Journal
MOLECULAR CANCER THERAPEUTICS
Volume 20, Issue 5, Pages 846-858Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-20-0476
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Funding
- Tata Education and Development Trust [RD/0117TATAE00-001]
- Wadhwani Research Centre for Bioengineering (WRCB) at IIT Bombay [DO/2017-WRCB002-016]
- Tata Centre at IIT Bombay [DGDON422]
- IIT Bombay [RD/0513-IRCCSH0-021, RD/0115-IRSGHI0-008]
- TMH
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Recent studies have described the potential of a novel humanized anti-CD19 CAR T cells in treating B-cell malignancies, showing a favorable balance of efficacy to toxicity. The humanized CAR T cells exhibit lower cytokine production upon antigen encounter and comparable proliferation upon repeated antigen encounter, effectively eliminating NALM6 tumor cells in a preclinical model.
Recent studies have described the remarkable clinical outcome of anti-CD19 chimeric antigen receptor (CAR) T cells in treating B-cell malignancies. However, over 50% of patients develop life-threatening toxicities associated with cytokine release syndrome which may limit its utilization in low-resource settings. To mitigate the toxicity, we designed a novel humanized anti-CD19 CAR T cells by humanizing the framework region of single-chain variable fragment (scFv) derived from a murine FMC63 mAb and combining it with CD8 alpha transmembrane domain, 4-1BB costimulatory domain, and CD3 zeta signaling domain (h1CAR19-8BB zeta). Docking studies followed by molecular dynamics simulation revealed that the humanized anti-CD19 scFv (h1CAR19) establishes higher binding affinity and has a flexible molecular structure with CD19 antigen compared with murine scFv (mCAR19). Ex vivo studies with CAR T cells generated from healthy donors and patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) expressing either h1CAR19 or mCAR19 showed comparable antitumor activity and proliferation. More importantly, h1CAR19-8BBz T cells produced lower levels of cytokines (IFN gamma, TNF alpha) upon antigen encounter and reduced the induction of IL6 cytokine from monocytes than mCAR19-8BB zeta T cells. There was a comparable proliferation of h1CAR19-8BB zeta T cells and mCAR19-8BB zeta T cells upon repeated antigen encounter. Finally, h1CAR19-8BB zeta T cells efficiently eliminated NALM6 tumor cells in a preclinical model. In conclusion, the distinct structural modification in CAR design confers the novel humanized anti-CD19 CAR with a favorable balance of efficacy to toxicity providing a rationale to test this construct in a phase I trial.
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