Journal of Allergy and Clinical Immunology, Journal Year: 2024, Volume and Issue: 153(3), P. 572 - 575

Published: Jan. 20, 2024

Systemic immunotherapeutics have been a clinical staple in the treatment of cancer, infectious diseases, organ and cell transplantation, autoimmunity, allergies. Although their utility remains unquestioned, systemic administration these drugs is associated with limited efficacy, significant adverse off-target effects, transient activity, requirement for frequent repeated dosing. To this end, recent technological advancements provided novel means sustained drug delivery to specific tissues targeted localized approaches immunotherapeutics. In article, we present various cutting-edge platform technologies, including implants, multireservoir systems, scaffolds encapsulating immunomodulatory agents local administration. Examples application allergy, diseases are discussed, highlighting potential such systems innovative intervention. Immunomodulatory therapies engage immune-relevant targets manage or treat variety diseases. Depending on disease, can be conventional small molecule pharmaceutics biologic agents, nucleic acids, proteins, cells.1Campa-Carranza J.N. Paez-Mayorga J. Chua C.Y.X. Nichols J.E. Grattoni A. Emerging strategies circumvent immunosuppression transplantation.Expert Opin Drug Del. 2022; 19: 595-610Crossref PubMed Scopus (7) Google Scholar demonstrated efficacy applications as transplantation allergic However, unfavorable physiologic kinetics subsequent therapeutic pose challenges. causes dispersion, whereas hinges presence high concentrations activity within target at disease site.2Kichloo Albosta M. Dahiya D. Guidi J.C. Aljadah Singh et al.Systemic effects toxicities immunotherapy: review.World J Clin Oncol. 2021; 12: 150-163Crossref Because low levels, typically required but not always feasible. Further, serious reactions on-target side owing overactivation oversuppression immune system impediments successful management. Additionally, attributable nonspecificity further exacerbate safety concerns. innovations that provide approach longer duration management poised new frontier therapies. Long-acting could reduce dosage, frequency, toxicities, which turn improves medication adherence, yielding long-lasting preventative curative effect. Of relevance, long-acting disease-targeting platforms clinically established chronic conditions HIV,3Pons-Faudoa F.P. Di Trani N. Capuani S. Campa-Carranza Nehete B. Sharma al.Long-acting refillable nanofluidic implant confers protection against SHIV infection nonhuman primates.Science Translational Medicine. 2023; 15eadg2887Crossref (6) diabetes, psychiatric illnesses.4Baryakova T.H. Pogostin B.H. Langer R. McHugh K.J. Overcoming barriers patient adherence: case developing systems.Nature Reviews Discovery. 22: 387-409Crossref (34) Considering success approaches, highlight few technologies developed immunomodulation achieve control particular focus (Fig 1). Immunotherapy has transformed cancer an unprecedented manner. inherent acquired heterogeneity leads variable responses. Immune evasion leading contributor failure. Thus, educate identify foreign, nonself allows eluding evasion. Pertinent this, context situ vaccines,5Liu H.-C. Davila Gonzalez Viswanath D.I. Vander Pol R.S. Saunders S.Z. al.Sustained intratumoral agonist CD40 antibody overcomes immunosuppressive tumor microenvironment pancreatic cancer.Adv Sci. 102370054Google Scholar,6Yousefpour P. Ni K. Irvine D.J. Targeted modulation cells using engineered biomaterials.Nat Rev Bioeng. 1: 107-124Crossref sphere applicability broad extends vaccines These rely biodegradable situ–forming hydrogels, polymers, nanoformulations capable immunomodulators antigens. preclinical setting, some highly efficacious models settings hold much promise translation.7Ou B.S. Saouaf O.M. Baillet Appel E.A. Sustained improving adaptive responses.Adv Deliver Rev. 187114401Crossref (30) ultimate multiple factors, practicality acceptability among others. note, may require booster administration, unfeasible limit relevance technology. addressing need long-term drug8Liu Pesaresi F. Xu Y. Zhang L. al.Potentiating antitumor through radiation anti-CD40 anti-PDL1.Int Radiat Oncol Biol Phys. 110: 492-506Abstract Full Text PDF (33) antigen developed. Among them, NanoLymph was designed homing and/or reprogramming targets.9Viswanath Liu H.C. Huston D.P. biomaterial-based personalized vaccines.Biomaterials. 