Systemic administration of immune checkpoint blockade (ICB) monoclonal antibodies (mAbs) can unleash antitumor functions of T cells but is associated with variable response rates and off-target toxicities. We hypothesized that antitumor efficacy of ICB is limited by the minimal accumulation of mAb within tissues where antitumor immunity is elicited and regulated, which include the tumor microenvironment (TME) and secondary lymphoid tissues. In contrast to systemic administration, intratumoral and intradermal routes of administration resulted in higher mAb accumulation within both the TME and its draining lymph nodes (LNs) or LNs alone, respectively. The use of either locoregional administration route resulted in pronounced T cell responses from the ICB therapy, which developed in the secondary lymphoid tissues and TME of treated mice. Targeted delivery of mAb to tumor-draining lymph nodes (TdLNs) alone was associated with enhanced antitumor immunity and improved therapeutic effects compared to conventional systemic ICB therapy, and these effects were sustained at reduced mAb doses and comparable to those achieved by intratumoral administration. These data suggest that locoregional routes of administration of ICB mAb can augment ICB therapy by improving immunomodulation within TdLNs.
Immunotherapy has reached clinical success in the last decade, with the emergence of new and effective treatments such as checkpoint blockade therapy and CAR T-cell therapy that have drastically improved patient outcomes. Still, these therapies can be improved to limit off-target effects, mitigate systemic toxicities, and increase overall efficacies. Nanoscale engineering offers strategies that enable researchers to attain these goals through the manipulation of immune cell functions, such as enhancing immunity against cancers and pathogens, controlling the site of immune response, and promoting tolerance via the delivery of small molecule drugs or biologics. By tuning the properties of the nanomaterials, such as size, shape, charge, and surface chemistry, different types of immune cells can be targeted and engineered, such as dendritic cells for immunization, or T cells for promoting adaptive immunity. Researchers have come to better understand the critical role the immune system plays in the progression of pathologies besides cancer, and developing nanoengineering approaches that seek to harness the potential of immune cell activities can lead to favorable outcomes for the treatment of injuries and diseases.
more » « less- Award ID(s):
- 1803517
- NSF-PAR ID:
- 10366582
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Nano Convergence
- Volume:
- 9
- Issue:
- 1
- ISSN:
- 2196-5404
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen-specific T cell responses and long-lived antitumor responses capable of combating metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first-generation clinical cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well-engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technology that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnology for increasing the immunogenicity of the tumor microenvironment (TME), which is critical to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.
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Nikolich-Žugich, Janko (Ed.)There is a critical need for adjuvants that can safely elicit potent and durable T cell-based immunity to intracellular pathogens. Here, we report that parenteral vaccination with a carbomer-based adjuvant, Adjuplex (ADJ), stimulated robust CD8 T-cell responses to subunit antigens and afforded effective immunity against respiratory challenge with a virus and a systemic intracellular bacterial infection. Studies to understand the metabolic and molecular basis for ADJ’s effect on antigen cross-presentation by dendritic cells (DCs) revealed several unique and distinctive mechanisms. ADJ-stimulated DCs produced IL-1β and IL-18, suggestive of inflammasome activation, but in vivo activation of CD8 T cells was unaffected in caspase 1-deficient mice. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, ADJ modulated multiple steps in the cytosolic pathway of cross-presentation by enabling accumulation of degraded antigen, reducing endosomal acidity and promoting antigen localization to early endosomes. Further, by increasing ROS production and lipid peroxidation, ADJ promoted antigen escape from endosomes to the cytosol for degradation by proteasomes into peptides for MHC I loading by TAP-dependent pathways. Furthermore, we found that induction of lipid bodies (LBs) and alterations in LB composition mediated by ADJ were also critical for DC cross-presentation. Collectively, our model challenges the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have strong implications in the rational development of safe and effective immune adjuvants to potentiate robust T-cell based immunity.more » « less
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Abstract Background Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.
Methods The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.
Results Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.
Conclusions Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.
Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.
