FIRST-IN-HUMAN CLL1-CD33 COMPOUND CAR T CELLS AS A TWO-PRONGED APPROACH FOR THE TREATMENT OF REFRACTORY ACUTE MYELOID LEUKEMIA
Author(s): ,
Fang Liu
Affiliations:
Department of Hematology,Chengdu Military General Hospital,Chengdu,China
,
Kevin Pinz
Affiliations:
Research and Development,iCell Gene Therapeutics,Stony Brook,United States
,
Yu Ma
Affiliations:
Manufacturing Division,iCAR Bio Therapeutics Ltd,Zhongshan,China
,
Masayuki Wada
Affiliations:
Research and Development,iCell Gene Therapeutics,Stony Brook,United States
,
Kevin Chen
Affiliations:
Research and Development,iCell Gene Therapeutics,Stony Brook,United States
,
Gina Ma
Affiliations:
Research and Development,iCell Gene Therapeutics,Stony Brook,United States
,
Yi Su
Affiliations:
Department of Hematology,Chengdu Military General Hospital,Chengdu,China
,
Shan Zhang
Affiliations:
Department of Hematology,Chengdu Military General Hospital,Chengdu,China
,
Guangcui He
Affiliations:
Department of Hematology,Chengdu Military General Hospital,Chengdu,China
Yupo Ma
Affiliations:
Research and Development,iCell Gene Therapeutics,Stony Brook,United States
EHA Learning Center. Liu F. Jun 15, 2018; 215925
Topic: 4Bj Indication for specific and gene-modified cell therapy

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Abstract
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Abstract: S149



 

Type: Presidential Symposium



 

Presentation during EHA23: On Friday, June 15, 2018 from 15:45 - 16:00



 

Location: Room A1



 

Background
Anti-CD19 CAR T cells have shown impressive efficacy in B-ALL (acute lymphoblastic leukemia) and lymphoma, and have obtained FDA approval.  However, treatment of relapsed/refractory acute myeloid leukemia (AML) remains a substantial clinical challenge. AML bears heterogeneous cells that can offset killing by single CAR-based therapies, resulting in disease relapse. Leukemic stem cells (LSCs) associated with CLL1 expression comprise a rare population that also plays an important role in disease progression and relapse. CD33 is a myeloid marker found on bulk AML disease cells in the majority of AML patients.  Here, we report on the robust anti-tumor activity of compound CAR (cCAR) T cells possessing discrete scFv domains targeting two different AML antigens, CLL1 and CD33, simultaneously.



 

Aims
To develop a first-in-human treatment of refractory acute myeloid leukemia using Compound CAR T Cells simultaneously targeting two AML antigens, in order to avoid antigen escape, and to be safe and well tolerated.



 

Methods
We have generated a cCAR bearing two complete CAR constructs connected by a self-cleavable peptide linker, P2A.  The anti-leukemic activities of CLL1-CD33 cCAR T cells were evaluated in vitro with killing assays using multiple AML cell lines, primary human AML samples as well as REH cells expressing either CLL1 or CD33. We tested cCAR in multiple mouse models in which mice were injected with REH expressing CLL1 or CD33 or U937 cell line. We also tested an alemtuzumab safety switch that allows for rapid cCAR therapy termination in vivo.



 

Results
We report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CLL1 and CD33, simultaneously.  We showed that the CLL1-CD33 cCAR was able to ablate both the CLL1- or CD33-expressing REH cells independently both in co-culture assays and in mouse models. Mice treated with CLL1-CD33 cCAR showed significantly improved survival as compared to control-treated mice. We also showed that CLL1-CD33 cCAR promoted sustained in vivo anti-leukemic activity against the AML U937 cell line, as well as superior murine survival in both models. As a safety-switch to protect against the high potency of our cCAR, we developed a strategy to the rapid cCAR therapy termination in mouse models. Our findings indicate that targeting both CLL1 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, potentially preventing relapse due to antigen escape or LSC persistence.



 

In the context of a first-in-human phase 1 clinical trial, informed consent from patients was obtained and CLL1-CD33 cCAR T cells expanded in AML patients. CLL1-CD33 cCAR T therapy was safe and well tolerated, and achieved complete response (CR).



 

 



 

Conclusion
Our study supports the development of CLL1-CD33 cCAR as a promising immunotherapy for AML. In the first-in-human clinical trial of CLL1-CD33 cCAR T cell therapy, we demonstrated the feasibility and safety of targeting both CLL1 and CD33 to achieve complete response (CR). Our findings suggest further exploration of CLL1-CD33 cCAR T therapy as a stand-alone therapy or “bridge to transplant” for patients with aggressive, relapsing/refractory AML leukemia.



 

Session topic: 4. Acute myeloid leukemia - Clinical




 
 

Keyword(s): Acute Myeloid Leukemia, Cancer immunotherapy, Immunotherapy


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