Dr. Robbie Majnzer, the Work Package 3 lead for NexTGen, and his team (including NexTGen member, Maria Caterina Rotiroti) published a paper entitled “Co-opting signaling molecules enables logic-gated control of CAR T cells” in the journal Nature in March 2023 As part of WP3, Robbie’s work aims to develop components of CAR T cells that will allow them to be used to treat solid tumors and avoid toxicity to the patient. In this Nature paper, Robbie and his team discovered a novel way to activate CAR T cell signaling and target tumors that bypasses a toxic aspect of previously generated CAR T cells.

The paper first describes how Robbie and his team confirmed that chimeric antigen receptors (CARs) use the same signaling pathways to carry out their function as normal T cell receptors (TCRs).  The challenge they then faced was to ensure that the CAR T cells will only attack a cancerous tumor and not normal healthy tissue that may express similar surface receptors (molecules on the surface of cells that allow for T cells to bind).  To solve this problem, the team investigated ways to manipulate molecules on the inside of T cells that could be embedded in the cell membrane (surface) and bound to CARs. They used this method in combination with an effector process that requires two types of CARs to be bound to a cancer cell and also linked to each other for their cancer killing activity to be activated. Their success in engineering these methods will prevent CAR T cells from attacking normal tissue and will improve their ability to kill solid tumors.

From a patient perspective, mitigating the toxic side effects that can arise from CAR T cell therapy is a key issue and this is a significant finding.

Robbie and his team have worked hard for many years on the work published in this paper.  It will serve as a crucial part of the development of NexTGen’s CAR T cell therapy.  Please click here to read the full version.