Anakinra (Amgen)

– ARCALYST® (rilonacept) Q4 2024 and full year 2024 net product revenue of $122.5 million and $417.0 million, respectively –– ARCALYST 2025 net product revenue expected to be $560 - $580 million –– KPL-387 Phase 2/3 clinical trial in recurrent pericarditis expected to initiate in mid-2025; Phase 2 data expected in 2H 2026 –– Abiprubart development in Sjögren’s Disease to be discontinued –– Current operating plan expected to remain cash flow positive on an annual basis –– Conference call and webcast scheduled for 8:30 am ET today – LONDON, Feb. 25, 2025 (GLOBE NEWSWIRE) -- Kiniksa Pharmaceuticals International, plc (Nasdaq: KNSA) (Kiniksa), a biopharmaceutical company developing and commercializing novel therapies for diseases with unmet need, with a focus on cardiovascular indications, today reported fourth quarter and full year 2024 financial results and recent portfolio execution. “Strong commercial execution in 2024 resulted in 79% year-over-year ARCALYST sales growth to $417.0 million. We believe substantial opportunity remains for ARCALYST, and expect 2025 sales of between $560 and $580 million,” said Sanj K. Patel, Chairman and Chief Executive Officer of Kiniksa. “Today, we are excited to announce the development program for KPL-387, which we believe could expand the treatment options for recurrent pericarditis patients by enabling a single monthly subcutaneous injection in a liquid formulation. We have interacted with the FDA and plan to initiate a Phase 2/3 clinical trial of KPL-387 in recurrent pericarditis in mid-2025. In line with our prioritization of cardiovascular indications, we plan to discontinue the development of abiprubart in Sjögren’s Disease. On behalf of our entire organization, I would like to thank the patients, caregivers, and investigators who contributed to our study.” Corporate Update Kiniksa continues to focus development on diseases with unmet need, prioritizing cardiovascular indications. Kiniksa announced today the development of KPL-387 in recurrent pericarditis, with a target profile of monthly subcutaneous (SC) dosing. KPL-387 is a fully human immunoglobulin G2 (IgG2) monoclonal antibody that binds human interleukin-1 receptor 1 (IL-1R1), inhibiting the signaling of the cytokines interleukin-1α (IL-1α) and interleukin-1β (IL-1β). Kiniksa announced today that it is advancing KPL-1161 towards clinical development with a target profile of quarterly SC dosing. KPL-1161 is an Fc-modified IgG2 monoclonal antibody that binds IL-1R1, inhibiting the signaling of the cytokines IL-1α and IL-1β. Kiniksa announced today that it plans to discontinue abiprubart development in Sjögren’s Disease. The company will explore strategic alternatives for the asset. Kiniksa announced today that it has exercised its right to terminate its exclusive license agreement for mavrilimumab with MedImmune. Kiniksa announced today the development of KPL-387 in recurrent pericarditis, with a target profile of monthly subcutaneous (SC) dosing. KPL-387 is a fully human immunoglobulin G2 (IgG2) monoclonal antibody that binds human interleukin-1 receptor 1 (IL-1R1), inhibiting the signaling of the cytokines interleukin-1α (IL-1α) and interleukin-1β (IL-1β). Kiniksa announced today that it is advancing KPL-1161 towards clinical development with a target profile of quarterly SC dosing. KPL-1161 is an Fc-modified IgG2 monoclonal antibody that binds IL-1R1, inhibiting the signaling of the cytokines IL-1α and IL-1β. Kiniksa announced today that it plans to discontinue abiprubart development in Sjögren’s Disease. The company will explore strategic alternatives for the asset. Kiniksa announced today that it has exercised its right to terminate its exclusive license agreement for mavrilimumab with MedImmune. Portfolio Execution ARCALYST (IL-1α and IL-1β cytokine