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Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide–TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens ( n  = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity. Cancer vaccines that self-assemble into uniform nanoparticles improve tumor clearance.

Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation. Antigen-specific tolerance represents a promising strategy to treat type 1 diabetes and islet allograft rejection. Here, the authors deliver immune signals to lymph nodes to promote antigen-specific regulatory T cells and prevent disease in models of type 1 diabetes and allogenic islet transplantation.

In situ metabolic labelling and targeted modulation of dendritic cells has been achieved using a hydrogel system in combination with covalent capture of antigens and adjuvants, facilitating improved tumour-specific immune response.

Many experimental cancer vaccines are exploring toll-like receptor agonists (TLRas) such as CpG, a DNA motif that agonizes toll-like receptor 9 (TLR9), to trigger immune responses that are potent and molecularly-specific. The ability to tune the immune response is especially important in the immunosuppressive microenvironments of tumors. Because TLR9 is located intracellularly, CpG must be internalized by immune cells for functionality. Polyplexes can be selfassembled through electrostatics using DNA (anionic) condensed by a positively charged carrier. These structures improve cell delivery and have been widely explored for gene therapy. In contrast, here we use cationic poly (β-amino esters) (PBAEs) to assemble polyplexes from CpG as an adjuvant to target and improve immune stimulation in cells and mouse models. Polyplexes were formed over a range of PBAE:CpG ratios, resulting in a library of complexes with increasingly positive charge and stronger binding as PBAE:CpG ratio increased. Although higher PBAE:CpG ratios exhibited improved CpG uptake, lower ratios of PBAE:CpG—which condensed CpG more weakly, activated DCs and tumorspecific T cells more effectively. In a mouse melanoma model, polyplexes with lower binding affinities improved survival more effectively compared with higher binding affinities. These data demonstrate that altering the polyplex interaction strength impacts accessibility of CpG to TLRs in immune cells. Thus, physiochemical properties, particularly the interplay between charge, uptake, and affinity, play a key role in determining the nature and efficacy of the immune response generated. This insight identifies new design considerations that must be balanced for engineering effective immunotherapies and vaccines.

Biomaterial vaccines offer cargo protection, targeting, and co-delivery of signals to immune organs such as lymph nodes (LNs), tissues that coordinate adaptive immunity. Understanding how individual vaccine components impact immune response has been difficult owing to the systemic nature of delivery. Direct intra-lymph node ( i.LN. ) injection offers a unique opportunity to dissect how the doses, kinetics, and combinations of signals reaching LNs influence the LN environment. Here, i.LN. injection was used as a tool to study the local and systemic responses to vaccines comprised of soluble antigen and degradable polymer particles encapsulating toll-like receptor agonists as adjuvants. Microparticle vaccines increased antigen presenting cells and lymphocytes in LNs, enhancing activation of these cells. Enumeration of antigen-specific CD8 + T cells in blood revealed expansion over 7 days, followed by a contraction period over 1 month as memory developed. Extending this strategy to conserved mouse and human tumor antigens resulted in tumor antigen-specific primary and recall responses by CD8 + T cells. During challenge with an aggressive metastatic melanoma model, i.LN . delivery of depots slowed tumor growth more than a potent human vaccine adjuvant, demonstrating local treatment of a target immunological site can promote responses that are potent, systemic, and antigen-specific.

