前言
随着AI时代的到来，科学研究人员和产品研发人员有机会从琐碎的辅助工作中脱身，一些有雄心壮志却受困于辅助资源的研究者也有机会加入研究的竞争之中。竞争的焦点逐渐聚焦于研究者能否清晰定义问题和解决方案的逻辑。形式化的建模会帮助研究者在利用AI的竞争中获得极大的优势。
本书以当前的热门研究领域——癌症免疫治疗为例，展示该领域的建模示例，并探讨由领域专家掌握建模技能并主导建模工作的可行性。
目前，系统生物学和计算生物学已经有了被广泛接受和使用的建模规范，例如图形表示法SBGN、文本规范SBML和CellML等，并且已经积累了相当丰富的模型。
本书将从“跨层级的统一”的视角切入，从微观的生物学层级（分子、细胞、组织、器官、个体）到宏观的医疗卫生体系（人员、设备、机构）层级，使用OMG制定的系统工程建模语言SysML，对与癌症免疫治疗相关的各个层级知识进行建模，以获得活的、可供研究者复用于多个研究项目的模型。
本书的目标读者是从事肿瘤免疫治疗及相关领域的专业人士，包括：
• 临床医学专家和肿瘤科医生
• 基础与转化医学研究人员
• 医药工业与生物技术领域的研发人员
• 正在开发相关系统的系统工程与软件工程从业者
本书的第1章讲解SysML v2的基本建模知识。即使读者之前没有任何的系统工程/软件工程和SysML/UML知识，在认真阅读第1章后，也可以进入后续的阅读。当然，如果读者不满足于第1章的内容，也可以补充任何一本/一部被推荐的书籍教程或视频教程。
从第2章开始，本书进入建模的实作，并针对具体模型内容，按需要补充第1章未涉及的高阶建模知识。
本书目前以连载的形式发布，中文版首发于微信公众号FagaoMBSE，英文版首发于github.com/FagaoMBSE。
当前写作时，所参照的SysML版本为2025年9月3日发布的2.0版规范，使用的图形渲染工具为Eclipse Modeling Tools和M-Design v2。随着市场上可得的建模工具增加，在后续写作进程中，可能会更换图形渲染工具。
欢迎您的任何反馈，作者的Email是fagaombse@gmail.com。
第2章 癌症免疫治疗的历史
本章使用SysML v2[1]对癌症免疫治疗的发展历史建模。主要参考文献为SITC教科书 Cancer Immunotherapy Principles and Practice第二版[2]，并结合2017–2025年间FDA公布的相关监管里程碑[3-10]。建模时，主要关注产生实际效果的历史事件，因此一些很有新闻价值的事件可能不在建模的事件列表中，例如和癌症免疫治疗相关的诺贝尔生理学或医学奖的授予。
2.1 癌症免疫治疗历史的SysML v2文本表示
在本章中，我们将历史事件统一建模为HistoricalEvent，并通过mainPersons与mainOrganizations引用关键人物和机构。
在CancerImmunotherapyHistoryFlow中，采用了线性的first … then …对历史事件做近似的排序。实际历史进程中，不同研究路线往往是并行推进、彼此交叉的，这一简化将在后续章节中通过更精细的时间建模来纠正。
SysML v2文本如代码清单1-1。
package CancerImmunotherapyHistory {
private import ScalarValues::String;
part def Person {
attribute fullName : String;
}
part def Organization {
attribute name : String;
}
action def HistoricalEvent {
attribute year : String;
attribute titleEn : String;
attribute titleZh : String;
attribute summaryEn : String;
attribute summaryZh : String;
ref part mainPersons[0..*] : Person;
ref part mainOrganizations[0..*] : Organization;
}
part williamColey : Person {
:>> fullName = "William B. Coley";
}
part paulEhrlich : Person {
:>> fullName = "Paul Ehrlich";
}
part aliceMoore : Person {
:>> fullName = "Alice Moore";
}
part donaldMorton : Person {
:>> fullName = "Donald Morton";
}
part stevenARosenberg : Person {
:>> fullName = "Steven A. Rosenberg";
}
part zeligEshhar : Person {
:>> fullName = "Zelig Eshhar";
}
part carlJune : Person {
:>> fullName = "Carl June";
}
part jamesPAllison : Person {
:>> fullName = "James P. Allison";
}
part parkeDavisCo : Organization {
:>> name = "Parke Davis & Co.";
}
part fda : Organization {
:>> name = "U.S. FDA";
}
action def CancerImmunotherapyHistoryFlow {
action coleysToxinInjection : HistoricalEvent {
:>> year = "1891";
:>> titleEn = "Coley's toxin injection therapy";
:>> titleZh = "科利毒素注射疗法";
:>> summaryEn = "Coley injects bacterial toxins to treat inoperable sarcomas.";
:>> summaryZh = "科利用细菌毒素注射治疗无法手术的肉瘤患者。";
:>> mainPersons = williamColey;
}
action ehrlichMagicBullet : HistoricalEvent {
:>> year = "early 1900s";
:>> titleEn = "Ehrlich's 'Magic Bullet' hypothesis";
:>> titleZh = "埃利希“魔弹”假说";
:>> summaryEn = "Concept that drugs could selectively target disease cells without harming normal tissues, providing a conceptual basis for targeted and immune-based therapies.";
