胞内免疫检查点

2023-12-28

免疫检查点是免疫系统的负反馈机制，激活后保护正常细胞免受T细胞介导的细胞毒性，维持免疫稳态。熟知的检查点（PD-(L)1、CTLA-4、TIM3、LAG3等）表达于细胞膜表面。除此之外，一些细胞内蛋白参与 TCR 下游的负反馈回路，可被视为胞内免疫检查点（(intracellular immune checkpoints ，iICPs)，目前有多个在临床研究阶段。SHP-2（Src homology region 2）PD-1可通过招募磷酸酶SHP-2来抑制T细胞的活化。然而，T细胞特异性缺失SHP2的小鼠并没有改善抗肿瘤免疫。后来发现，在没有SHP-2的情况下，PD-1招募了SHP-1来维持此功能。因此，同时阻断SHP-1和SHP-2对于改善TCR信号通路是必要的。Front. Immunol. 2019在骨髓中，GM-CSF诱导PD-1的磷酸化，PD-1-SHP-2的募集到GM-CSF受体。SHP-2或PD-1的缺失增强了GM-CSF介导的转录因子HOXA10和IRF8的磷酸化，这分别调节髓系分化和单核-moDC谱系分化。因此，SHP-2和PD1-SHP-2信号抑制髓细胞分化，产生抑制性髓系细胞，抑制抗肿瘤免疫。此外，SHP-2是生长因子-ERK信号通路的重要调节分子。抗PD-1抗体 PD-1抗体与SHP-2抑制剂联合的临床研究ICP-189 诺诚健华NCT05370755：A Study of ICP-189 and ICP-189 in Combination With Anti-PD-1 Monoclonal Antibody PD-1 Monoclonal Antibody in Patients With Advanced Solid Tumors。BBP-398 Navire Pharma Inc., a BridgeBio companyNCT05375084：SHP2 Inhibitor BBP-398 in Combination With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation。单药及与小芬抑制剂联合TNO155 Novartis NCT03114319 Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors（单药或联合EGF816 (nazartinib)HBI-2376 沪亚生物NCT05163028 A Dose Escalation Study of SHP2 Inhibitor in Patients With Solid Tumors Harboring KRAS of EGFR Mutations HS-10381 江苏豪森药业NCT05378178 A PhaseⅠStudy of HS-10381 in Patients With Advanced Solid Tumors ET0038 上海奕拓医药NCT05354843 SHP2 Inhibitor ET0038 Monotherapy in Patients With Advanced Solid TumorsJAB-3068 加科思NCT03565003 A First-in-Human Study of JAB-3068 (SHP2 Inhibitor) in Adult Patients With Advanced Solid Tumors in ChinaJAB-3312 加科思NCT05288205 Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C MutationERAS-601 Erasca, Inc.(Nasdaq: ERAS)NCT04866134 A Study of ERAS-007 as Monotherapy or in Combination With ERAS-601 in Patients With Advanced or Metastatic Solid Tumors (HERKULES-1)NCT04670679 A Dose Escalation/Expansion Study of ERAS-601 in Patients With Advanced or Metastatic Solid Tumors (FLAGSHP-1)PF-07284892 辉瑞NCT04800822 PF-07284892 in Participants With Advanced Solid TumorsRMC-4630 Revolution Medicines, Inc.NCT05054725 Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard TherapiesCbl-bCbl-b是CBL(Casitas B-lymphoma))家族的一个成员。CBL蛋白具有环指催化结构域，负责蛋白质泛素化和目标蛋白的顺序降解。CBL蛋白导致多个靶点的降解，从而下调TCR信号级联。Cbl-b靶向PI3K的调控亚基p85，降低了PI3K的活性，干扰其激活不同信号通路的能力。Cbl-b参与调控CD28或抑制受体CTLA-4和PD-1的共刺激信号，TCR上Cbl-b的丢失导致Akt/Erk磷酸化、增殖、激活、细胞因子的产生（IFNγ、TNFα、IL-2）和细胞溶解能力（颗粒酶B）。Journal for ImmunoTherapy of Cancer 2023一些抑制T细胞CBL-b的临床试验正在进行中。CISH一个SOCS（细胞因子信号抑制因子）家族蛋白成员，负调控CD8+ T细胞信号通路。缺陷小鼠的CD8+ T淋巴细胞对TCR信号响应改善，效应功能相关基因（Il2、Prf1、GrzmB、Eomes、Tbx21、c-Myc和Bcl2l）的表达增加。通过CRISPR-Cas9敲除TILs中CISH，进行肿瘤治疗的临床试验正在进行中。Cells 2021HPK1造血祖细胞激酶 1 （Hematopoietic progenitor kinase 1，HPK1）由 MAP4K1 基因编码，是一种蛋白激酶，被确定为 TCR 信号转导的关键调节因子。Expert Opinion on Therapeutic Patents（2021）HPK1被 TCR 复合物激活，HPK1 结合并磷酸化 LAT 信号小体上的SLP-76。磷酸化的SLP-76随后与GAD和14-3-3蛋白结合，破坏了SLP-76与LAT信号体的相互作用，从而触发了SLP-76降解，SLP-76降解对MAPK-ERK通路信号转导产生负调控。小鼠中的 HPK1基因敲除导致 T 细胞增殖、活化和细胞因子分泌增加，从而赋予它们控制肿瘤生长的能力。许多HPK1小分子抑制剂正在进行癌症免疫治疗临床试验。CFI-402411 Treadwell Therapeutics, IncNCT04521413 Safety and Efficacy Study of CFI-402411 in Subjects With Advanced Solid MalignanciesRGT-264 锐格医药 NCT05764915 A Phase I Study of RGT-264 in Subjects With Advanced Solid TumorsBGB-26808 百济神州NCT05981703 A Study Investigating BGB-26808 Alone or in Combination With Tislelizumab in Participants With Advanced Solid TumorsPF-07265028 辉瑞NCT05233436 PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid TumorsNDI 1150-101 Nimbus Saturn, Inc.NCT05128487 A Study of NDI 1150-101 in Patients With Solid Tumors参考文献Anthos Christofides etal, SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses，Nat Immunol. 2023 Jan;24(1):55-68Niogret C, Birchmeier W and Guarda G (2019) SHP-2 in Lymphocytes’ Cytokine and Inhibitory Receptor Signaling. Front. Immunol. 10:2468. doi: 10.3389/fimmu.2019.02468Augustin RC, Bao R, Luke JJ. Targeting Cbl-b in cancer immunotherapy. Journal for ImmunoTherapy of Cancer 2023;11:e006007. doi:10.1136/ jitc-2022-00600Kumar, S.; Sarthi, P.; Mani, I.; Ashraf, M.U.; Kang, M.-H.; Kumar, V.; Bae, Y.-S. Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH. Cells 2021, 10, 2250. https://doi-org.libproxy1.nus.edu.sg/ 10.3390/cells10092250 Ian D Linney & Neelu Kaila (2021): Inhibitors of immuno-oncology target HPK1 – a patent review (2016 to 2020), Expert Opinion on Therapeutic Patents, DOI: 10.1080/13543776.2021.1924671