Cancer typically arises from a very small number of cancer stem cells. Cancer stem cells that survive initial therapy can hide for a long time. Even years after successful treatment, the cancer stem cells can prompt the cancer to return. If the cancer returns after treatment, it becomes much harder to treat, so doctors try to avoid this. On the other hand, killing cancer stem cells has proven to be an effective strategy to achieve long-term cure and to prevent the cancer from returning at a later time. In addition, this strategy helps to improve survival and reduce side-effects of treatment. This proposal studies cancer that arises from cells of the immune system, the so-called “B-cells”. Unlike other types of cancer, stem cells in B-cell cancer have not been identified. As a consequence, the therapies that are tailored to target stem cells in other types of cancer would not work for patients with B-cell cancer. We recently discovered that stem cells in B-cell cancers express a surface molecule, which allows to escape drug-treatment for some time. We have shown that a drug that delivers a poison into the cancer cells has strong effects in animals that bear the human cancer. In addition, we have engineered a patient’s own immune cells to recognize and fight B-cell cancer stem cells. This strategy will help the patient’s immune system to spot and kill B-cell cancer stem cells more efficiently. We will leverage these approaches to improve outcomes for patients with B-cell cancer while at the same time we aim at reducing the burden of side-effects that would come from typical chemotherapy.