Disease recurrence is the main cause of treatment failure after CD19-directed CAR T cells, often due to CD19 antigen loss, stability and/or coverage. To overcome single-antigen escape, we evaluated a trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain. Preclinical studies demonstrated potent, antigen-specific cytotoxicity in in vitro and in vivo lymphoma models. We then conducted a first-in-human phase I trial in patients with relapsed/refractory B-cell malignancies. Sixteen patients received infusions at a median vein-to-vein time of 7 days, at doses of 0.5-2×10⁶ cells/kg. No severe cytokine release syndrome nor neurotoxicity occurred. Overall response rate was 50%, including complete responses in 83% of lymphoma patients. One-year overall survival rate was 61%, with durable remissions observed in lymphoma. CAR T expansion did not correlate with dose or response. T-cell exhaustion in apheresis cells correlated with progressive disease. Trispecific CAR T cells are safe and potentially active in lymphoma.
S. Vasu, N. Denlinger, No-Joon Song et al.· Blood Cancer Discovery· 0 citations
Rigorous research over the years has revealed that the cellular composition of the tumor microenvironment (TME) matters, and a major constituent that facilitates tumor progression is the regulatory T cell (Treg). Tregs are essential for maintaining immune homeostasis and preventing autoimmune conditions but can also be a detriment via their suppression of immune responses against cancer. The significance of Treg research is far-reaching as supported by the 2025 Nobel Prize in Physiology or Medicine awarded to Drs. Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, “for their discoveries concerning peripheral immune tolerance”. However, identifying differences in Treg subtypes to specifically disrupt the activities of tumor-promoting Tregs, without affecting Tregs that maintain immune homeostasis remain elusive. Here, we sought to discover how to blunt pro-tumorigenic Tregs without compromising the abilities of Tregs in mediating self-tolerance.
To this end, we used state-of-the-art methods in immunology, including high dimensional flow cytometry, lineage-specific loss-of-function studies and single-cell RNA sequencing, as well as multiple tumor models in animals to investigate these fundamental gaps in the field.
In doing so, we discovered that expression of the genome organizer special AT-rich sequence binding protein 1 (Satb1) could readily separate two Treg subtypes: pro-tumorigenic Tregs (termed Satb1+) and immune-regulatory Tregs (termed Satb1-). Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions. Notably, Satb1- Tregs remained intact in knockout mice and were necessary for maintaining immune homeostasis and preventing autoimmunity.
Our results reveal a key mechanism to safely and potently enhance cancer immunity without causing systemic autoimmune diseases.
Pelotonia Institute for Immuno-Oncology
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Ephraim A. Ansa-Addo, Parviz Azimnasab-sorkhabi, Musab Bouhajra et al.· Journal of Immunology· 0 citations