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Il-6 is non-essential to murine CD19 CAR efficacy, but can mediate acute GVHD following allogeneic BMT with CAR T cell infusion
© Jacoby et al. 2015
Published: 4 November 2015
Chimeric-antigen-receptor (CAR) T cells targeting CD19 show dramatic remissions in refractory or relapsed acute lymphoblastic leukemia. Interleukin-6 (IL-6) has been associated with severe cytokine release syndrome (CRS) following CAR T cell treatment, leading to significant toxicity and death. CRS could be treated with an anti-IL6-receptor antibody, with reversal of most of the inflammatory response within hours to days. In addition, the significance of IL-6 in prevention and treatment of graft-versus-host disease (GVHD) following allogeneic bone marrow transplant (allo-BMT) has been shown in pre-clinical and clinical settings.
Here, we used an immunocompetent murine model of ALL to study CD19 CAR biology. In a syngeneic/autologous model, we found no significant increase in IL-6 in leukemia bearing mice following CD19 CAR treatment. No significant alteration in efficacy was seen when administering CD19 CAR from wild-type mice or IL6-/-mice to wild-type or IL6-/-recipients, with all achieving long term remissions compared to controls.
To elucidate IL-6 in this system, we used a minor-mismatch allo-BMT mouse model (B6àC3h.sw), previously shown to have increased IL-6 levels when T cell replete BMT given. Using a T cell depleted allo-BMT platform, we saw significant increase in IL-6 in leukemia bearing mice treated with CD19 CAR T cells compared to leukemia-bearing controls treated with mock-T cells, and non-leukemia bearing allogeneic CAR recipients. Peak of IL-6 levels was seen 5 days following CAR-T cell infusion, either when given in proximity to the BMT or in later time points. The rise in IL-6 correlated with an acute systemic inflammatory process resembling acute GVHD, that caused early lethality despite being a minor-mismatch model, and at relatively low T cell doses. This acute GVHD could not be reversed when T cells were given early (day 0-2 post BMT), using either IL6-receptor blockade or IL6-/-bone marrow on day 0. However, when leukemia and CD19 CAR administered late (day +12-+17) following allo-BMT, wild-type marrow recipients still died of acute GVHD while IL6-/-recipients were rescued.
Altogether, we show that IL-6 is not essential for CD19 CAR efficacy in this murine model, but can drive significant toxicity following an allogeneic BMT with CAR.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.