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, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

Enhancing adoptive T cell therapy with synergistic host immune engagement promotes long-term protection against solid tumors

“…When used for localized T cell-only delivery, injectable T cell depots resulted in enhanced therapeutic benefits in solid tumors relative to IV and direct peritumoral T cell injection. These observations are consistent with previous studies that have reported greater therapeutic effects of biomaterial-based adoptive T cell delivery relative to traditional modes of T cell delivery [6][7][8][9][10] . While intravenous delivery could be optimal for hematological cancers, T cells delivered this way must traffic to solid tumors, and only a fraction of the adoptively transferred T cells find the tumor at a given time.…”

“…Biomaterial-based delivery systems serve as T cell reservoirs that help to overcome the hurdle of trafficking while providing the requisite environment for T cell persistence. Previous biomaterial-based platforms used for adoptive T cell delivery have mostly been in the form of spherical or sheet-like implantable scaffolds [6][7][8] , or injectable in-situ forming gels 9,10 . Implantable scaffolds require invasive surgeries for administration, and the spherical or sheet-like shapes could pose difficulties in terms of scaling for larger mammals.…”

“…Inspired by reports that localized, intra-tumoral injection of T cells yield superior therapeutic outcomes 4,5 , recent efforts have focused on developing biomaterial-based T cell depots which can be implanted or injected at the tumor site to further enhance therapeutic T cell efficacy [6][7][8][9][10] . While adoptively transferred T cells provide the T cell source needed for immediate tumor debulking, their long-term efficacy can be hindered by their narrow repertoire of antigen recognition, which can result in tumor antigen escape, T cell exhaustion and limited long-term protection [11][12][13] .…”

Yield‐Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration

“…A representative H-NMR analysis of both starting materials (Hypromellose (USP grade, 1 g) and dodecyl isocyanate (99%, 125 µL, 0.52 mmol)) and HPMC-C 12 was published. [34,54] H-NMR analysis indicated an 8.5 wt.% dodecyl modification compared to theoretical max of 10 wt.% modification of HPMC-C 12 . [54] Polymer-Nanoparticle Hydrogel Synthesis: Supramolecular PNP hydrogels were formulated according to methodology described in prior work.…”

Tumor microbiome metabolism: A game changer in cancer development and therapy

“…For example, the utilization of biomaterials, such as nanoparticles ( 194 , 195 ) and hydrogels ( 174 ), to modulate and deliver microbial communities to specific sites of the TME opens a new door for future cancer therapies ( Figure 4 ). These novel materials can be designed to be stimuli responsive ( 196 ) and utilized for the controlled and targeted release of toxic chemotherapy drugs ( 197 ), therapeutic antibodies ( 198 , 199 ), CAR-T cells ( 200 , 201 ), or live microbes to reshape the TME ( 202 – 204 ). These applications of new biomaterials will offer a promising platform for basic and translational research and will accelerate clinical outcomes of drugs that may have poor solubility and high toxicity.…”