DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

Abstract

Advanced biomaterials provide versatile ways to spatially and temporally control immune cell activity, potentially enhancing their therapeutic potency and safety. Precise cell modulation demands multi-modal display of functional proteins with controlled densities on biomaterials. Here, we develop an artificial immune cell engager (AICE) platform -biodegradable particles onto which multiple proteins are densely loaded with ratiometric control via short nucleic acid tethers. We demonstrate the impact of AICE with varying ratios of anti-CD3 and anti-CD28 antibodies on ex vivo expansion of human primary T cells. We also show that AICE can be used to control the activity of engineered T cells in vivo. AICE injected intratumorally can provide a local priming signal for systemically administered AND-gate chimeric antigen receptor T cells, driving local tumor clearance while sparing uninjected tumors that model potentially cross-reactive healthy tissues. This modularly functionalized biomaterial thus provides a flexible platform to achieve sophisticated control over cell-based immunotherapies.Functionalized biomaterials can work synergistically with natural or engineered immune cells for cancer immunotherapy 1-15 . Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) engineered T cells has shown success and clinical approval for the treatment of B cell cancers 16 . However, for CAR T cells to fulfill their promising potential, particularly for targeting solid tumors 17, 18 , important challenges must be overcome to improve both efficacy 17-20 and safety 21-24 . For engineered anti-tumor T cells to achieve durable tumor remission in patients, a demanding manufacturing process is required to ensure the quantity and quality of the cell product for therapeutic use 1, 25-27 . To increase the tumor targeting specificity and All rights reserved. No reuse allowed without permission.

Emerging Biomimetic Materials for Studying Tumor and Immune Cell Behavior

“…Mesoporous silica microrods, PEG with polypeptide blocks, synthetic peptides with specific motifs, and DNA-scaffolded biomaterials are being developed for this purpose. 53,56,74,142 Additionally, natural biopolymers such as alginate, chitosan, gelatin, and HA have been explored. 74,139 Lee et al used DNA polyaptamer hydrogels with Cas9/sgRNA to promote the controlled delivery of immune checkpoint inhibitors for cancer immunotherapy.…”

Supramolecular Self-Assembled Nanostructures for Cancer Immunotherapy

“…The supramolecular interactions between DNA base pairs have also been employed for antibody conjugation on nanostructures to enable modular and tunable control of cell-based cancer immunotherapies. Huang et al developed an artificial immune cell engager (AICE) nanoplatform for the modular and tunable control of cell-based cancer immunotherapies (Huang et al, 2019). Multiple proteins and antibodies were decorated on the surface of biodegradable nanoparticles via complementary DNA-scaffolding through the direct hybridization.…”

“…The bases pairing recognition based on multiple hydrogen bonds is very precise and stable, and the hierarchical construction strategy enabled precise and ratiometic loading of multiple cargos on the nanoparticle surface. AICE constructed by this way have been proven to be effective for ex vivo expansion of T cells and providing priming signals for systemically administered AND-gate CAR-T cells (Huang et al, 2019).…”

Synthetic Biology and Tissue Engineering: Toward Fabrication of Complex and Smart Cellular Constructs

“…Initial explorations of this paradigm are evident in the artificial immune cell engager (AICE), a particle-based conjugation platform that can be tuned with high specificity to interact with the engineered components of T cells. [167] Beyond using these methods for modifying cells and tissues for reintroduction into the body, synthetic biology can also synergize with organ-on-chip technology to create more representative disease models and personalized ex vivo tissues.…”