:>> summaryZh = "提出药物可以选择性靶向病变细胞而尽量避免损伤正常组织的设想，为后来的靶向治疗和免疫治疗提供了重要的观念基础。";
:>> mainPersons = paulEhrlich;
}
action firstViralOncolysis : HistoricalEvent {
:>> year = "circa 1949";
:>> titleEn = "First viral oncolysis experiment";
:>> titleZh = "首例病毒溶瘤疗法实验";
:>> summaryEn = "Clinical and preclinical observations that certain viral infections could lead to temporary tumor regression, inspiring oncolytic virus strategies.";
:>> summaryZh = "在临床与前临床观察中发现某些病毒感染可导致肿瘤暂时性缩小，由此启发了后续的溶瘤病毒治疗构想。";
:>> mainPersons = aliceMoore;
}
action coleyToxinDiscontinued : HistoricalEvent {
:>> year = "1950s";
:>> titleEn = "Coley's toxin discontinued by Parke Davis";
:>> titleZh = "Parke Davis公司停止生产科利毒素";
:>> summaryEn = "Industrial production of Coley toxin was discontinued, marking the decline of early empirical cancer immunotherapy approaches.";
:>> summaryZh = "制药公司停止生产科利毒素，标志着早期经验性癌症免疫治疗策略的走向式微。";
:>> mainOrganizations = parkeDavisCo;
}
action melanomaVaccineTrials : HistoricalEvent {
:>> year = "1970s–2000s";
:>> titleEn = "Melanoma vaccine clinical trials";
:>> titleZh = "黑色素瘤疫苗临床试验";
:>> summaryEn = "Multiple melanoma vaccine trials were conducted over several decades, but most showed limited clinical benefit, highlighting the difficulty of inducing effective anti-tumor immunity.";
:>> summaryZh = "在数十年的时间里开展了多种黑色素瘤疫苗临床试验，多数疗效有限，凸显出诱导有效抗肿瘤免疫反应的困难。";
:>> mainPersons = donaldMorton;
}
action intratumoralBCG : HistoricalEvent {
:>> year = "1970s";
:>> titleEn = "Intratumoral BCG immunotherapy";
:>> titleZh = "肿瘤内卡介苗免疫治疗";
:>> summaryEn = "BCG is injected directly into tumors to stimulate local immune responses.";
:>> summaryZh = "将卡介苗直接注入肿瘤以激活局部免疫反应。";
:>> mainPersons = donaldMorton;
}
action lakCellTherapy : HistoricalEvent {
:>> year = "1980s";
:>> titleEn = "LAK (lymphokine-activated killer) cell therapy";
:>> titleZh = "LAK（淋巴因子激活杀伤细胞）疗法";
:>> summaryEn = "Ex vivo activation of peripheral lymphocytes with high-dose IL-2 to kill tumors.";
:>> summaryZh = "体外用大剂量IL-2激活外周淋巴细胞以增强其杀伤肿瘤的能力。";
:>> mainPersons = stevenARosenberg;
}
action cytokineTherapies : HistoricalEvent {
:>> year = "1980s";
:>> titleEn = "Cytokine therapies with IL-2 and IFN-alpha";
:>> titleZh = "IL-2 与 IFN-α 细胞因子治疗";
:>> summaryEn = "High-dose IL-2 and interferon-alpha are used as systemic immunotherapies.";
:>> summaryZh = "大剂量IL-2和干扰素-α被用作全身性免疫治疗手段。";
}
action tILTherapy : HistoricalEvent {
:>> year = "1988";
:>> titleEn = "Tumor-infiltrating lymphocyte (TIL) therapy";
:>> titleZh = "肿瘤浸润淋巴细胞（TIL）疗法";
:>> summaryEn = "Isolation and expansion of TILs from resected tumors followed by reinfusion.";
:>> summaryZh = "从切除肿瘤中分离并扩增TIL，然后回输给同一患者。";
:>> mainPersons = stevenARosenberg;
}
action cartConcept : HistoricalEvent {
:>> year = "1990s";
:>> titleEn = "Chimeric antigen receptor T cell (CAR-T) concept";
:>> titleZh = "嵌合抗原受体 T 细胞（CAR-T）构想";
:>> summaryEn = "First designs of chimeric antigen receptors combined antibody-derived recognition with T-cell signaling, providing a framework for genetically engineered T-cell therapies.";
