瘤内免疫治疗临床研究组织实施推荐与建议

摘要/Abstract

摘要： 近年来，免疫检查点疗法（ICT）在肿瘤治疗领域取得重大突破。然而，仅有少部分患者获得客观缓解，而发生的免疫相关副反应却可能致命，费用较高、免疫耐受等问题限制了其临床应用。瘤内免疫治疗直接将免疫刺激剂注入肿瘤，通过释放肿瘤抗原，激活肿瘤特异性效应T细胞，激活/增强局部和全身免疫反应。瘤内免疫治疗应用前景广阔，但目前在国内尚未在临床广泛应用，相关临床研究较少，且缺乏相应规范。本研究团队立足于丰富的肿瘤非血管介入诊疗经验，在瘤内免疫治疗方向开展了深入探索。本研究综述瘤内免疫治疗药代动力学和药效学研究内容和方向，并总结临床研究中的要点，以期为瘤内免疫治疗临床试验提供规范统一的方法、数据收集方案和结果报告规范，为临床研究人员、制药公司、伦理委员会、独立审查委员会、患者招募员和监管机构提供指导，提高瘤内免疫治疗临床试验的质量，促进研究者之间的相互理解，方便更好地评估瘤内免疫治疗临床试验，从而获得监管机构的批准，最终提高患者生存和生活质量，降低治疗相关副反应。
[关键词]

关键词: font-size:medium, ">瘤内注射；瘤内免疫治疗；临床试验；药代动力学；药效动力学；疗效评价

Abstract: In recent years， immune checkpoint therapy (ICT) has made major breakthroughs in the field of cancer therapy. However， only a small number of patients achieved objective remission， but the occurrence of immune-related side effects may be fatal. The high cost and immune tolerance problems limit its clinical application. Intratumoral immunotherapy， though direct injection of immunologic stimulants into the tumor，activates tumor-specific effector T cells by releasing tumor antigens to activate or enhance local and systemic immune responses. Intratumoral immunotherapy has a broad prospect， but at present， it has not been widely used in clinical practice in China，and there are few related clinical studies and lack of corresponding norms. Based on rich experience of non-vascular intervention， the author′s team has carried out in-depth exploration in the direction of intratumoral immunotherapy. This paper reviewed the content and direction of the researches on pharmacokinetics and pharmacodynamics of intratumoral immunotherapy， and summarized the main points of clinical researches of intratumoral immunotherapy， to provide standardized and unified methods， data collection protocols and results reporting norms for clinical trials of intratumoral immunotherapy， and provide guidance to clinical researchers， pharmaceutical companies， ethics committees， independent review boards， patient recruiters， and regulatory agencies， so as to improve the quality of clinical trials of intratumoral immunotherapy， promote mutual understanding among researchers， facilitate better evaluation of clinical trials for intratumoral immunotherapy for regulatory approval， and ultimately improving patient survival and quality of life and reducing treatment-related side effects.

Key words: font-size:medium, ">Intratumoral injection； Intratumoral immunotherapy； Clinical trials； Pharmacokinetics； Pharmacodynamics； Efficacy evaluation

中图分类号:

单鹄声. 瘤内免疫治疗临床研究组织实施推荐与建议[J]. 中国医药导刊, 2023, 25(3): 249-255.

SHAN Husheng. Implement Recommendations for Clinical Trials of Intratumoral Immunotherapy[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2023, 25(3): 249-255.

