Enticing the immune system to regain control of a patient’s malignancies has remained a seemingly unsurmountable challenge until discoveries on T cell costimulation and -inhibition provided the critical insight to overcome passive and active immune resistance by cancers. Equipping a patient’s T cell with the ability to target tumor cell lineage-specific surface proteins using an engineered antibody grafted onto T cell signaling domains was truly innovative, as was the provision of costimulation in cis in some of the final designs of chimeric antigen receptors (CAR). Second generation CARs thus designed in the mid 2000s and clinically evaluated by the end of that decade have been transformative and such designs have since delivered on a cure in acute and chronic B cell leukemias as well as in lymphomas. However, much remains to be done. Areas still with a high, unmet need of a cure are myeloma, T cell malignancies, and the many solid tumors. In my talk I will highlight the progress made in CLL and look forwards future developments in this domain.

• Chimeric antigen receptors (CAR) went in rapid succession from research tool to means of fighting cancer
• Only with second generation CARs did we start seeing durable remissions and even cures in B cell cancers
• The road ahead will tell us whether this same technology will tell us whether this technology will be similarly transformative in other areas of unmet need