In Vivo Stimulation of Therapeutic Antigen‐Specific T Cells in an Artificial Lymph Node Matrix

• Published in: Advanced materials (Weinheim) 2024-06, Vol.36 (23), p.e2310043-n/a
• Main Authors: Livingston, Natalie K., Hickey, John W., Sim, Hajin, Salathe, Sebastian F., Choy, Joseph, Kong, Jiayuan, Silver, Aliyah B., Stelzel, Jessica L., Omotoso, Mary O., Li, Shuyi, Chaisawangwong, Worarat, Roy, Sayantika, Ariail, Emily C., Lanis, Mara R., Pradeep, Pratibha, Bieler, Joan Glick, Witte, Savannah Est, Leonard, Elissa, Doloff, Joshua C., Spangler, Jamie B., Mao, Hai‐Quan, Schneck, Jonathan P.
• Format: Article
• Language: English
• Subjects: adoptive T cell therapy; Antigens; artificial lymph node; Biomedical materials; cancer; hydrogel; Immune system; Immunotherapy; in vivo activation; Lymphatic system; Lymphocytes; Stimulation; T cell stimulation; Tumors
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202310043

T cells are critical mediators of antigen‐specific immune responses and are common targets for immunotherapy. Biomaterial scaffolds have previously been used to stimulate antigen‐presenting cells to elicit antigen‐specific immune responses; however, structural and molecular features that directly stimulate and expand naïve, endogenous, tumor‐specific T cells in vivo have not been defined. Here, an artificial lymph node (aLN) matrix is created, which consists of an extracellular matrix hydrogel conjugated with peptide‐loaded‐MHC complex (Signal 1), the co‐stimulatory signal anti‐CD28 (Signal 2), and a tethered IL‐2 (Signal 3), that can bypass challenges faced by other approaches to activate T cells in situ such as vaccines. This dynamic immune‐stimulating platform enables direct, in vivo antigen‐specific CD8+ T cell stimulation, as well as recruitment and coordination of host immune cells, providing an immuno‐stimulatory microenvironment for antigen‐specific T cell activation and expansion. Co‐injecting the aLN with naïve, wild‐type CD8+ T cells results in robust activation and expansion of tumor‐targeted T cells that kill target cells and slow tumor growth in several distal tumor models. The aLN platform induces potent in vivo antigen‐specific CD8+ T cell stimulation without the need for ex vivo priming or expansion and enables in situ manipulation of antigen‐specific responses for immunotherapies. Here, an injectable T cell‐stimulating scaffold, the artificial lymph node (aLN), is developed that works with the host immune system to create an immunostimulatory niche. The aLN can activate and expand rare, antigen‐specific CD8+ T cells from fully naïve, endogenous populations. aLN stimulated cells are fully functional and synergize with immune checkpoint blockade to reduce tumor burden and prolong survival.