Designed biosensor to enhance CAR T cell therapy for multiple myeloma
Caroline Arber
MDCentre Hospitalier Universitaire Vaudois
Project Term: September 1, 2023 - August 31, 2026
We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works. If successful, we expect that CAR T cell therapy for MM can be made more efficient, and the same strategy could potentially also be applied to other cancer types.
Significant advances have been made in the treatment of patients with multiple myeloma (MM) by the approval of chimeric antigen receptor (CAR) T cell therapies. Most patients achieve good responses with this treatment, but durability of the responses is still limited. One of the main reasons for treatment failure is the limited long-term persistence of the CAR T cells and their poor function in the patient. For this reason, we propose to develop a new strategy that can be used to make CAR T cells persist longer and function better in the patients. We know that the bone marrow (BM) environment in MM has an important role in dampening the CAR T cell function and making them inefficient in the long-term control of myeloma. Therefore, we propose to take advantage of one of the soluble factors present in the BM environment and use it to make CAR T cells better. We will do this by designing a novel type of chimeric receptor that has the function of a biosensor, responding to soluble factors in the BM, and rewiring the messages given to the T cells to make them live longer and be able to kill tumor cells long term. We will express the biosensor together with the CAR in T cells and evaluate their function in the culture dish as well as in mouse models of human MM. We will use several techniques to deeply characterize this novel type of treatment to understand precisely what effects it has in the T cells and on the myeloma cells. If our approach is successful, we think it has the potential to make CAR T cell therapies for MM better in the long term. In addition, our approach will also be applicable to T cell therapies for other tumor types as we target soluble factors that are also important and abundant in other cancers.