The 2018 Nobel prize in physiology or medicine was awarded to pioneers in the field of cancer immunotherapy, as the utility of leveraging a patient’s coordinated and adaptive immune system to fight the patient’s unique tumour has now been validated robustly in the clinic. Inflammation and immune evasion play an important role in the development and progression of malignancies. While traditional treatments such as chemotherapy or radiotherapy are aimed directly at the tumor cell, with oncological immunotherapy the tumor immune microenvironment is intervened in order to create an effective immune response against the tumor, or increase the existing effector mechanisms that try to kill it. Still, the proportion of patients who respond to immunotherapy remains modest: the clinical benefits are limited by the difficulties in obtaining effective delivery of therapeutic agents to the target site. The strategies must allow immunotherapeutic drugs to have appropriate kinetics and distribution, avoiding as much as possible to generate adverse effects. In this context, nanoparticles have emerged as a versatile solution thanks to their favorable transport and surface functionalization properties. Thanks to the recent development of biomaterials that respond to different stimuli (variations in pH, temperature, electric charge), sophisticated multifunctional nanoparticle systems have been developed that have expanded the therapeutic possibilities. The tumor microenvironment is a fundamental target for immunotherapy: its impact on the effectiveness of the therapy can be far-reaching. During tumor growth, the microenvironment interacts with tumor cells using different types of immune cells (T cells, lymphocytes, dendritic cells, macrophages and myeloid-derived cells) in order to mediate their immune tolerance, with consequent influence on the effects clinical therapy. In recent years, nanoparticles have been shown to possess the suitable requirements for reshaping the tumor microenvironment through the elimination of immunosuppressive cells, the reprogramming of regulatory immune cells, the promotion of cytokine secretion, the delivery of immunomodulating agents, the immune checkpoints blockade. Cancer vaccines play an important role in cancer immunotherapy, but in the clinical setting, their use is limited because primary tumor antigens can induce only a partial response. The possibility of encapsulating antigens and adjuvants together in nano vaccines ensures that both components will be delivered together with the same antigen-presenting cells and allows the T cells to be activated more, improving the antitumor response. Biodegradable nanoparticles are among the most promising vehicles for cancer vaccines, in the most recent studies nanovaccines based on lipid particles, liposomes and micelles but also inorganic and metallic nanoparticles have been tested. Nanotechnologies have also been applied ex vivo and used in the activation and expansion of T cells for adoptive therapy. Advances in genetic engineering have led to new approaches to redirect T cells to tumor antigens through chimeric synthetic antigen receptors (CARs). The use of nanoparticles facilitates the production of T cells for adoptive therapy by improving the antigen presentation by dendritic cells. The development of nanoparticles represents one of the most challenging areas of nanotechnology research; the main challenge concerns the definition of chemical, production and control methods that are reproducible and translatable on a large scale. The convergence of cancer immunotherapy, nanotechnology and bioengineering is maturing to the point that it may impact patient lives in the not-too-distant future.
Nel 2018, il premio Nobel per la fisiologia o la medicina è stato assegnato ai pionieri nel campo dell’immunoterapia antitumorale; l’utilità di far leva sul sistema immunitario del paziente è stata convalidata nella clinica. L’infiammazione e l’evasione immunitaria giocano un ruolo importante nello sviluppo e nella progressione delle malignità. Mentre i trattamenti tradizionali come la chemioterapia o la radioterapia sono rivolti direttamente alla cellula tumorale, con l’immunoterapia oncologica si interviene sul microambiente immunitario tumorale al fine di creare una risposta immunitaria efficace contro il tumore. La percentuale di pazienti che rispondono all’immunoterapia rimane ancora modesta: i benefici clinici sono limitati dalle difficoltà nell’ottenere la liberazione efficace degli agenti terapeutici al sito bersaglio. Le strategie devono permettere ai farmaci immunoterapeutici di avere una cinetica e una distribuzione appropriata evitando il più possibile di generare effetti avversi. In questo ambito le nanoparticelle sono emerse come una soluzione versatile grazie alle loro favorevoli proprietà di trasporto e di funzionalizzazione superficiale. Grazie al recente sviluppo di biomateriali che rispondono a diversi stimoli (variazioni di pH, di temperatura, di carica elettrica) sono stati sviluppati sofisticati sistemi di nanoparticelle multifunzionali che hanno ampliato le possibilità terapeutiche. Il microambiente tumorale è un bersaglio fondamentale per l’immunoterapia: durante la crescita del tumore il microambiente interagisce con le cellule tumorali per mezzo di diversi tipi di cellule immunitarie (cellule T, linfociti, cellule dendritiche, macrofagi e cellule di derivazione mieloide) allo scopo di mediare la loro tolleranza immunitaria, con conseguente influenza sugli effetti clinici della terapia. Negli ultimi anni, le nanoparticelle hanno mostrato di possedere i requisiti adatti per rimodellare il microambiente tumorale attraverso l’eliminazione delle cellule immunosoppressive, la riprogrammazione