重新设计CAR-T疗法治疗实体瘤：肾癌治愈新途径.pdf

1、Redesigning CAR T cells for solid tumors:A new path toward Cures of ccRCCWayne A Marasco,M.D.,Ph.D.Dana-Farber Cancer InstituteSLIDE DIMENSIONS SHOULD FOLLOW 16:9 RATIO G250 CAR-T in the Phase I clinical trial caused severe toxicity but no antitumor effects due to(1)murine scFv(2)CD3 first generatio

2、n CAR(3)OTOT(Lamers et al.,J Clin Oncol 2006;Mol Ther 2013)PSMA inducible CAIX targeted CAR AB-2100 secreting shRNA targeting Fas and TGFBR2(Arsenal Bio)(Mohanty et al.,Cancer Res 2024)Anti-CD70 CTX-130(CRISPR Therapeutics)Phase I COBALT-RCC:8%durable CR(18+months)and 69.2%SD with no dose-limiting t

3、oxicities(DLTs)(N=14)(Pal et al.,Cancer Discov 2024)Anti-CD70 ALLO-316(Allogene)Phase I TRAVERSE trial:best overall Response Rate(ORR)of 50%(Srour et al.,JCO 2025)SLIDE DIMENSIONS SHOULD FOLLOW 16:9 RATIODual-Targeting(Improving Efficacy)Tumor Cell Heterogeneity Capture both populations of single+ce

4、lls onlyPrevent neutralization escapeFine-Tuned(Improving Safety)Safety issue sharing of tumor associated antigens with normal tissuesFine tune targeting moiety affinity to target only high density antigen expressed on tumor cells but not low density antigen on healthy tissuesImmune Restoring(Revers

5、al of local immunosuppression to achieve“Cures”)Change the tumor microenvironment by locally secreting checkpoint blockade inhibitors to restore anti-tumor immunityBispecific antibodies Ab-cytokine fusions T cell engagers either conditional or constitutive Efficacy-Overcoming tumor cell heterogeneit

6、y(immune editing)CAIX+CD70+CD70+CAIX-CAIX+CD70-050100ccRCC patients(Stage I-IV)percentage population(%)477477477501477469477496477498477504477475477481477482477483477479477476477487477488477497477499477500477502477485477486477468477489477494477503477493Stage IStage IIStage IIISta