Vaccines and immunotherapies have provided enormous benefit to human health. However, the development of effective vaccines and immunotherapies for many diseases is hindered by challenges created by the complex pathologies of these targets. For example, in cancer the tumor microenvironment suppresses the function of tumor-specific T cells. In autoimmune diseases, lymphocytes specific for self-antigens attack self-tissue. New technologies providing more sophisticated control over immune response are needed to address these challenges. Lymph nodes (LNs) are tissues where adaptive immune responses develop. Therefore, local delivery of combinations of immune signals is a potential strategy to modulate antigen-specific T cell response for pro-immune or regulatory function. However, application of this idea is hindered since traditional administration routes provide little control over the kinetics, combinations and concentrations with which immune signals are delivered to LNs.Biomaterials have emerged as important tools to overcome these challenges as they provide unique capabilities, including co-delivery, targeting, and controlled release. The research presented here harnesses biomaterials to control immune signals present in LNs to modulate antigen-specific T cell response. In one area, intra-LN injection (i.LN) was used to deposit microparticles (MPs) encapsulating tumor-antigens, adjuvants and immunomodulators to promote tumor-specific central memory T cells. These cells display increased proliferative capacity and resistance to tumor-mediated immunosuppression. MPs encapsulating CpG, an inflammatory adjuvant, and a melanoma antigen potently expanded tumor-specific T cells. MPs delivering low doses of rapamycin–a regulatory immune signal–promoted tumor-specific central memory T cells when co-delivered with the melanoma vaccine. Another important aspect of T cell phenotype which can be modulated for therapeutic benefit is regulatory immune response to control autoimmunity. In this second area, biomaterial-based strategies were used to deliver regulatory immune signals to expand regulatory T cells (TREG) and promote immune tolerance. In one direction, liposomes were designed to deliver regulatory metabolic modulators to bias T cells. In a parallel direction, MPs encapsulating rapamycin and islet self-antigens were designed to promote tolerance in T1D. i.LN delivery of MPs expanded islet-specific TREG and inhibited disease in a mouse model of T1D. Together this work demonstrates potent and modular strategies to therapeutically modulate T cell response.

Background and hypothesisCurrent cancer therapies rely on nonspecific chemotherapies which cause severe side effects without combating relapse. Therapeutic cancer vaccines aim to harness the adaptive immune response to specifically target and eliminate established tumors, while generating durable tumor-specific T cell responses to prevent relapse. Toll like receptor agonists (TLRas) such as CpG strongly activate dendritic cells (DCs) and show promise as adjuvants for cancer vaccines when co-administered with tumor associated antigens (TAAs). Current strategies are exploring direct vaccination with TLRas and TAAs to prime DCs in vivo, but are hampered by the instability of vaccine components, inefficient co-localization of antigen and adjuvant, and poor trafficking and persistence in lymph nodes (LN) - tissues that orchestrate adaptive immunity. Direct LN injection of soluble vaccines show enhanced efficacy over systemic administration, but are limited by rapid flushing of vaccine components. Biomaterials offer the potential to enhance cancer vaccination by allowing sustained release, co-delivery, and protection of encapsulated cargo. We recently demonstrated that local delivery of non-toxic, degradable biomaterials loaded with antigens or adjuvants potently enhances antigen specific T cell immunity. Building on this work, we hypothesized that local introduction of particles loaded with CpG and soluble tumor lysates (TLs) might combat tumor progression in murine neuroblastoma models.Methods and resultsDegradable vaccine depots consisting of Poly(Lactide-co-Glycolide) microparticles encapsulating CpG (3.45±0.37 µg of CpG per mg of polymer) were synthesized by double emulsion. For prophylactic studies, mice were primed by intra lymph node (i.LN) injection at the inguinal lymph nodes using vaccine depots suspended in lysates prepared from murine neuroblastoma cells (Neuro-2a). Mice were boosted two weeks later subcutaneously at the tail base with soluble vaccine components. One week after the boost, lymphocytes from peripheral blood were pulsed with TL and stained intracellularly for IFNg by FACS. 0.71±0.13% of CD8+ T cells from mice immunized with vaccine depots secreted IFNg compared to 0.38±0.1% from the untreated group. Two weeks after the boost mice were challenged with 106 N2a cells. Strikingly, while 75% of mice in the unvaccinated group reached defined endpoints based on tumor burdens by day 15, 75% of mice vaccinated i.LN with vaccine depots were tumor free at day 20. Ongoing studies are comparing efficacy of i.LN vaccine depots to leading clinical adjuvants, and investigating therapeutic treatment regimens. These data demonstrate a potential new route for harnessing biomaterial vaccine carriers to program the LN environment to help combat pediatric cancer.