280121297Crossref (26) The 3-dimensional (3D) printable subcutaneous deployment dual reservoirs, each immunomodulator elution presentation. scale (∼8 mm diameter 2 thickness) "D-shaped" agnostic offers flexibility use wide spectrum When reservoirs loaded GM-CSF resiquimod (a Toll-like receptor 7/8 agonist) well peptide antigen, dendritic (DCs) recruited site activated antigen-presenting (APCs). Thereafter, DCs migrate lymph nodes initiate antigen-specific T-cell response. versatility immunomodulators, antigens, will permit orchestration cell–mediated response across range acting prophylactic vaccine clear antigens adopted generate immunity pathogens. autologous whole lysates used source, facilitating generation directed toward unique antigenic repertoire patient's own tumor.10Diao Rethinking source: based cell/tissue lysate cell.Adv 102300121Crossref (13) crucial generating potent activation. context, peritumoral implantation more effective than distal site, although placement would compromise accessibility adjuvant loading refilling. refillability aspect technology advantageous treatment. Other platforms, nanoparticle microencapsulation, gradually release components (antigens adjuvants) pathogens, ensuring immunization.11Kerr M.D. Johnson W.T. McBride D.A. Chumber A.K. Shah N.J. Biodegradable enhancing delivery.Bioeng Transl Med. 8e10591Crossref (1) Scholar,12Roth G.A. Picece V.C.T.M. Ou Luo W. Pulendran Designing spatial temporal responses.Nat Mater. 7: 174-195Crossref (114) Compared traditional vaccines, shown enhanced fewer doses, makes them particularly relevant resource-limited areas. challenges include stability viability components, precise rates, extensive testing development. An alternative form immunomodulation, adoptive therapy, engineers T ex vivo vivo. after reinfusion, only fraction actually reach tumor, where they encounter difficulty penetrating mass.13Zhang A.Q. Hostetler Chen L.E. Mukkamala V. Abraham Padilla L.T. al.Universal redirection CAR solid tumours via membrane-inserted ligands CAR.Nat Biomed Eng. 1113-1128Crossref (9) More importantly, surface increases it proliferates, resulting short-lived responses therapy. address challenges, biomaterials–based platform, termed synergistic vaccination depot (SIVET), developed.14Adu-Berchie Brockman J.M. T.W. D.K.Y. Najibi A.J. al.Adoptive transfer host recruitment cryogel promotes tumors.Nat Commun. 14: 3546Crossref SIVET advances beyond previous work centered solely DCs. Composed alginate-collagen hybrid cryogel, controlled adoptively transferred immunostimulants attract APCs. facilitates debulking, dying serve source. Simultaneous FMS-like tyrosine kinase 3 ligand (FLT3L) CpG stimulates continual APC activation, respectively. This enables escape representing intervention immunomodulation. Transplant patients viable allografts restore dysfunctional organs tissues. both transplantation. rejection barrier widespread adoption. Graft results destruction transplanted tissues, triggered by even slight mismatches HLA alleles. As such, regimens commonly avoid rejection. Unfortunately, severe increased risks infections, neoplasms, damage. challenge, numerous modulation, sparing body from deleterious effect lifelong suppression.15Chua Jiang A.Y. Eufrásio-da-Silva T. Dolatshahi-Pirouz Orive G. al.Emerging therapeutics.Trends Biotechnol. 