delle cellule immunitarie regolatorie, la promozione della secrezione di citochine, la veicolazione di agenti immunomodulanti, il blocco dei checkpoint immunitari. I vaccini antitumorali svolgono un ruolo importante nell’immunoterapia contro il cancro, ma in ambito clinico l’utilizzo è limitato perché dagli antigeni tumorali primari può essere indotta solo una risposta parziale. La possibilità di incapsulare insieme antigeni e adiuvanti in nanovaccini assicura che entrambi i componenti saranno liberati insieme alle stesse cellule presentanti l’antigene e permette di attivare maggiormente le cellule T, migliorando la risposta antitumorale. Le nanoparticelle biodegradabili sono tra i veicoli più promettenti per i vaccini contro il cancro, negli studi più recenti sono stati testati nanovaccini a base di particelle lipidiche, liposomi e micelle ma anche nanoparticelle inorganiche e metalliche. Le nanotecnologie sono state applicate anche ex vivo e utilizzate nell’attivazione ed espansione delle cellule T per la terapia adottiva. I progressi nell’ingegneria genetica hanno portato a nuovi approcci per reindirizzare le cellule T verso gli antigeni tumorali attraverso i recettori chimerici per l’antigene sintetici (CAR). L’utilizzo di nanoparticelle facilita la produzione di cellule T per la terapia adottiva migliorando la presentazione dell’antigene da parte delle cellule dendritiche. Lo sviluppo delle nanoparticelle rappresenta una delle aree più impegnative della ricerca sulle nanotecnologie, la sfida principale riguarda la definizione di metodi produttivi e controlli riproducibili e trasferibili in scala industriale secondo le regole di buona fabbricazione. La convergenza dell’immunoterapia del cancro, della nanotecnologia e della bioingegneria sta maturando a tal punto che l’impatto sulle vite dei pazienti potrà avvenire in un futuro non molto lontano.
Impiego di sistemi nanoparticellari per l’immunoterapia antitumorale
REDAELLI, GIADA MARTHA
2019/2020
Abstract
The 2018 Nobel prize in physiology or medicine was awarded to pioneers in the field of cancer immunotherapy, as the utility of leveraging a patient’s coordinated and adaptive immune system to fight the patient’s unique tumour has now been validated robustly in the clinic. Inflammation and immune evasion play an important role in the development and progression of malignancies. While traditional treatments such as chemotherapy or radiotherapy are aimed directly at the tumor cell, with oncological immunotherapy the tumor immune microenvironment is intervened in order to create an effective immune response against the tumor, or increase the existing effector mechanisms that try to kill it. Still, the proportion of patients who respond to immunotherapy remains modest: the clinical benefits are limited by the difficulties in obtaining effective delivery of therapeutic agents to the target site. The strategies must allow immunotherapeutic drugs to have appropriate kinetics and distribution, avoiding as much as possible to generate adverse effects. In this context, nanoparticles have emerged as a versatile solution thanks to their favorable transport and surface functionalization properties. Thanks to the recent development of biomaterials that respond to different stimuli (variations in pH, temperature, electric charge), sophisticated multifunctional nanoparticle systems have been developed that have expanded the therapeutic possibilities. The tumor microenvironment is a fundamental target for immunotherapy: its impact on the effectiveness of the therapy can be far-reaching. During tumor growth, the microenvironment interacts with tumor cells using different types of immune cells (T cells, lymphocytes, dendritic cells, macrophages and myeloid-derived cells) in order to mediate their immune tolerance, with consequent influence on the effects clinical therapy. In recent years, nanoparticles have been shown to possess the suitable requirements for reshaping the tumor microenvironment through the elimination of immunosuppressive cells, the reprogramming of regulatory immune cells, the promotion of cytokine secretion, the delivery of immunomodulating agents, the immune checkpoints blockade. Cancer vaccines play an important role in cancer immunotherapy, but in the clinical setting, their use is limited because primary tumor antigens can induce only a partial response. The possibility of encapsulating antigens and adjuvants together in nano vaccines ensures that both components will be delivered together with the same antigen-presenting cells and allows the T cells to be activated more, improving the antitumor response. Biodegradable nanoparticles are among the most promising vehicles for cancer vaccines, in the most recent studies nanovaccines based on lipid particles, liposomes and micelles but also inorganic and metallic nanoparticles have been tested. Nanotechnologies have also been applied ex vivo and used in the activation and expansion of T cells for adoptive therapy. Advances in genetic engineering have led to new approaches to redirect T cells to tumor antigens through chimeric synthetic antigen receptors (CARs). The use of nanoparticles facilitates the production of T cells for adoptive therapy by improving the antigen presentation by dendritic cells. The development of nanoparticles represents one of the most challenging areas of nanotechnology research; the main challenge concerns the definition of chemical, production and control methods that are reproducible and translatable on a large scale. The convergence of cancer immunotherapy, nanotechnology and bioengineering is maturing to the point that it may impact patient lives in the not-too-distant future.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/12200