参考文献

[1]Tang J， Yu JX， Hubbard-Lucey VM， et al. Trial watch： the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors[J]. Nat Rev Drug Discov， 2018，17(12)：854-855.
     [2]Postow MA， Sidlow R， Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade[J]. N Engl J Med， 2018，378(2)：158-168.
     [3]Wang Y， Zhou S， Yang F， et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials： a systematic review and meta-analysis[J]. JAMA Oncol， 2019，5(7)：1008-1019.
     [4]Blanco E， Chocarro L， Fernández-Rubio L， et al. Leading edge： intratumor delivery of monoclonal antibodies for the treatment of solid tumors[J]. Int J Mol Sci， 2023，24(3)：2676.
     [5]Marabelle A， Tselikas L， de Baere T， et al. Intratumoral immunotherapy： using the tumor as the remedy[J]. Ann Oncol， 2017，28(suppl_12)：xii33-xii43.
     [6]Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893[J]. Clin Orthop Relat Res， 1991，(262)：3-11.
     [7]Milling L， Zhang Y， Irvine DJ. Delivering safer immunotherapies for cancer[J]. Adv Drug Deliv Rev， 2017，114：79-101.
     [8]Marin-Acevedo JA， Dholaria B， Soyano AE， et al. Next generation of immune checkpoint therapy in cancer： new developments and challenges[J]. J Hematol Oncol， 2018，11(1)：39.
     [9]Mullins SR， Vasilakos JP， Deschler K， et al. Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies[J]. J Immunother Cancer， 2019，7(1)：244.
     [10]Wu YT， Fang Y， Wei Q， et al. Tumor-targeted delivery of a STING agonist improvescancer immunotherapy[J]. Proc Natl Acad Sci U S A， 2022，119(49)：e2214278119.
     [11]Shekarian T， Valsesia-Wittmann S， Brody J， et al. Pattern recognition receptors： immune targets to enhance cancer immunotherapy[J]. Ann Oncol， 2017，28(8)：1756-1766.
     [12]Chen L， Zhou C， Chen Q， et al. Oncolytic Zika virus promotes intratumoral T cell infiltration and improves immunotherapy efficacy in glioblastoma[J]. Mol Ther Oncolytics， 2022，24：522-534.
     [13]Hamid O， Ismail R， Puzanov I. Intratumoral immunotherapy-update 2019[J]. Oncologist， 2020，25(3)：e423-e438.
     [14]Moran AE， Kovacsovics-Bankowski M， Weinberg AD. The TNFRs OX40， 4-1BB， and CD40 as targets for cancer immunotherapy[J]. Curr Opin Immunol， 2013，25(2)：230-237.
     [15]Andrews LP， Yano H， Vignali DAA. Inhibitory receptors and ligands beyond PD-1， PD-L1 and CTLA-4： breakthroughs or backups[J]. Nat Immunol， 2019，20(11)：1425-1434.
     [16]Agliardi G， Liuzzi AR， Hotblack A， et al. Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma[J]. Nat Commun， 2021，12(1)：444.
     [17]Liu JQ， Zhang C， Zhang X， et al. Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy[J]. J Control Release， 2022，345：306-313.
     [18]Makkouk A， Yang XC， Barca T， et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma[J]. J Immunother Cancer， 2021，9(12)： e003441.
     [19]Maresca KP， Chen J， Mathur D， et al. Preclinical evaluation of (89)Zr-Df-IAB22M2C PET as an imaging biomarker for the development of the GUCY2C-CD3 bispecific PF-07062119 as a T cell engaging therapy[J]. Mol Imaging Biol， 2021， 23(6)：941-951..
     [20]Fu Y， Ye F， Zhang X， et al. Decrease in tumor interstitial pressure for enhanced drug intratumoral delivery and synergistic tumor therapy[J]. ACS Nano， 2022，16(11)：18376-18389.
     [21]Marabelle A， Andtbacka R， Harrington K， et al. Starting the fight in the tumor： expert recommendations for the development of human intratumoral immunotherapy (HIT-IT) [J]. Ann Oncol， 2018，29(11)：2163-2174.
     [22]Sepich-Poore GD， Zitvogel L， Straussman R， et al. The microbiome and human cancer[J]. Science， 2021，371(6536)： eabc4552.
     [23]Melero I， Castanon E， Alvarez M， et al. Intratumoural administration and tumour tissue targeting of cancer immunotherapies[J]. Nat Rev Clin Oncol， 2021，18(9)：558-576.
     [24]Badiee P， Maritz MF， Dmochowska N， et al. Intratumoral anti-PD-1 nanoformulation improves its biodistribution[J]. ACS Appl Mater Interfaces， 2022，14(14)：15881-15893.
     [25]Koyama T， Shimizu T， Sato J， et al. Practical consideration for successful sequential tumor biopsies in first-in-human trials[J]. Invest New Drugs， 2022，40(4)：841-849.
