Journal Article

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

Subbiah, Naren, McLaughlin, Douglas C., Khamhoung, Annie, Schmidt, Andrea, Gribble, Mary, Amin, Viral, Luo, Mengyao, Bayhi, Nicholas, Turka, Laurence A., Zhang, Xuqing, Soman, Vikram, Mellen, Jennifer, Pawar, Sneha, Moore, Christopher L., Dastagir, Shamael R., Pepi, Ryan, Nixon, Mellissa, Lee, Albert, Chen, Tiffany F., Wickham, Thomas J., Lyford, Timothy J., Carpenter, Christopher L.

2021

Overview

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 E7 11-19 , 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. Red blood cells (RBCs) have unique properties that have been exploited for therapeutic uses. Here the authors engineer RBCs to co-express tumor associated antigens on MHC I, 4-1BBL and IL-12, generating artificial antigen presenting cells that can induce antigen-specific T cell responses and antitumor immune responses in preclinical models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 14/63 / 38/23 / 4-1BB Ligand - genetics / 4-1BB Ligand - immunology / 4-1BB Ligand - metabolism / 631/61/24 / 631/67/580 / 64/110 / 64/60 / 692/4028/67/580 / Animals / Antigen (tumor-associated) / Antigen-presenting cells / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - metabolism / Antigen-Presenting Cells - transplantation / Antigens / Antitumor activity / Blood / Cell Engineering - methods / Cell Line, Tumor / Coculture Techniques / Coordination compounds / Disease Models, Animal / Effector cells / Engineers / Erythrocytes / Erythrocytes - immunology / Erythrocytes - metabolism / Female / Head & neck cancer / Histocompatibility antigen HLA / Histocompatibility Antigens Class I - genetics / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / HLA-A2 Antigen - genetics / HLA-A2 Antigen - immunology / HLA-A2 Antigen - metabolism / Human papillomavirus / Humanities and Social Sciences / Humans / Immune checkpoint / Immunological memory / Immunotherapy / Immunotherapy, Adoptive - methods / Interleukin 12 / Interleukin-12 - genetics / Interleukin-12 - immunology / Interleukin-12 - metabolism / Leukocytes / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Major histocompatibility complex / multidisciplinary / Neoplasms - immunology / Neoplasms - therapy / Papillomavirus E7 Proteins - genetics / Papillomavirus E7 Proteins - immunology / Papillomavirus E7 Proteins - metabolism / Peptides / Primary Cell Culture / Science / Science (multidisciplinary) / Spleen / T-Lymphocytes - immunology / T-Lymphocytes - transplantation / Transplantation, Homologous - methods / Tumors