trap) ARCALYST net product revenue was $122.5 million and $417.0 million for the fourth quarter and full year 2024, respectively. Since launch, more than 2,850 prescribers have written ARCALYST prescriptions for recurrent pericarditis. As of the end of the fourth quarter of 2024, average total duration of ARCALYST therapy in recurrent pericarditis was approximately 27 months. As of the end of the fourth quarter of 2024, approximately 13% of the target 14,000 multiple-recurrence patients were actively on ARCALYST treatment. KPL-387 (monoclonal antibody IL-1 receptor antagonist) Kiniksa is conducting a single ascending dose (SAD) and multiple ascending dose Phase 1 clinical trial of KPL-387 in healthy volunteers. Topline data from the SAD portion of the Phase 1 trial support potential monthly SC dosing in recurrent pericarditis. Kiniksa has interacted with the U.S. Food and Drug Administration (FDA) and expects to initiate a Phase 2/3 clinical trial of KPL-387 in recurrent pericarditis in mid-2025, with Phase 2 data expected in the second half of 2026. Topline data from the SAD portion of the Phase 1 trial support potential monthly SC dosing in recurrent pericarditis. KPL-1161 (Fc-modified monoclonal antibody IL-1 receptor antagonist) Kiniksa is conducting Investigational New Drug (IND)-enabling development activities with a target profile of quarterly SC dosing. Financial Results Total revenue for the fourth quarter of 2024 was $122.5 million, compared to $83.4 million for the fourth quarter of 2023. Total revenue for the full year 2024 was $423.2 million, compared to $270.3 million for the full year 2023. Total revenue for the fourth quarter of 2024 did not include any license and collaboration revenue, compared to $12.2 million for the fourth quarter of 2023. Total revenue for the full year 2024 included $6.2 million in license and collaboration revenue, compared to $37.1 million for the full year 2023. Total operating expenses for the fourth quarter of 2024 were $141.8 million, compared to $83.3 million for the fourth quarter of 2023. Total operating expenses for the full year 2024 were $468.9 million, compared to $295.5 million for the full year 2023. Total operating expenses for the fourth quarter of 2024 included $48.2 million in collaboration expenses, which are driven by ARCALYST collaboration profitability, compared to $16.9 million for the fourth quarter of 2023. Total operating expenses for the full year 2024 included $128.3 million in collaboration expenses, compared to $56.5 million for the full year 2023. Total operating expenses for the fourth quarter of 2024 included $8.3 million in non-cash, share-based compensation expense, compared to $7.8 million for the fourth quarter of 2023. Total operating expenses for the full year 2024 included $30.7 million in non-cash, share-based compensation expense, compared to $27.1 million for the full year 2023. Net loss for the fourth quarter of 2024 was $8.9 million, compared to a net income of $25.2 million for the fourth quarter of 2023. Net loss for the full year 2024 was $43.2 million, compared to net income of $14.1 million for the full year 2023. Net loss for the fourth quarter of 2024 included a tax benefit of $8.1 million, compared to a tax benefit of $22.8 million for the fourth quarter of 2023, both primarily due to the treatment of non-cash deferred tax assets. Net loss for the full year 2024 included a tax expense of $7.0 million, compared to a tax benefit of $30.7 million for the full year 2023, both primarily due to the treatment of non-cash deferred tax assets. As of December 31, 2024, Kiniksa had $243.6 million of cash, cash equivalents, and short-term investments and no debt, compared to $206.4 million as of December 31, 2023. Total revenue for the fourth quarter of 2024 did not include any license