Abstract LB-146: Phase I CD22 CAR T-cell trial updates
Authors: Shah Nirali N. , Shalabi Haneen , Yates Bonnie , Yuan Constance , Qin Haiying , Ombrello Amanda , Wang Hao-Wei , Hoffman Leah , Tran Minh , Panch Sandhya , Stetler-Stevenson Maryalice , Jin Jianjian , Mackall Crystal , Highfill Steve , Stroncek David , Fry Terry J. 
Published: August 2019

Abstract
Introduction: Patients who relapse after or are resistant to CD19 targeting are in need of novel therapies. We previously reported on the initial experience with our highly-active, first-in-human, first-in-child, CD22 CAR trial in the first 21 subjects with ALL. We now report on the cumulative experience with 52 treated subjects.
Methods: This phase I study of anti-CD22 CAR-T cells (Clinicaltrials.gov NCT02315612) enrolled subjects between the ages of 3-30 years with relapsed/refractory CD22+ disease. All subjects received fludarabine 25 mg/m2 x 3 days and cyclophosphamide 900 mg/m2 x 1 day for lymphodepletion. Disease assessments were performed prior to initiation of lymphodepletion and at day 28 (+/- 4 days) post CAR infusion. Three dose levels were explored; with an interim manufacturing modification incorporating CD4/CD8 bead T-cell selection (TCS); current dose is DL1-TCS. (Table 1)
Results: The median age was 18.1 years (range, 4.4-30.6). 36 (69.2%) subjects had undergone HSCT; 30 (57.7%) had prior CD19 CAR; 22 (42.3%) had prior blinatumomab; 28 (53.8%) subjects had a CD19 negative population, including two who were inherently partial CD19 negative without prior targeted therapy. 46 (88.4%) experienced CRS, 5 (10.9%) had grade 3-4 CRS. Unique toxicities apparent with expanded experience included capillary leak syndrome (n=3), including one grade 5 event; atypical HUS (n=2), symptomatic coagulopathy (n=8) and HLH-like manifestations (n=18). The complete remission rate was 72.5% overall; 84% at the current dose level. This included complete remissions seen in subjects who were non-responders to CD19 CAR and/or blinatumomab. The longest remission is &gt; 3 years (n=1) post-CAR. Relapse occurred at a median of 6 months post CAR in 23 (64%) subjects primarily due to CD22 modulation. 12 proceeded to HSCT following CD22 CAR.
Conclusion: In the largest study of CD22 CAR T-cell therapy to date, this extended experience confirms the initial efficacy, while highlighting novel aspects of the toxicity profile that warrant special attention. Results from our study support further testing of this CD22 CAR in a phase 2 clinical trial.
Treated SubjectsDL1 (3 x 10e5)DL2 (1 x 10e6)DL3 (3 x 10e6)DL2 TCS (1 x 10e6)DL1 TCS&gt; (3 x 10e5)n5261827#19n, (% of all subjects)526 (11.5%)18 (34.6%)2 (3.8%)7 (13.4%)19 (36.5%)DemographicsMedian age, (range, years)18.1 (4.4-30.6)21.3 (7.3-22.7)16.7 (8.0-30.7)17.1 (7.9-26.4)12.8 (4.4-28.9)18.5 (4.9-30.4)Prior HSCT, n (%)36 (69.2%)6 (100%)13 (72.2%)2 (100%)6 (85.7%)9 (47.3%)Prior CD19 CAR, n (%)30 (57.7%)6 (100%)11 (61.1%)1 (50%)5 (71.4%)7 (36.8%)Prior Blinatumomab, n (%)22 (42.3%)1 (16.7%)4 (22.2%)2 (100%)2 (28.6%)13 (68.4%)Prior Inotuzumab, n (%)14 (26.9%)1 (16.7%)4 (22.2%)1 (50%)3 (42.9%)5 (26.3%)Prior CD22 CAR, n (%)3 (5.8%)0002 (28.6%)1 (5.3%)Any CD19 negative population (&lt;90%+), n (%)28 (53.8%)4 (66.7%)9 (50%)05 (71.4%)10 (52.6%)&gt;M2 marrow, n (%)38 (73.0%)4 (66.7%)11 (61.1%)2 (100%)6 (85.7%)15 (78.9%)Toxicity ProfileTotal with CRS, n (%)46 (88.4%)3 (50%)16 (88.9%)2 (100%)6 (85.7%)19 (100%)Amongst all CRSCRS Grades 1-2, n (% of all with CRS)41 (89.1%)3 (100%)15 (93.8%)2 (100%)6 (100%)15 (78.9%)CRS Grades &gt; 3, n (% of all with CRS)5 (10.9%)01 (5.6%)004 (21.1%)Received Tocilizumab, n (%)19 (36.5%)03 (16.7%)04 (57.1%)12 (63.2%)Received Steroids, n (%)17 (32.7%)02 (11.1%)1 (50%)4 (57.1%)10 (52.6%)Developed symptomatic coagulopathy, n (%)8 (15.4%)03 (16.7%)04 (57.1%)1 (5.3%)Developed HLH, n (%)18 (34.6%)03 (16.7%)05 (71.4%)10 (52.6%)Developed CLS, n (%)3 (5.8%)01 (5.6%)^002Developed aHUS, n (%)2 (3.8%)0001 (14.2%)2Grade 5 events, n (%)2 (3.8%)02 (11.1%)000Response RateComplete Remissions, n (%)@37 (72.5%)*1 (16.7%)13 (76.5)**1 (50%)6 (85.7%)16 (84.2%)MRD negative CR, n(%)@32 (62.7)*1 (16.7%)10 (58.8%)**0 (0%)6 (85.7%)15 (78.9%)CRS: cytokine release syndrome, as graded per Lee et al. HLH: hemophagocytic lymphohistiocytosis, retrospectively identified and defined as present if the following criteria were met: peak ferritin &gt;100,000 with at least one of the following criteria: a) liver function tests &gt; grade 3, b) creatinine &gt; grade 3, c) pulmonary edema &gt;grade 3 or d) evidence of hemophagocytosis on the bone marrow. *51 subjects evaluable for response. One subject had a grade 5 toxicity prior to disease restaging; **17 subjects evaluable for response. One subject had a grade 5 toxicity prior to disease restaging; ^CLS developed into fatal adult respiratory distress syndrome; #Subject 27 had stable disease with the first infusion with grade 1 CRS not requiring steroids or tocilizumab and limited CAR expansion. Notably he had received a CD22 CAR construct at an outside hospital prior to treatment on this protocol. Data presented in this table reflect the response and toxicity profile following the second infusion as it informed the toxicity and response profile at this dose. @Reflects the best response at any time point without any interval therapy; &gt;Implementation of pre-emptive tocilizumab dosing initiated in this cohort.
Citation Format: Nirali N. Shah, Haneen Shalabi, Bonnie Yates, Constance Yuan, Haiying Qin, Amanda Ombrello, Hao-Wei Wang, Leah Hoffman, Minh Tran, Sandhya Panch, Maryalice Stetler-Stevenson, Jianjian Jin, Crystal Mackall, Steve Highfill, David Stroncek, Terry J. Fry. Phase I CD22 CAR T-cell trial updates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-146.