41: 358-373Abstract (8) minimizing immunogenicity clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) genome editing; leveraging RNA therapeutics cytokine induce tolerance; cotransplantation reg cells, Sertoli mesenchymal stem cells; agents.15Chua share suitable ideal achieves retention while providing tissue microenvironment. One NICHE, dual-reservoir 3D-printed nylon subdermal islets type 1 diabetes (T1D). native microenvironment, densely vascularized intraislet capillaries, obtain approximately 20% blood supply. Following implantation, NICHE relies angiogenic properties dense vessel network supplying oxygen, nutrients, rapid glucose insulin exchange function islets.16Paez-Mayorga Farina Lotito M.L. Niles J.A. Salazar H.F. al.Enhanced vascularization encapsulation device platelet-rich plasma cells.Adv Healthc 2020; 9e2000670PubMed prevented immunosuppressants thymoglobulin, cytotoxic lymphocyte–associated antigen-4 (CTLA-4) immunoglobulin, anti-CD40-L, depleting impeding activation costimulatory pathway Notably, transcutaneous reloading reservoir, extending functionality over long term. different (eg, growth immunoadjuvants, cytokines) alone combination, simultaneous sequential support during phases engraftment remodeling. allogenic islet model, immunocompetent diabetic rats, achieved T1D reversal no sign throughout 180 days analysis.17Paez-Mayorga Hernandez al.Implantable niche allotransplantation rats.Nature Communications. 13: 7951Crossref (11) Local also codelivery adjuvant–releasing microparticles gels cells.18Wang X. Brown N.K. Wang Shariati Fuchs al.Local prevent allo-rejection insulin-producing cells.Advanced Science. 82003708Google notable example, FasL-modified microgels conferred co.transplanted non.human primates. Here, Fas receptor/Fas (FasL) leveraged confer privilege tolerance self-antigens inducing apoptosis infiltrating lymphocytes inflammatory cells.19Lei Coronel M.M. Yolcu E.S. Deng H. Grimany-Nuno O. Hunckler al.FasL acceptance primates.Sci Adv. 8eabm9881Crossref (29) translatable T1D, neurodegenerative cardiovascular pathologies hormone deficiencies. Their adaptability dosing timing duration, ability localize distribution render development therapeutics. given multicomponent nature, regulatory approval complex translational efforts. Allergic disorders affect one-third population remain challenge. allergen avoidance method prevention, possible, symptomatic medications adequate. Over past century, immunotherapy (AIT) evolved IgE-mediated hypersensitivity disorders.20Durham S.R. Shamji M.H. Allergen past, future.Nat Immunol. 23: 317-328Crossref (75) AIT strategy many aeroallergens stinging insect allergens injection extracts, recently, recombinant allergens, chemically altered (allergoids), cell-targeted peptides. Sublingual aeroallergens, oral approved peanut allergy desensitization. Epicutaneous, microneedle patch, mRNA vaccine, intralymphatic under investigation, growing number additional improve exploratory. combining immunomodulating agonists, mAbs cytokines, receptors. goal tolerance.20Durham Mechanistically, AIT-induced manifested induction DCs, B produce IL-10 TGF-β inhibiting TH2 innate lymphoid hence reducing cytokines IgG-blocking antibodies inhibit binding IgE allergen. Efforts enhance tolerance-inducing exploring nanoparticles, patches,21Paris J.L. Vora L.K. Torres M.J. Mayorga C. Donnelly R.F. Microneedle array patches allergen-specific immunotherapy.Drug Discov Today. 28103556Crossref (4) programmable implants agents. Nanoparticle formulations optimized physical chemical size, pH, loading, optimal cellular targeting uptake.22Johnson Duschl Himly Nanotechnology-based potentials adjuvants research.Vaccines (Basel). 8: 237Crossref (28) Importantly, offer topical, oral, Murine studies allergen-loaded nanoparticles tolerance.23Hughes K.R. M.N. Landers J.J. Janczak K.W. Turkistani Rad L.M. al.Masked safely attenuates anaphylactic murine allergy.Front Allergy. 3829605Crossref potentially passive epicutaneous APCs skin, thereby AIT. tolerance.24Landers Shakya Zarnitsyn Patel Baker Jr., J.R. al.Targeted skin desensitization peanut.Immunotherapy. 539-552Crossref (16) There implantable microchambers, aforementioned 3D printed applications,3Pons-Faudoa exploited Such entail NanoLymph, chamber promote migration differentiation tolerance. Overall, convergence engineering interdisciplinary collaborations likely yield treating near future. conclusion, antigen-delivery broadened management, tunable extend simplifying regimen quality life. evident field immunotherapy, long-lasting, transformative impact care. cost-effectiveness medical treatments contribute health care equity. Enhanced reduced lower frequency direct costs decrease expenses, those related

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