Abstract CT051: Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL
Authors: Shalabi Haneen , Yates Bonnie , Shahani Shilpa , Qin Haiying , HIghfill Steven L. , Panch Sandhya , Tran Minh , Stroncek David , Hoffman Leah , Little Lauren , Graap Katherine , Stetler-Stevenson Maryalice , Yuan Constance , Wang Hao-Wei , Fry Terry J. , Shah Nirali N. 
Published: September 2020

Abstract
Background: With the hypothesis that dual antigen targeting strategies may prevent antigen negative escape, we tested a novel humanized bispecific CD19/CD22 CAR T cell construct in patients with relapsed/refractory B ALL. Building upon our experience with effective CD19 (NCT01593696) and CD22 (NCT02315612) CAR T cell constructs, we report our initial findings.
Design: This was a phase 1 dose escalation study which started at 3 x 105 transduced CAR T-cell/kg. The CD19/CD22 construct was comprised of FMC63 (CD19 scFv) and m971 (CD22 scFv) with a 4-1BB costimulatory domain (NCT: 03448393). The primary objective was safety and toxicity; secondary objectives included efficacy, CAR persistence and cytokine profiling. CAR T cells were manufactured onsite utilizing a closed system device (CliniMACS Prodigy®). ASTCT consensus guidelines were used for cytokine release syndrome (CRS) grading. Prior CAR T cells were not exclusionary.
Results: Eleven subjects (median age 21) were infused at 3 dose levels. Four experienced mild, reversible CRS without neurotoxicity (Table). Eight subjects had an objective response (MRD negative CR, n=4; partial response, n=4), and 2 proceeded to transplant. Complete responders were CAR naïve and received &gt; 1 x 106 CAR T-cells/kg. CAR expansion peaked at a median of 13 days (range, 6-20) and were detectable by flow cytometry to a median of 54 days (range: 25-110 days) post infusion. Patients with higher disease burden trended towards having higher CRS, CAR expansion, and cytokine elevation. Two patients have relapsed (1 post BMT) with CD19+/CD22+ disease.
Table 1:Subject Characteristics, Toxicity, Response, and CAR PersistenceSubjectAge (years)Dose Level(DL)CD19/22 CAR T cell Dose(x 106)Disease StatusExtramedullary DiseasePrior CARGrade CRSResponseD28Peak absolute circulating CD19 CAR T cells (cells/mL)Peak BM CAR% at 1-monthPersistence of Circulating CAR-T(Day %CAR=0)Consolidative HSCTFollow up##118115.9M2NoYes, CD19 4-1BB; CD19/22 4-1BB0SD00%N/ANo1-month2516.3M3NoYes, CD19-28z1PR44.6815%56No1-month319117.1M1YesYes, CD22 4-1BB0SD3.974.8%61*No1-month419116.8M1YesYes,CD19-28z0PR1.210.1%26No1-month528275M3YesNo3^MRD negative CR84.2222%110Yes8.5-months**628268M3NoNo3^MRD negative CR33.832.1%54No4-months**723272M2NoYes,CD19 4-1BB0SD00%N/ANo1-month818248M1YesNo0PR$72.535.2%87No2-months9213183M1NoNo1MRD negative CR6.160%27Yes5-months@10283264M1NoNo0&MRDNegative CR76.641.3%25No4-months@12283258M1YesNo0&PR#11.410.3%27No1-monthDL1: 3×105 transduced CAR T-cells/kg, DL2: 1×106 transduced CAR T-cells/kg, and DL3: 3×106 transduced CAR T-cells/kg; M1 &lt; 5% blasts, M2 5-25% blasts, M3 &gt;25% blasts; SD: stable disease, PR: partial response defined by decrease in marrow blasts by at least 50% with absence of peripheral blasts, MRD negative CR: minimal residual disease negative complete remission; CRS cytokine release syndrome; ;^ received tocilizumab & Patient had CAR expansion and malaise without fever $ Patient had complete response in bone marrow however had extramedullary disease that was progressive; #Patient had complete response in CSF, partial response in extramedullary breast mass, and residual low-level bone marrow disease. N/A: not applicable; * CAR=0.2%, ##Time to event (relapse, progression, or remission) **at the time of relapse, @remain in remission
Conclusion: In our preliminary experience, CD19/22 CAR was well tolerated and effective in CAR naïve patients, with 4/6 patients achieving MRD negative CR. Relapses were antigen positive likely due to limited CAR persistence. Future plans include exploring an additional dose level, intensifying lymphodepletion for prior CAR patients, and evaluating CAR T-cell product characteristics with outcomes.
Citation Format: Haneen Shalabi, Bonnie Yates, Shilpa Shahani, Haiying Qin, Steven L. HIghfill, Sandhya Panch, Minh Tran, David Stroncek, Leah Hoffman, Lauren Little, Katherine Graap, Maryalice Stetler-Stevenson, Constance Yuan, Hao-Wei Wang, Terry J. Fry, Nirali N. Shah. Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT051.