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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
  1. Elad Jacoby1,
  2. Haiying Qin2,
  3. James Kochenderfer3,
  4. Yinmeng Yang1,
  5. Chris Chien1 and
  6. Terry Fry4
  1. Aff1 grid.48336.3a0000000419368075Pediatric Oncology BranchNational Cancer Institute Bethesda MD USA
  2. Aff2 grid.48336.3a0000000419368075NCI, NIH Bethesda MD USA
  3. Aff3 grid.48336.3a0000000419368075National Cancer Institute Bethesda MD USA
  4. Aff4 grid.48336.3a0000000419368075Pediatric Oncology BranchCCR, NCI, NIH Bethesda MD USA

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Meeting abstracts

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.