靶向CD47治疗淋巴瘤研究进展

doi:10.19803/j.1672-8629.20230332

摘要/Abstract

摘要： CD47是近年淋巴瘤治疗中的新兴免疫检查点之一,最重要的作用是在多种通路调控下与巨噬细胞SIRP α受体相互作用,从而抑制巨噬细胞的免疫杀伤作用,使肿瘤细胞达到免疫逃逸。CD47阻断分子种类繁多,其中CD47单克隆抗体最先应用于临床,由于其突出的血液系统不良反应/事件,进一步发展了选择性SIRP α抗体、双克隆抗体等新型药物及联合用药。本文主要综述了CD47分子在淋巴瘤治疗的调控通路、生物学机制、不良反应、相关药物等临床研究进展,以期通过CD47阻断剂的创新药物及联合用药,进一步提高CD47阻断剂的临床疗效。

关键词: CD47, 信号调节蛋白α, 巨噬细胞, 淋巴瘤, 免疫治疗

Abstract: CD47 is one of the emerging immune checkpoints in the treatment of lymphoma in recent years. The most important role of CD47 is to interact with the macrophage receptor SIRP α under the regulation of various pathways, thereby inhibiting the immune attacks of macrophages and enabling tumor cells to achieve immune escape. There are various of CD47 blocking molecules at present, among which CD47 monoclonal antibody is the first to be applied in clinical practice. In order to reduce the prominent adverse reactions of the blood system, new drugs such as selective SIRP α antibody and double clonal antibody and combined therapy have been further developed. This article mainly reviews the clinical research progress on the regulatory mechanism, adverse reactions and related CD47 blockades in the treatment of lymphoma, so as to further improve clinical development through the innovation and combination of CD47 blockers

Key words: CD47, signal regulatory protein α (sirp α), macrophage, lymphoma, cancer immunotherapy

中图分类号:

何慧珍, 郭轶先, 孙婉玲. 靶向CD47治疗淋巴瘤研究进展[J]. 中国药物警戒, 2023, 20(9): 1071-1077.

HE Huizhen, GUO Yixian, SUN Wanling. Research progress on targeting CD47 in treatment of lymphoma[J]. Chinese Journal of Pharmacovigilance, 2023, 20(9): 1071-1077.