and collaboration revenue, compared to $12.2 million for the fourth quarter of 2023. Total revenue for the full year 2024 included $6.2 million in license and collaboration revenue, compared to $37.1 million for the full year 2023. Total operating expenses for the fourth quarter of 2024 included $48.2 million in collaboration expenses, which are driven by ARCALYST collaboration profitability, compared to $16.9 million for the fourth quarter of 2023. Total operating expenses for the full year 2024 included $128.3 million in collaboration expenses, compared to $56.5 million for the full year 2023. Total operating expenses for the fourth quarter of 2024 included $8.3 million in non-cash, share-based compensation expense, compared to $7.8 million for the fourth quarter of 2023. Total operating expenses for the full year 2024 included $30.7 million in non-cash, share-based compensation expense, compared to $27.1 million for the full year 2023. Net loss for the fourth quarter of 2024 included a tax benefit of $8.1 million, compared to a tax benefit of $22.8 million for the fourth quarter of 2023, both primarily due to the treatment of non-cash deferred tax assets. Net loss for the full year 2024 included a tax expense of $7.0 million, compared to a tax benefit of $30.7 million for the full year 2023, both primarily due to the treatment of non-cash deferred tax assets. Financial Guidance Kiniksa expects 2025 ARCALYST net product revenue of between $560 million and $580 million. Kiniksa expects its current operating plan to remain cash flow positive on an annual basis. Conference Call Information Kiniksa will host a conference call and webcast at 8:30 a.m. Eastern Time on Tuesday, February 25, 2025, to discuss fourth quarter and full year 2024 financial results and to provide a corporate update. Individuals interested in participating in the call via telephone may register here. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. To access the webcast, please visit the Investors and Media section of Kiniksa’s website. A replay of the event will also be available on Kiniksa’s website within approximately 48 hours after the event. About KiniksaKiniksa is a biopharmaceutical company dedicated to improving the lives of patients suffering from debilitating diseases by discovering, acquiring, developing, and commercializing novel therapies for diseases with unmet need, with a focus on cardiovascular indications. Kiniksa’s portfolio of assets is based on strong biologic rationale or validated mechanisms and offers the potential for differentiation. For more information, please visit www.kiniksa.com. About ARCALYSTARCALYST is a weekly, subcutaneously injected recombinant dimeric fusion protein that blocks interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) signaling. ARCALYST was discovered by Regeneron Pharmaceuticals, Inc. (Regeneron) and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and children 12 years and older. ARCALYST is also approved by the FDA for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 years and older, and the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing 10 kg or more. The FDA granted Orphan Drug Exclusivity to ARCALYST upon its approval for recurrent pericarditis in 2021. The European Commission granted Orphan Drug Designation to ARCALYST for the treatment of idiopathic pericarditis in 2021. IMPORTANT SAFETY INFORMATION ABOUT ARCALYST ARCALYST may affect your immune system and can lower the ability of your immune system to fight infections. Serious infections, including life-threatening infections and death, have happened in patients taking ARCALYST. If you have any signs of an infection, call your doctor right away. Treatment with ARCALYST should be stopped if you get a serious infection. You should not begin treatment with ARCALYST