:>> summaryZh = "最初的嵌合抗原受体设计将抗体来源的识别结构域与T细胞信号转导结构域结合，为后续基因工程T细胞疗法奠定了框架。";
:>> mainPersons = zeligEshhar;
}
action cartClinical : HistoricalEvent {
:>> year = "2010s";
:>> titleEn = "Clinical breakthrough of CAR-T cell therapy";
:>> titleZh = "CAR-T 细胞疗法的临床突破";
:>> summaryEn = "CD19-targeted CAR-T cell therapies achieved dramatic remissions in refractory leukemia and lymphoma, leading to regulatory approvals and establishing CAR-T as a major modality of cancer immunotherapy.";
:>> summaryZh = "以 CD19 为靶点的 CAR-T 细胞疗法在难治性白血病和淋巴瘤中获得了显著缓解，促成相关产品获批，使 CAR-T 成为肿瘤免疫治疗的重要治疗模式。";
:>> mainPersons = carlJune;
}
action sipuleucelTApproval : HistoricalEvent {
:>> year = "2010";
:>> titleEn = "Approval of the first therapeutic cancer vaccine (Sipuleucel-T)";
:>> titleZh = "首个治疗性癌症疫苗 Sipuleucel-T 获批";
:>> summaryEn = "Regulatory approval of the autologous cellular product Sipuleucel-T for metastatic prostate cancer demonstrated that personalized cancer vaccines could reach the clinic.";
:>> summaryZh = "自体细胞制剂Sipuleucel-T获批用于转移性前列腺癌治疗，说明个体化癌症疫苗策略可以进入日常临床实践。";
:>> mainOrganizations = fda;
}
action checkpointInhibitors : HistoricalEvent {
:>> year = "2011–2014";
:>> titleEn = "Immune checkpoint inhibitor era (CTLA-4, PD-1/PD-L1)";
:>> titleZh = "免疫检查点抑制剂时代（CTLA-4与PD-1/PD-L1）";
:>> summaryEn = "Approval of CTLA-4 and PD-1/PD-L1 antibodies established immune checkpoint blockade as a transformative cancer treatment, with durable responses across multiple tumor types.";
:>> summaryZh = "CTLA-4与PD-1/PD-L1抗体相继获批，使免疫检查点阻断成为改变治疗格局的肿瘤治疗方式，在多种肿瘤类型中带来了可持续的缓解。";
:>> mainPersons = jamesPAllison;
}
action oncolyticVirusApproval : HistoricalEvent {
:>> year = "2015";
:>> titleEn = "Approval of the oncolytic virus T-VEC";
:>> titleZh = "溶瘤病毒T-VEC 获批";
:>> summaryEn = "The approval of the oncolytic herpesvirus Talimogene laherparepvec (T-VEC) for melanoma provided proof of concept for genetically engineered oncolytic viruses as a clinical cancer immunotherapy.";
:>> summaryZh = "基因工程溶瘤单纯疱疹病毒Talimogene laherparepvec（T-VEC）在黑色素瘤中的获批，证明了基因改造溶瘤病毒作为临床肿瘤免疫治疗手段的可行性。";
:>> mainOrganizations = fda;
}
action tumorAgnosticICIApproval : HistoricalEvent {
:>> year = "2017";
:>> titleEn = "First tumor-agnostic approval of an immune checkpoint inhibitor";
:>> titleZh = "首个与肿瘤原发部位无关的免疫检查点抑制剂适应证获批";
:>> summaryEn = "The FDA granted approval to pembrolizumab for solid tumors with MSI-H or dMMR, regardless of the tissue of origin, marking the first tumor-agnostic indication for an immune checkpoint inhibitor.";
:>> summaryZh = "FDA批准帕博利珠单抗用于携带MSI-H或dMMR的实体瘤患者，而不再以肿瘤原发部位划分适应证，成为免疫检查点抑制剂首个真正意义上的“肿瘤类型无关”适应证。";
:>> mainOrganizations = fda;
}
action firstCartApproval : HistoricalEvent {
:>> year = "2017";
:>> titleEn = "First CAR-T therapy approval (Tisagenlecleucel)";
:>> titleZh = "首个 CAR-T 疗法 (Tisagenlecleucel) 获批";
:>> summaryEn = "FDA approved Tisagenlecleucel (Kymriah) for pediatric acute lymphoblastic leukemia, marking the first regulatory approval of a gene therapy in the US.";
