CAR T-cell therapy in central nervous system (CNS) lymphoma: a study in safety and efficacy and a model in which to study mechanisms of neurotoxicity
Caron Jacobson
MDDana-Farber Cancer Institute
Project Term: October 1, 2021 - September 30, 2026
CAR T-cells are highly effective in lymphoma but limited by a profound and potentially fatal toxicity involving the central nervous system (CNS). Little is known about how CAR T-cells eliminate lymphoma cells in the CNS nor how this therapy causes toxicity. I will study CAR T-cells in patients with CNS lymphomas with the goal of expanding CAR T-cell indications. I will also examine serial blood and CNS samples to understand neurologic toxicity to inform new therapies to control this toxicity.
Central nervous system lymphoma (CNSL) involving the brain or spinal cord is a challenging and often fatal diagnosis. Chemotherapy does not effectively get into the brain, limiting treatment options. Immunotherapies have offered hope, and cases of CNSL patients treated successfully and safely with a cellular immune therapy, chimeric antigen receptor (CAR) T-cell therapy, have been reported. CAR T-cells have revolutionized the treatment of lymphoma outside the brain but are associated with neurologic toxicity. Although largely reversible, CAR T-cell-related neurologic toxicity can be considerably morbid and potentially fatal. The mechanisms behind neurologic toxicity are largely unknown, but studies have shown that CAR T-cells do effectively get into the brain, where they are felt to have an immunologic and inflammatory effect. Because of this, we expect that CAR T-cells would be effective in treating CNSL but may also cause neurological toxicity as it sometimes does in other lympohomas. This project is centered on a clinical trial of CAR T-cells in patients with CNSL to assess safety as well as efficacy in this patient population. Additionally, because patients with CNSL have a reservoir surgically placed to allow direct access to cerebral spinal fluid (CSF) that bathes the brain and spinal cord, we have the unique opportunity to directly study what happens in the nervous system following CAR T-cell therapy. We will collect paired blood and CSF samples from these patients at several timepoints before and after treatment in order to study the dynamic changes in inflammatory mediators and immune cell populations that occur after CAR T-cell therapy that lead to neurologic toxicity, as well as an anti-lymphoma response. This project may not only expand the indications for CAR T-cell therapy in order to help patients with a fatal lymphoma, but it may also help us to develop new strategies and therapies to prevent the most significant toxicity seen with CAR T-cell therapy, namely neurologic toxicity. Importantly, our studies on neurological toxicity in CAR T-cell-treated CNSL may yield results that are beneficial to other blood cancer patients receiving CAR T-cell therapy who are experiencing neurological toxicity.