if you have an infection or have infections that keep coming back (chronic infection). While taking ARCALYST, do not take other medicines that block interleukin-1, such as Kineret® (anakinra), or medicines that block tumor necrosis factor, such as Enbrel® (etanercept), Humira® (adalimumab), or Remicade® (infliximab), as this may increase your risk of getting a serious infection. Talk with your doctor about your vaccine history. Ask your doctor whether you should receive any vaccines before you begin treatment with ARCALYST. Medicines that affect the immune system may increase the risk of getting cancer. Stop taking ARCALYST and call your doctor or get emergency care right away if you have any symptoms of an allergic reaction. Your doctor will do blood tests to check for changes in your blood cholesterol and triglycerides. Common side effects include injection-site reactions (which may include pain, redness, swelling, itching, bruising, lumps, inflammation, skin rash, blisters, warmth, and bleeding at the injection site), upper respiratory tract infections, joint and muscle aches, rash, ear infection, sore throat, and runny nose. For more information about ARCALYST, talk to your doctor and see the Product Information. About KPL-387KPL-387 is an independently developed, investigational, fully human IgG2 monoclonal antibody that binds IL-1R1, inhibiting the signaling of the cytokines IL-1α and IL-1β. Kiniksa believes KPL-387 could expand the treatment options for recurrent pericarditis patients by enabling dosing with a single monthly SC injection in a liquid formulation. About KPL-1161KPL-1161 is an independently developed, investigational, Fc-modified IgG2 monoclonal antibody that binds IL-1R1, inhibiting the signaling of the cytokines IL-1α and IL-1β, with a target profile of quarterly SC dosing. Kiniksa is currently engaging in IND-enabling development activities for KPL-1161. About AbiprubartAbiprubart is an investigational humanized monoclonal antibody that binds to CD40 and is designed to inhibit the CD40-CD154 (CD40 ligand) interaction, a key T-cell co-stimulatory signal critical for B-cell maturation and immunoglobulin class switching and Type 1 immune responses. Kiniksa believes disrupting the CD40-CD154 co-stimulatory interaction is an attractive approach to addressing multiple autoimmune disease pathologies. Forward-Looking Statements This press release contains forward-looking statements. In some cases, you can identify forward looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions, although not all forward-looking statements contain these identifying words. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation, statements regarding: our belief that substantial opportunity remains for ARCALYST and our expectation that ARCALYST 2025 net product revenue will be between $560 million and $580 million; our plan to initiate a Phase 2/3 clinical trial of KPL-387 in recurrent pericarditis in mid-2025, with Phase 2 data expected in the second half of 2026; our plan to discontinue abiprubart development in Sjögren’s Disease and explore strategic alternatives for the asset; our expectation that our current operating plan will remain cash flow positive on an annual basis; our plan to focus development on diseases with unmet need, prioritizing cardiovascular indications; our belief that KPL-387 could expand the treatment options for recurrent pericarditis patients by enabling a single monthly SC injection in a liquid formulation; our target profile of monthly and quarterly dosing for KPL-387 and KPL-1161, respectively; our beliefs about the mechanisms of our assets and potential impact of their approach; and our belief that our portfolio of assets offers the potential for differentiation. