Genetic study reveals how TPRT1 enhances T cell immunotherapy

Scientists from the Dartmouth Institute for Immunology and Cancer Research (DIIRC) and the Broad Institute have published a genetic sequence analysis of tumor cells from patients with primary chronic lymphocytic leukemia the most common form of solid cancer. The research done in collaboration with scientists from the hazard and toxicity response research programs of the Massachusetts General Hospital (MGH) highlights a possible avenue of therapeutic development for one of the most commonly activated but least studied immune checkpoint proteins. The finding which is published in the journal Blood could inform new strategies to enhance T cell immunotherapy – a promising new cancer treatment for solid cancers and a major problem facing leukemia in the United States.

Over the past decades the identification of specific immunotherapy molecules (proteins that activate programmed immunity against foreign substances) – most of which have utilized synthetic mechanisms – has advanced cancer immunotherapies. In a handful of examples several functional and potent tumor-specific killer T cell and T cell receptor inhibitors have been reported including T-sT cell therapy a synthetic T cell therapy approved by the FDA as a treatment for the immune-related disease in children with leukemia.

One of the most well-characterized enzymes in the innate immune system is the transcription factor NF-B1 (Ckn1). Activation of NF-B1 is involved in the recruitment to the dendritic cells of the innate immune system but this involvement is thought to be limited by factors beyond the cells programming ability. In solid cancers such as leukemia the recruitment and crosstalk between dendritic cells and complement deficient NK cells (allergic T lymphocytes) has been shown to be a major obstacle for activation of the potent antiviral T cells.

It is well known that NF-B1 expression predicts clinical response to T cell-based therapy but administration of a synthetic inhibitor of NF-B1 was utilized in the current study as well as in prior studies (e.g. 12GaNF) to demonstrate that NF-B1 release mediates conversion of NK cell function and efficiency to enhance T-cell immunotherapy effectiveness in relapsed or refractory solid cancers while minimizing tumor-induced cytotoxicity said the studys principal investigator Christopher B. Davis MD MS Director of the National Center for Integrative Biology and Cancer at the Segal Cancer Center (SCI) at Dartmouth and an Associate Professor of Hematology-Oncology in the Sackler Faculty of Medicine.