Delivery of CAR-T Cells in a Transient Injectable Stimulatory Hydrogel Niche Improves Treatment of Solid Tumors

Abstract

Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers such as B cell malignancies, but traditional approaches to ACT are poorly effective in treating the multifarious solid tumors observed clinically. Locoregional cell delivery methods have shown promising results in treating solid tumors compared to standard intravenous delivery methods, but the approaches that have been described to date have several critical drawbacks ranging from complex manufacturing and poor modularity to challenging adminstration. In this work, we develop a simple-to-implement self-assembled and injectable hydrogel material for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improves treatment of solid tumors. We evaluate a range of hydrogel formulations to optimize the creation of a transient inflammatory niche that affords sustained exposure of CAR-T cells and cytokines. This facile approach yields increased CAR-T cell expansion, induces a more tumor-reactive CAR-T phenotype, and improves efficacy in treating solid tumors in mice.

Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot

“…Previous work has shown that immune cells can infiltrate into these PNP hydrogel materials when certain types of cargo such as vaccine components are present and that encapsulated therapeutic cells exhibit motility, indicating that an active antibody transport mechanism could be possible. 31,34 It is also possible that biological interactions with the material change its physical properties over time, which could alter its drug release characteristics. 63 Future work should include investigating cellular infiltration into antibody-loaded PNP hydrogels as well as measuring antibody biodistribution beyond the bloodstream, such as the lymphatic system.…”

“…49 Finally, the yield stress of each formulation was determined to assess the ability of the depot to retain its shape under the forces present the site of injection; it has previously been demonstrated that yield stress is an important rheological property for subcutaneous depot formation and retention. 34,50 Yield stresses of 70 and 350 Pa were measured for the 1:5 and 2:10 formulations, respectively (Figure 2e). Again, previous work has shown that increasing nanoparticle content results in higher yield stress values.…”

“…These PNP hydrogels have been shown to be injectable, biocompatible in vivo, and drug-stabilizing and have been shown to be effective for a range of biomedical applications including cell encapsulation and delivery, vaccine delivery, cancer immunotherapy, and adhesion prevention. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] In this work, we study the suitability of the PNP hydrogel platform to effectively deliver antibodies against SARS-CoV-2, and more broadly, we seek to investigate what is required to effectively design materials to act as a subcutaneous delivery depot for antibody therapeutics. We first evaluate the rheological characteristics, in vitro antibody release kinetics, and antibody stability in the PNP hydrogel system.…”

Progress of immunotherapy in the treatment of pancreatic cancer

“…Therapy Phase trial Mesothelin-Specific CAR-T cells I CEACAM5-specific CAR-T cells I Because of low invasion of T cells, lack of targeted TME, and unstable expression after injection, CAR-T cells are hindered from infiltrating into the tumor site. A simple and efficient CAR-T delivery method is developed recently by adding CAR-T cells and cytokines into the hydrogel to improve the curative effect on solid tumors [12]. At present, other challenges for CAR-T therapy contain the absence of sustained attack and the evolution of CD19-tumor cells which cannot be recognized.…”

T Recent advances of FDA-approved CAR-T therapies in multiple myeloma

“…For example, the pro-inflammatory cytokine IL-1 and TNF-α polarize macrophages into a pro-inflammatory phenotype, whose overactivation can lead to tissue damage [14]. In addition, while displaying promising results in targeting blood cancers, CAR-T treatments show reduced efficacy against solid tumours [15]. Therefore, CAR-T therapies are still under active research and optimization to minimize side effects.…”