Subcutaneous delivery of theranostic cell-based therapies

Descrizione del progetto

Somministrazione sottocutanea di farmaci immunoterapici

La somministrazione per via endovenosa permette di immettere farmaci o liquidi in maniera rapida e precisa direttamente nel flusso sanguigno, assicurandone un’azione rapida e un dosaggio accurato, particolarmente utili per i pazienti che non possono assumere farmaci per via orale. Tuttavia, l’uso della terapia endovenosa comporta dei rischi, tra cui potenziali infezioni, danni o irritazioni alle vene e la possibilità di perdite di farmaci. Sebbene la somministrazione sottocutanea (SC) sia considerata un’alternativa promettente, lo sviluppo di farmaci biologici e terapie cellulari adatti a questo uso è limitato. Il progetto Sub-NK, finanziato dal Consiglio europeo della ricerca, si propone di sviluppare idrogel funzionalizzati per il rilascio controllato di cellule killer naturali modificate, aprendo la strada alla creazione di una via sottocutanea per l’immunoterapia del cancro.

Obiettivo

This PoC project seeks to develop a simple-to-implement self-assembled and injectable hydrogel material for the controlled co-delivery of our simili-CAR NK cells and stimulatory cytokines to improves treatment of both solid and liquid tumors. Similar to biologics delivery where monoclonal antibodies (mAbs) are commonly administered by IV infusion due to regulatory criteria favoring such route which had limited confounding factors, the IV administration remains responsible for some over costs and clinical challenges including the need for dedicated infusion facilities, aseptic preparation of required infusion batches, extended infusion times, potential difficulties and risks with IV catheter. The subcutaneous (SC) administration is deemed to overcome many of these challenges and might appear as an attractive alternative to the IV administration. In addition, the SC route used for mAb administration was received with an overwhelming preference according to patients despite limited and reversible local adverse events induced by the rHuPH20. Alternative solutions are being evaluated through clinical trials such as the direct SC injection of mAbs without recombinant human hyaluronidase or using novel enzymes but none are currently being clinically-developed for cellular therapies. Moreover, those alternative SC methods induced large pharmacokinetic heterogeneity between patients confirming the need to develop novel alternative approaches to accelerate the development of SC mAbs formulation. Hence, in parallel to the biological approach, chemistry-based approaches, such as hydrogels have been proposed. However, to date, none of them successfully managed to be translated to the clinic; this can be explained by the absence of full biodegradability after injection or/and potential poor biocompatibility inducing inflammatory responses. Here, we sought to develop a novel formulation of functionalized-chitosans for controlled release of modified NK cells.