Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic

Abstract

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential ‘off-the-shelf’ in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.

Vaccine-Based Immunotherapy for Head and Neck Cancers

“…RTX-321 is a drug composed of red blood cells that are transformed into artificial antigen-presenting cells that harbor on their surface the HLA-A*02:01 presenting an HPV E7 peptide, the co-stimulatory molecule 4-1BBL and IL-12. In in vitro assays, RTX-321 has shown activation of HPV-specific T cells with effector function [ 112 ].…”

A Multifunctional Magnetic Red Blood Cell-Mimetic Micromotor for Drug Delivery and Image-Guided Therapy

“…Red blood cells (RBCs) with a special structural feature (biconcave discoidal shape) and relatively simple biological complexity (lack of the cell nucleus and most of the organelles) served as a popular research object in the field of biomimicry. − RBCs possess the capability to realize long-term circulation in organisms and pass through the capillary vessels . The immune escape mechanism is based on the presence of various molecular biomarkers including proteins and glycan and sialic acid moieties on the RBC membrane surface.…”

In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles

“…The ability to target Agspecific T cells offers opportunities to selectively augment diseaserelevant T cell subsets (e.g., viral or tumor Agspecific T cells) in vivo while maintaining homeostasis and selftolerance of the immune system (10). To target Agspecific T cells in vivo, strategies include engineered human pMHCI [human leukocyte Ag (HLA)]-Fc fusion dimers to expand human papillomavirus (HPV)-specific CD8 + T cells against HPVassociated malignancies (11) or track virus specific CD8 + T cells by immuno-positron emission tomography imaging (12), artificial Agpresenting cells composed of pMHCI on nanoparticles or engineered red blood cells to activate Agspecific T cells and enhance their effector function for cancer treatment (13)(14)(15), tumortargeting antibodies to deliver viral peptides that are cleaved by tumor proteases and then loaded onto MHCI on the tumor cell surface to redirect virusspecific T cells against tumors (16,17), and nanoparticles decorated with pMHCII molecules to reprogram autoantigenreactive CD4 + T cells into diseasesuppressing regula tory T cells (T reg ) (18,19). These studies highlight the broad appli cations of in vivo delivery to Agspecific T cells.…”