     [26]Prud′homme C， Deschamps F， Allorant A， et al. Image-guided tumour biopsies in a prospective molecular triage study (MOSCATO-01)： what are the real risks?[J]. Eur J Cancer， 2018，103：108-119.
     [27]Radwan E， Mali V， Haddox S， et al. Treg cells depletion is a mechanism that drives microvascular dysfunction in mice with established hypertension[J]. Biochim Biophys Acta Mol Basis Dis， 2019，1865(2)：403-412.
     [28]Locati M， Curtale G， Mantovani A. Diversity， mechanisms， and significance of macrophage plasticity[J]. Annu Rev Pathol， 2020，15：123-147.
     [29]du Bois H， Heim TA， Lund AW. Tumor-draining lymph nodes： at the crossroads of metastasis and immunity[J]. Sci Immunol， 2021，6(63)：eabg3551.
     [30]Schumacher TN， Thommen DS. Tertiary lymphoid structures in cancer[J]. Science， 2022，375(6576)：eabf9419.
     [31]Gerlinger M， Rowan AJ， Horswell S， et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing[J]. N Engl J Med， 2012，366(10)：883-892.
     [32]Gerlinger M， Horswell S， Larkin J， et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing[J]. Nat Genet， 2014，46(3)：225-233.
     [33]McGranahan N， Furness AJ， Rosenthal R， et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade[J]. Science， 2016，351(6280)：1463-1469.
     [34]Gerlinger M， Quezada SA， Peggs KS， et al. Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas[J]. J Pathol， 2013，231(4)：424-432.
     [35]Madore J， Vilain RE， Menzies AM， et al. Pd-L1 expression in melanoma shows marked heterogeneity within and between patients： implications for anti-PD-1/PD-L1 clinical trials[J]. Pigment Cell Melanoma Res， 2015，28(3)：245-253.
     [36]Champiat S， Tselikas L， Farhane S， et al. Intratumoral immunotherapy： from trial design to clinical practice[J]. Clin Cancer Res， 2021，27(3)：665-679.
     [37]Xia T， Zhou F， Chu H， et al. Incidence and risk factors of postoperative symptomatic spinal epidural hematoma in cervical spine surgery： a single center， retrospective study of 18，220 patients[J]. Eur Spine J， 2022，31(10)：2753-2760.
     [38]England EC， Spear CR， Huang DD， et al. REBOA as a rescue strategy for catastrophic vascular injury during robotic surgery[J]. J Robot Surg， 2020，14(3)：473-477.
     [39]Som A， Rosenboom JG， Chandler A， et al. Image-guided intratumoral immunotherapy： developing a clinically practical technology[J]. Adv Drug Deliv Rev， 2022，189：114505.
     [40]Munoz NM， Williams M， Dixon K， et al. Influence of injection technique， drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy[J]. J Immunother Cancer， 2021，9(2)：e001800.
     [41]Marc B， Monino L， Rimbas M. EUS-guided intra-tumoral therapies[J]. Best Pract Res Clin Gastroenterol， 2022，60-61：101817.
     [42]Li M， Zhu Y， Yang C， et al. Acoustic triggered nanobomb for US imaging guided sonodynamic therapy and activating antitumor immunity[J]. Drug Deliv， 2022，29(1)：2177-2189.
     [43]Goins B， Phillips WT， Bao A. Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy[J]. Expert Opin Drug Deliv， 2016，13(6)：873-889.
     [44]Carbone C， Piro G， Agostini A， et al. Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer[J]. J Immunother Cancer， 2021，9(9)：e002876.
     [45]Meric-Bernstam F， Larkin J， Tabernero J， et al. Enhancing anti-tumour efficacy with immunotherapy combinations[J]. Lancet， 2021，397(10278)：1010-1022.
     [46]Arina A， Gutiontov SI， Weichselbaum RR. Radiotherapy and immunotherapy for cancer： from "systemic" to "multisite"[J]. Clin Cancer Res， 2020，26(12)：2777-2782.
     [47]Simmet V， Eberst L， Marabelle A， et al. Immune checkpoint inhibitor-based combinations： is dose escalation mandatory for phase I trials?[J]. Ann Oncol， 2019，30(11)：1751-1759.
     [48]Okada H， Weller M， Huang R， et al. Immunotherapy response assessment in neuro-oncology： a report of the rano working group[J]. Lancet Oncol， 2015，16(15)：e534-e542.
     [49]Seymour L， Bogaerts J， Perrone A， et al. iRECIST： guidelines for response criteria for use in trials testing immunotherapeutics[J]. Lancet Oncol， 2017，18(3)：e143-e152.
     [50]Castanon Alvarez E， Aspeslagh S， Soria JC. 3D waterfall plots： a better graphical representation of tumor response in oncology[J]. Ann Oncol， 2017，28(3)：454-456.

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