Axicabtagene ciloleucel are autologous anti-CD19 chimeric antigen receptor (CAR) T cells that have been FDA approved for treatment of relapsed or refractory large cell lymphoma. The ZUMA-1 registration study demonstrated an objective response rate of 83% with a median OS that has not been reached 2. The primary acute toxicities observed to date with CAR T cells have been cytokine release synderom (CRS) and neurotoxicity (NTX). CRS is defined as a constellation of symptoms which may include fever, chills, hypotension, and hypoxia. Manifestations of NTX vary and include confusion, obtundation, seizures, hallucinations, aphasia, ataxia, and rarely, cerebral edema5. Real world data with axicabtagene has confirmed the robust response rates and durability, but further emphasized the need for improved toxicity management, with CRS and NTX rates of 96% and 76%, with grade ? 3 events in 17% and 38%, respectively4. The future success and application of CAR T cells to a broader population of patients is limited by the incidence and severity of these toxicities. Anakinra, a human interleukin 1 receptor (IL-1R) antagonist, has demonstrated clinical efficacy in the treatment of rheumatoid and sepsis related macrophage activation syndrome, as well as in recent mouse models of CRS and NTX9-11. These data suggest that IL-1R blockade may play a critical role in the pathophysiology of both CRS and NTX, but does not appear to be required for CAR-T cell efficacy. Furthermore, signaling through IL-1R potentiates IL-6 production, and blockade of IL-1R therefore has the potential to block IL-6 production and its downstream consequences. We are opening a Phase 2 single center, open-label study evaluating the safety and efficacy of anakinra when combined with axicabtagene ciloleucel in subjects with relapsed or refractory NHL. Our hypothesis is that blocking IL-1R signaling will prevent the development of grade 2 or higher NTX and CRS, and that this will be evident clinically and by correlative evidence of modulation of cytokines and immune cell interactions in the peripheral blood and cerebrospinal fluid (CSF). Dr. Maus (PI) will be holding the IND, Dr. Frigault (co-I) will be the clinical investigator, and Kite Pharma will provide the drugs (axi-cel and anakinra) as well as partial financial support for the clinical study. We seek NIH funding (this R01 proposal) for salary support for the investigators of the clinical study and to conduct the correlative studies, including abstracting clinical data on CRS and NTX using two different grading systems, conducting laboratory measurements of cytokine levels, and detailed phenotyping and functional mapping of both the T cell and myeloid cell compartments at the protein and single-cell transcriptome level in the blood and cerebral spinal fluid that will enable probing the mechanisms of immune interactions in the presence or absence of ankinra. We will use samples from patients treated with commercial axicabtagene ciloleucel as comparators. Completion of this study is significant because it could enable routine outpatient use of CAR T cell therapy, and we will use innovative methods to define the mechanisms and networks of immune cell interactions that drive CRS and neurotoxicity.
Human T cells that have been engineered with receptors called CARs have been very effective in leukemia and lymphoma, but frequently cause severe side effects called cytokine release syndrome and neurologic symptoms. We aim to prevent these side effects by giving a drug called anakinra, which blocks an immune cell product called interleukin-1, because we think that the interleukin-1 drives a lot of the side effects but is not necessary for the anti-tumor effects of the CAR T cells. In this proposal, we will analyze the data from our clinical trial to see the anakinra worked to decrease the side effects, and we will measure the levels of molecules related to interleukin-1 in the blood and the spinal fluid around the brain; these measurements will enable us to map the relationships among immune cells and understandt what drives the side effects of CAR T cell therapy.