参考文献

[1] KARIZAK AZ, SALMASI Z, GHEIBIHAYAT SM, et al.Understanding the regulation of “Don't Eat-Me” signals by inflammatory signaling pathways in the tumor microenvironment for more effective therapy[J]. Journal of Cancer Research and Clinical Oncology, 149(1): 511-529.
[2] JIANG Z, SUN H, YU J, et al.Targeting CD47 for cancer immunotherapy[J]. J Hematol Oncol, 2021, 14(1): 180.
[3] YANG H, XUN Y, YOU H.The landscape overview of CD47-based immunotherapy for hematological malignancies[J]. Biomarker Research, 2023, 11(1): 15.
[4] ELADL E, TREMBLAY-LEMAY R, RASTGOO N, et al.Role of CD47 in hematological malignancies[J]. Journal of Hematology & Oncology, 2020, 13(1): 96.
[5] JUNG YS, PARK JI.Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond beta-catenin and the destruction complex[J]. Experimental and Molecular Medicine, 2020, 52(2): 183-191.
[6] CASEY SC, TONG L, LI Y, et al.MYC regulates the antitumor immune response through CD47 and PD-L1[J]. Science, 2016, 352(6282): 227-231.
[7] MARQUARDT V, THERUVATH J, PAUCK D, et al.Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation[J]. J Immunother Cancer, 2023, 11(1): e5871.
[8] XU L N, WANG S H, SU X L, et al.Targeting glycogen synthase kinase 3 beta regulates CD47 expression after myocardial infarction in rats via the NF-κB signaling pathway[J]. Front Pharmacol, 2021,12: 662726.
[9] CHEN C, WANG R, CHEN X, et al.Targeting CD47 as a novel immunotherapy for breast cancer[J]. Front Oncol, 2022, 12: 924740.
[10] HU H, CHENG R, WANG Y, et al.Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47[J]. The Journal of Clinical Investigation, 2023, 133(2): e153470.
[11] LIAN S, XIE R, YE Y, et al.Dual blockage of both PD-L1 and CD47 enhances immunotherapy against circulating tumor cells[J]. Sci Rep, 2019, 9(1): 4532.
[12] LÓPEZ-PEREIRA B, FERNÁNDEZ-VELASCO AA, FERNÁNDEZ-VEGA I, et al. Expression of CD47 antigen in Reed-Sternberg cells as a new potential biomarker for classical Hodgkin lymphoma[J]. Clin Transl Oncol, 2020, 22(5): 782-785.
[13] GHOLIHA AR, HOLLANDER P, LOF L, et al.Checkpoint CD47 expression in classical Hodgkin lymphoma[J]. Br J Haematol, 2022, 197(5): 580-589.
[14] BOUWSTRA R, HE Y, DE BOER J, et al.CD47 Expression defines efficacy of rituximab with CHOP in non-germinal center B-cell (Non-GCB) diffuse large B-cell lymphoma patients (dlbcl), but not in GCB DLBCL[J]. Cancer Immunology Research, 2019, 7(10): 1663-1671.
[15] CHO J, YOON SE, KIM SJ, et al.CD47 overexpression is common in intestinal non-GCB type diffuse large B-cell lymphoma and associated with 18q21 gain[J]. Blood Adv, 2022, 6(24): 6120-6130.
[16] KAZAMA R, MIYOSHI H, TAKEUCHI M, et al.Combination of CD47 and signal-regulatory protein-α constituting the“don't eat me signal”is a prognostic factor in diffuse large B-cell lymphoma[J]. Cancer Sci, 2020, 111(7): 2608-2619.
[17] CHEN YP, KIM HJ, WU H, et al.SIRPα expression delineates subsets of intratumoral monocyte/macrophages with different functional and prognostic impact in follicular lymphoma[J]. Blood Cancer J, 2019, 9(10): 84.
[18] FREILE JA, USTYANOVSKA AN, CORRALES MG, et al.CD24 Is a potential immunotherapeutic target for mantle cell lymphoma[J]. Biomedicines, 2022, 10(5): 1175.
[19] MARQUES-PIUBELLI ML, PARRA ER, FENG L, et al.SIRPα+ macrophages are increased in patients with FL who progress or relapse after frontline lenalidomide and rituximab[J]. Blood Adv, 2022, 6(11): 3286-3293.
[20] VALENTIN R, PELUSO MO, LEHMBERG TZ, et al.The fully human anti-CD47 antibody SRF231 has dual-mechanism antitumor activity against chronic lymphocytic leukemia (CLL) cells and increases the activity of both rituximab and venetoclax[J]. Blood, 2018, 132(Suppl 1): 4393.
[21] YANAGIDA E, MIYOSHI H, TAKEUCHI M, et al.Clinicopathological analysis of immunohistochemical expression of CD47 and SIRPα in adult T-cell leukemia/lymphoma[J]. Hematol Oncol, 2020, 38(5): 680-688.
[22] KAMIJO H, MIYAGAKI T, TAKAHASHI-SHISHIDO N, et al.Thrombospondin-1 promotes tumor progression in cutaneous T-cell lymphoma via CD47[J]. Leukemia, 2020, 34(3): 845-856.
[23] PAN YY, YU YD, WANG XJ, et al.Tumor-associated macrophages in tumor immunity[J]. Frontiers in Immunology, 2020, 11: 11.
[24] OH HH, PARK YL, PARK SY, et al.CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis[J]. Pathol Res Pract, 2022, 240: 154220.
[25] AUTIO A, WANG H, VELÁZQUEZ F, et al. SIRPα- CD47 axis regulates dendritic cell-T cell interactions and TCR activation during T cell priming in spleen[J]. PLoS One, 2022, 17(4): e266566.
[26] SHENG M, LIN Y, XU D, et al.CD47-Mediated Hedgehog/SMO/GLI1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation[J]. Hepatology, 2021, 74(3): 1560-1577.
[27] YU J, LI S, CHEN D, et al.SIRPα-Fc fusion protein IMM01 exhibits dual anti-tumor activities by targeting CD47/SIRPα signal pathway via blocking the“don't eat me”signal and activating the“eat me”signal[J]. J Hematol Oncol, 2022, 15(1): 167.
[28] CHEN Y, KLINGEN TA, AAS H, et al.CD47 and CD68 expression in breast cancer is associated with tumor-infiltrating lymphocytes, blood vessel invasion, detection mode, and prognosis[J]. The Journal of Pathology: Clinical Research, 2023, 9(3): 151-164.
