Abstract 4574: Use of CD19-targeted Chimeric Antigen Receptor-modified T (CART19) cells in ALL and CLL produce transient cytokine release syndrome (CRS), macrophage activation syndrome (MAS) and durable responses.
Authors: Grupp Stephan A. , Kalos Michael , Barrett David M. , Teachey David T. , Levine Bruce , Milone Michael , Porter David , June Carl H. 
Published: August 2014

Abstract
CART19 combines an antiCD19 scFv antibody antigen recognition domain with intracellular signal 1 (CD3z) and signal 2 (4-1BB) domains into a single chimeric protein, which results in remarkable antitumor activity with massive in vivo expansion and long-term persistence of CART19 cells in NSG mice. We reported dramatic anti-tumor activity of CART19 T cells in 3 pts with CLL with shorter follow up (Porter, et al NEJM 2011). We now report on outcomes, longer follow up, and complete responses in CLL and ALL from 12 pts treated with CART19.
12 pts with relapsed/refractory leukemia have received CART19: 10 adults with CLL and 2 children with ALL (1 s/p cord blood transplant); all had high disease burdens. A median of 7.5x108 total cells (range 1.7-50; 1.5x108 CAR+ [0.1-5.9]) were infused. Of 10 CLL pts, 1 is not yet evaluable, 7 had a CR or PR, including 3 sustained CRs and 2 complete BM responses. Both ALL patients had a CR, one sustained for 6mo. While there was no acute infusional toxicity, all responding pts also developed CRS. All had high fevers, as well as grade 3 or 4 hypotension/hypoxia. CRS preceded the peak of CART19 cells, and then increased in intensity until the peak (D10-70 post infusion). One ALL pt experienced grade 4 hypotension and respiratory failure and steroid therapy produced no improvement. On D9, with high levels of TNFa and IL6 (peak increases above baseline: IFNg=6040x; IL6=988x; IL2=163x and TNFa=17x), we gave TNFa and IL6 antagonists etanercept and tocilizumab. This resulted in resolution of fever and hypotension within 12hr and rapid wean off the ventilator. This had no apparent impact on CART19 cell expansion or efficacy, with a peak of CAR T cells (2539 CAR+ cells/uL; 77% of CD3 cells) occurred on D11, and D23 BM showed CR with negative MRD, compared to 65% ALL in her on-study BM. Clinical assessment of patients with major responses showed all had evidence of MAS including dramatic elevations of ferritin, peaking at 44,000 to 605,000 around the time of peak T cell proliferation. Subsequently, 3 CLL patients have also been treated with tocilizumab, also with prompt and striking resolution of symptoms. Interestingly, both ALL pts showed detectable CART19 cells in the CSF in each post-treatment sample (40-78% CAR+). CART19 cells and B cell aplasia have persisted in patients who achieved a CR out to the longest follow up (beyond 2yrs in 2 CLL pts)CART19 T cells may produce massive in-vivo expansion, long-term persistence, and potent and sustained responses, but can also cause significant CRS with features suggestive of MAS that responds rapidly to cytokine blockade. Prior to the CART19 proliferative phase IL6 blockade may interfere with proliferation and effector function, but if given at a point where cell proliferation is underway, it may ameliorate the symptoms that correlate with robust clinical responses.
Citation Format: Stephan A. Grupp, Michael Kalos, David M. Barrett, David T. Teachey, Bruce Levine, Michael Milone, David Porter, Carl H. June. Use of CD19-targeted Chimeric Antigen Receptor-modified T (CART19) cells in ALL and CLL produce transient cytokine release syndrome (CRS), macrophage activation syndrome (MAS) and durable responses. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4574. doi:10.1158/1538-7445.AM2013-4574