:>> summaryZh = "FDA 批准 Tisagenlecleucel (Kymriah) 用于治疗儿童急性淋巴细胞白血病，标志着美国首个基因疗法获得监管批准。";
:>> mainOrganizations = fda;
:>> mainPersons = carlJune;
}
action lag3Approval : HistoricalEvent {
:>> year = "2022";
:>> titleEn = "Regulatory approval of a LAG-3–targeted immune checkpoint inhibitor";
:>> titleZh = "以LAG-3为靶点的免疫检查点抑制剂获批";
:>> summaryEn = "The FDA approved the combination of relatlimab (anti-LAG-3) and nivolumab, validating LAG-3 as the third immune checkpoint pathway for clinical use.";
:>> summaryZh = "FDA批准了Relatlimab（抗LAG-3）与Nivolumab的联合疗法，证实LAG-3是第三个可用于临床的免疫检查点通路。";
:>> mainOrganizations = fda;
}
action tebentafuspApproval : HistoricalEvent {
:>> year = "2022";
:>> titleEn = "First TCR-based bispecific therapeutic approved (Tebentafusp)";
:>> titleZh = "首个基于 TCR 的双特异性抗癌药物（Tebentafusp）获批";
:>> summaryEn = "Tebentafusp, a soluble TCR–CD3 bispecific therapeutic targeting gp100, receives regulatory approval as the first T cell receptor (TCR)-based anticancer drug, but it is not an adoptive TCR-T cell therapy.";
:>> summaryZh = "Tebentafusp作为靶向gp100的可溶性TCR–CD3双特异性药物，成为首个获批的基于T细胞受体（TCR）的抗癌药物，但并非回输型TCR-T细胞疗法。";
:>> mainOrganizations = fda;
}
action tilTherapyRealized : HistoricalEvent {
:>> year = "2024";
:>> titleEn = "First TIL therapy approval (Lifileucel)";
:>> titleZh = "首个TIL疗法 (Lifileucel) 正式获批";
:>> summaryEn = "The FDA granted accelerated approval to Lifileucel for advanced melanoma, making it the first approved tumor-infiltrating lymphocyte therapy, realizing the long-awaited potential of adoptive cell transfer for solid tumors.";
:>> summaryZh = "FDA加速批准Lifileucel用于治疗晚期黑色素瘤，使其成为首个获批的肿瘤浸润淋巴细胞疗法，实现了过继细胞疗法治疗实体瘤的长期愿景。";
:>> mainOrganizations = fda;
}
action tarlatamabApproval : HistoricalEvent {
:>> year = "2024";
:>> titleEn = "First DLL3-targeted bispecific antibody (Tarlatamab)";
:>> titleZh = "首个靶向 DLL3 的双特异性抗体 (Tarlatamab)";
:>> summaryEn = "FDA granted accelerated approval to tarlatamab for extensive-stage small cell lung cancer (SCLC). It is the first BiTE (bispecific T-cell engager) to successfully target a solid tumor antigen (DLL3) in a major cancer type.";
:>> summaryZh = "FDA加速批准 Tarlatamab 用于广泛期小细胞肺癌。这是首个成功靶向实体瘤抗原 (DLL3) 并用于常见主要癌种的双特异性T细胞接合器 (BiTE)。";
:>> mainOrganizations = fda;
}
action afamicelApproval : HistoricalEvent {
:>> year = "2024";
:>> titleEn = "First TCR-T therapy for solid tumors (Afami-cel)";
:>> titleZh = "首个实体瘤TCR-T细胞疗法 (Afami-cel)";
:>> summaryEn = "Approval of afamitresgene autoleucel (Afami-cel) for synovial sarcoma. Unlike CAR-T which targets surface antigens, this engineered TCR-T therapy targets the intracellular antigen MAGE-A4, marking a breakthrough for engineered cell therapy in solid tumors.";
:>> summaryZh = "Afamitresgene autoleucel (Afami-cel) 获批用于滑膜肉瘤。不同于靶向表面抗原的CAR-T，这种基因工程TCR-T疗法能靶向胞内抗原MAGE-A4，标志着工程化细胞疗法在实体瘤领域的重大突破。";
:>> mainOrganizations = fda;
}
first coleysToxinInjection then ehrlichMagicBullet;
first ehrlichMagicBullet then firstViralOncolysis;
first firstViralOncolysis then coleyToxinDiscontinued;
