Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation.A phase Ⅰ/Ⅱ clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×105/kg,1×106/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1％,the complete response rate(CRR)was 50.0％.The mPFS was 6 months and the 1-year overall survival rate was 77.8％.Cytokine release syndrome(CRS)occurred in 13 patients(59.1％),with 54.5％of grade 1-2 CRS.Only one patient(4.5％)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation.

Zhitao Ying;Ting He;Shanzhao Jin;Xiaopei Wang;Wen Zheng;Ningjing Lin;Meifeng Tu;Yan Xie;Lingyan Ping;Weiping Liu;Lijuan Deng;Yanping Ding;Xuelian Hu;Bing Bu;Xin'an Lu;Yuqin Song;Jun Zhu

Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Lymphoma,Peking University Cancer Hospital&Institute,Beijing 100042,China;Beijing Immunochina Pharmaceuticals Co.,Ltd.,Beijing 100195,China;Department of Medical Oncology,Shandong Cancer Hospital and Institute,Shandong First Medical University and Shandong Academy of Medical Sciences,Jinan 250117,China

中国癌症研究（英文版）

[1]Zhitao Ying;Ting He;Shanzhao Jin;Xiaopei Wang;Wen Zheng;Ningjing Lin;Meifeng Tu;Yan Xie;Lingyan Ping;Weiping Liu;Lijuan Deng;Yanping Ding;Xuelian Hu;Bing Bu;Xin'an Lu;Yuqin Song;Jun Zhu-.A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma)[J].中国癌症研究（英文版）,2022(01):53-62

IM19,FMC63

durable,1BB,CD19,CAR,treatment,relapsed,refractory,Hodgkin,lymphoma,Objective,Previous,studies,reported,that,chimeric,antigen,receptor,cells,were,more,beneficial,clinical,outcomes,than,CD28,especially,lower,incidence,severe,adverse,events,However,median,progression,free,survival,mPFS,product,Kymriah,was,shorter,Yescarta,months,suggesting,limited,long,term,efficacy,Thus,needs,developed,Methods,We,designed,targeted,named,which,consisted,scFv,CD3,intracellular,domain,manufactured,into,memory,enriched,formulation,phase,trial,launched,evaluate,NHL,Dose,escalation,investigation,dose,performed,patients,All,received,single,infusion,after,day,conditional,regimen,Results,At,overall,response,ORR,complete,CRR,year,Cytokine,release,syndrome,CRS,occurred,grade,Only,one,experienced,neurotoxicity,Conclusions,These,results,demonstrated,safety,promising,further,development

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