enhance the therapeutic efficacy and safety profiles of cancer vaccines. Materials with very different structures and physicochemical properties can be used as a basis for engineering the delivery of adjuvants and antigens to optimize immune activation. Such materials can be organic materials (A), including those derived from or mimicking biological materials (B), or inorganic materials (C) ISCOM: Immunostimulatory complex.

FIGURE 4

Overview of strategies for cancer cell targeting. Biomolecular engineering can be used to preferentially target the cancer cell at multiple levels, using differences between cancer cells and healthy ones to discriminate between them. (A) Cancer cells can be targeted with cell surface-binding moieties, based on specific affinities with cell-surface antigens, receptors, glycans, lipids or based on physicochemical properties (e.g., membrane charges). Most cell surface targeting strategies will lead to endocytosis of the targeting moiety. (B) The cancer cell cytoplasm can be directly targeted by using channel receptors that transport small molecules, or by using small molecules capable of crossing cell membranes. (C) Cancer cells reactivate specific promoters that are silenced in healthy cells, allowing cancer cell targeting by the delivery of genes placed under cancer specific promoters. (D) Finally, some pathogens (e.g., oncolytic viruses, bacteria) favorably infect and replicate in cancer cells, often leading to their death, thus providing additional means for preferential cancer cell targeting.