first coleyToxinDiscontinued then melanomaVaccineTrials;
first melanomaVaccineTrials then intratumoralBCG;
first intratumoralBCG then lakCellTherapy;
first lakCellTherapy then cytokineTherapies;
first cytokineTherapies then tILTherapy;
first tILTherapy then cartConcept;
first cartConcept then cartClinical;
first cartClinical then sipuleucelTApproval;
first sipuleucelTApproval then checkpointInhibitors;
first checkpointInhibitors then oncolyticVirusApproval;
first oncolyticVirusApproval then tumorAgnosticICIApproval;
first tumorAgnosticICIApproval then firstCartApproval;
first firstCartApproval then lag3Approval;
first lag3Approval then tebentafuspApproval;
first tebentafuspApproval then tilTherapyRealized;
first tilTherapyRealized then tarlatamabApproval;
first tarlatamabApproval then afamicelApproval;
}
}
代码清单2-1 关于癌症免疫治疗的历史的SysML v2文本
2.2 癌症免疫治疗历史的SysML v2图形表示
上述 SysML v2 文本的图形化渲染效果如图1-1至图1-3所示。
图2-1 通用视图（M-Design v2渲染）
图2-2 通用视图（Eclipse Modeling Tools渲染）
图2-3 动作流视图（Eclipse Modeling Tools渲染）
2.3 参考文献
-
Object Management Group. OMG Systems Modeling Language (SysML) Version 2.0. Object Management Group; 2025. Accessed December 6, 2025. www.omg.org/spec/SysML/…
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Lotze MT, Atkins MB. The history of cancer immunotherapy. In: Butterfield LH, Kaufman HL, Marincola FM, eds. Cancer Immunotherapy Principles and Practice. 2nd ed. Demos Medical Publishing; 2021:1-15.
-
FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA Drugs. Published May 23, 2017. Accessed December 5, 2025. www.fda.gov/drugs/resou…
-
U.S. Food and Drug Administration. FDA approval brings first gene therapy to the United States. PR Newswire. Published August 30, 2017. Accessed December 5, 2025. www.prnewswire.com/news-releas…
-
U.S. Food and Drug Administration. FDA approves Opdualag for unresectable or metastatic melanoma. FDA Drugs. Published March 18, 2022. Accessed December 5, 2025. www.fda.gov/drugs/resou…
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U.S. Food and Drug Administration. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. FDA Drugs. Published January 25, 2022. Accessed December 5, 2025. www.fda.gov/drugs/resou…
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U.S. Food and Drug Administration. FDA Approves First Cellular Therapy to Treat Patients with Unresectable or Metastatic Melanoma. FDA News Release. Published February 16, 2024. Accessed December 5, 2025. www.fda.gov/news-events…
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U.S. Food and Drug Administration. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA Drugs. Published May 16, 2024. Accessed December 5, 2025. www.fda.gov/drugs/resou…
-
U.S. Food and Drug Administration. FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma. FDA Drugs. Published August 2, 2024. Accessed December 5, 2025. www.fda.gov/drugs/resou…
-
U.S. Food and Drug Administration. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA Drugs. Published November 19, 2025. Accessed December 5, 2025. www.fda.gov/drugs/resou…