[29] HU T, LIU H, LIANG Z, et al.Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis[J]. Theranostics, 2020, 10(9): 4056-4072.
[30] RAO L, WU L, LIU Z, et al.Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis[J]. Nat Commun, 2020, 11(1): 4909.
[31] LIU X, WU X, WANG Y, et al.CD47 promotes human glioblastoma invasion through activation of the PI3K/Akt pathway[J]. Oncol Res, 2019, 27(4): 415-422.
[32] SIKIC BI, LAKHANI N, PATNAIK A, et al.First-in-human, first-in-class phase i trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers[J]. J Clin Oncol, 2019, 37(12): 946-953.
[33] ADVANI R, FLINN I, POPPLEWELL L, et al.CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma[J]. N Engl J Med, 2018, 379(18): 1711-1721.
[34] ADVANI RH, FLINN I, POPPLEWELL L, et al.Activity and tolerabilty of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: Initial phase 1b/2 results[J]. Journal of Clinical Oncology, 2018, 36(15suppl): 7504.
[35] NI H, CAO L, WU Z, et al.Combined strategies for effective cancer immunotherapy with a novel anti-CD47 monoclonal antibody[J]. Cancer Immunol Immunother, 2022, 71(2): 353-363.
[36] ANSELL SM, MARIS MB, Lesokhin A M, et al.Phase I study of the CD47 BLocker TTI-621 in patients with relapsed or refractory hematologic malignancies[J]. Clin Cancer Res, 2021, 27(8): 2190-2199.
[37] QUERFELD C, THOMPSON JA, Taylor MH, et al.Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study[J]. Lancet Haematol, 2021, 8(11): e808-e817.
[38] PIETSCH E C, DONG J, CARDOSO R, et al.Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies[J]. Blood Cancer Journal, 2017, 7(2): e536.
[39] PATEL K, ZONDER JA, SANO D, et al.CD47-Blocker TTI-622 shows single-agent activity in patients with advanced relapsed or refractory lymphoma: update from the ongoing first-in-human dose escalation study[J]. Blood, 2021, 138(Suppl 1): 3560.
[40] YANG Y, YANG Z, YANG Y.Potential role of cd47-directed bispecific antibodies in cancer immunotherapy[J]. Front Immunol, 2021, 12: 686031.
[41] BUATOIS V, JOHNSON Z, SALGADO-PIRES S, et al.Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the Treatment of B-Cell lymphoma and leukemia[J]. Mol Cancer Ther, 2018, 17(8): 1739-1751.
[42] YU J, LI S, CHEN D, et al.IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPalpha, exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells[J]. Leukemia, 2023, 37(3): 695-698.
[43] KE H, ZHANG F, WANG J, et al.HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models[J]. Scientific Reports, 2023, 13(1): 5419.
[44] CENDROWICZ E, JACOB L, GREENWALD S, et al.DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity[J]. J Exp Clin Cancer Res, 2022,41(1): 97.
[45] ClinicalTrials.gov. Platform Study for the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma (PRISM Study)[EB/OL]. (2018-06-07)[2023-05-06]. https://classic.clinicaltrials.gov.
[46] NAN Y, ZHANG X, WANG S, et al.Targeting CD47 enhanced the antitumor immunity of PD-L1 blockade in B-cell lymphoma[J]. Immunotherapy, 2023, 15(3): 175-187.
[47] HAN Z, WU X, QIN H, et al.Blockade of the immune checkpoint CD47 by TTI-621 Potentiates the response to anti-PD-L1 in Cutaneous T cell lymphoma[J]. J Invest Dermatol, 2023, 143(8): 1569-1578.
[48] XU L, WANG S, LI J, et al.CD47/SIRPα blocking enhances CD19/CD3-bispecific T cell engager antibody-mediated lysis of B cell malignancies[J]. Biochem Biophys Res Commun, 2019, 509(3): 739-745.
[49] LI M, YU H, QI F, et al.Anti-CD47 immunotherapy in combination with BCL-2 inhibitor to enhance anti-tumor activity in B-cell lymphoma[J]. Hematol Oncol, 2022, 40(4): 596-608.
[50] CAO X, WANG Y, ZHANG W, et al.Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced immunosuppression[J]. Blood, 2022, 139(22): 3290-3302.
[51] DACEK MM, KURTZ K, WALLISCH P, et al.Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker[J]. Blood, 2023, 12: 857927.
[52] CHEN H, YANG Y, DENG Y, et al.Delivery of CD47 blocker SIRPα-Fc by CAR-T cells enhances antitumor efficacy[J]. J Immunother Cancer, 2022, 10(2): e3737.
[53] CHIANG ZC, FANG S, SHEN YK, et al.Development of novel CD47-Specific ADCs possessing high potency against non-small cell lung cancer in vitro and in vivo[J]. Front Oncol, 2022, 12: 857927.
[54] SON J, HSIEH RC, LIN HY, et al.Inhibition of the CD47-SIRPalpha axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data[J]. Front Immunol, 2022, 13: 1027235.
[55] HAWKES E, LEWIS KL, DOO NW, et al.First-in-human (FIH) study of the fully-human kappa-lambda CD19/CD47 bispecific antibody TG-1801 in patients (pts) with B-Cell lymphoma[J]. Blood, 2022, 140: 6599-6601.
[56] SHI YK, SONG YP, ZHANG MZ, et al.Preliminary safety and efficacy evaluation of IMM0306, a CD47 and CD20 bispecific monoclonal antibody-trap (mAbTrap), from an ongoing phase i dose-escalation study in patients with relapsed or refractory B-Cell non- hodgkin's lymphoma (R/R B-NHL)[J]. Blood, 2022, 140: 9323-9324.
[57] WANG J, SUN Y, CHU Q, et al.Phase I study of IBI322 (anti-CD47/PD-L1 bispecific antibody) monotherapy therapy in patients with advanced solid tumors in China[J]. Cancer Research, 2022, 82(12Suppl): T513.