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including without limitation, the following: delays or difficulty in enrollment of patients in, and activation or continuation of sites for, our clinical trials; delays or difficulty in completing our clinical trials as originally designed; potential for changes between final data and any preliminary, interim, top-line or other data from clinical trials; our inability to replicate results from our earlier clinical trials or studies; impact of additional data from us or other companies, including the potential for our data to produce negative, inconclusive or commercially uncompetitive results; potential undesirable side effects caused by our products and product candidates; our inability to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities; potential for applicable regulatory authorities to not accept our filings, delay or deny approval of any of our product candidates or require additional data or trials to support approval; our reliance on third parties as the sole source of supply of the drug substance and drug product used in our products and product candidates; raw material, important ancillary product and drug substance and/or drug product shortages; our reliance on third parties to conduct research, clinical trials, and/or certain regulatory activities for our product candidates; complications in coordinating requirements, regulations and guidelines of regulatory authorities across jurisdictions for our clinical trials; business development activities and their impact on our financial performance and strategy; changes in our operating plan, business development strategy or funding requirements; and existing or new competition. These and other important factors discussed in our filings with the U.S. Securities and Exchange Commission, including under the caption “Risk Factors” contained therein, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. Except as required by law, we disclaim any intention or obligation to update or revise any forward-looking statements. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. ARCALYST® is a registered trademark of Regeneron Pharmaceuticals, Inc. Every Second Counts! ® Kiniksa Investor ContactJonathan Kirshenbaum(781) 829-3949jkirshenbaum@kiniksa.com Kiniksa Media ContactTyler Gagnon (781) 431-9100tgagnon@kiniksa.com

2024 编 者 按 近年来，血液肿瘤领域迎来了诸多鼓舞人心的突破，其中中国学者在细胞治疗领域的研究贡献日益显著，极大地助力推动该领域的学科建设与临床实践的发展。值此新年伊始之际，《肿瘤瞭望-血液时讯》特别邀请浙江大学医学院附属第二医院钱文斌教授，对CAR-T细胞治疗B细胞淋巴瘤现状与进展进行深入的回顾与总结，包括目前获批的CAR-T产品、临床试验结果、真实世界数据以及面临的挑战，同时，探讨了CAR-T治疗的多种升级策略，如新靶点、双靶CAR-T、基因编辑技术改进等，旨在为临床诊疗实践与未来研究方向提供宝贵的参考与启示。 2024 B细胞淋巴瘤作为一类常见的恶性肿瘤，其治疗领域一直备受关注。CAR-T细胞治疗通过基因工程技术将嵌合抗原受体导入T细胞，使其能够特异性地识别并杀伤肿瘤细胞，逐渐成为了B细胞淋巴瘤治疗领域的热点。本文将对CAR-T细胞治疗B细胞淋巴瘤的现状进行综述，以期为临床实践提供参考。 2024 01 已获批产品概况 迄今为止，全球范围内已有多款靶向CD19的CAR-T产品获批用于治疗B细胞淋巴瘤。不仅体现了全球范围内在CAR-T疗法领域的快速进展，也彰显了医学界对于B细胞淋巴瘤治疗策略的不断优化与创新。 2017年10月，美国批准了Yescarta（Axi-cel）用于复发/难治性大B细胞淋巴瘤（R/R LBCL）和复发/难治性滤泡性淋巴瘤（R/R FL）。随后，2020年7月批准Tecartus（Brexu-cel），用于R/R 套细胞淋巴瘤（R/R MCL）；2021年2月批准Breyanzi（Liso-cel），治疗R/R LBCL。 在中国，该领域的进步同样引人注目。2021年6月，阿基仑赛注射液获批上市，同年9月瑞基奥仑赛注射液也获得批准，二者均针对R/R LBCL，为中国患者提供了更多元化的治疗选项。 02 临床试验与真实世界结果 截至目前，已有多项临床试验数据揭示了CD19 CAR-T产品的疗效。具体而言，Axi-cel在R/R LBCL和R/R FL的治疗中，展现出了令人瞩目的客观缓解率（ORR），分别高达82%与94%，同时，其完全缓解（CR）率也分别达到了54%和79%。针对R/R MCL，Brexu-cel的ORR为91%，CR率高达73%。此外，Liso-cel在治疗R/R LBCL时，亦取得了73%的ORR和53%的CR率。国产瑞基奥仑赛注射液在R/R LBCL的治疗中，同样表现出色，其ORR为77.6%，CR率为53.5%。 在真实世界研究的范畴内，以Axi-cel为例，针对1297例R/R LBCL患者的治疗数据进一步验证了其在临床实践中的疗效，其ORR为70.9%，CR率为52.4%，与临床试验结果相媲美。此外，即便对于部分未能满足ZUMA-1研究纳入标准的患者，Axi-cel治疗同样显示出了临床获益。采用倾向评分匹配（PSM）消除偏差后显示，相较于Tisa-cel，Axi-cel虽展现出更优的疗效，但其毒性反应也相对更高。 这些数据不仅强化了CD19 CAR-T产品在临床应用中的价值，也为新时代背景下治疗策略的制定提供了有力的依据。 03 领域挑战：耐药与复发 尽管CAR-T细胞疗法在B细胞淋巴瘤的治疗中已展现出显著的疗效，然而，该领域仍面临诸多亟待解决的挑战，其中最为突出的是CAR-T耐药性和肿瘤复发问题。CAR-T细胞治疗耐药性的机制复杂，主要涵盖CAR-T细胞功能障碍、肿瘤固有耐药性，以及免疫抑制性肿瘤微环境三大方面。 具体而言，CAR-T细胞耗竭与多种因素密切相关，包括持续的抗原刺激、免疫抑制性细胞及因子的作用、抑制性受体（IRs）的上调表达，以及代谢因素的干扰。而肿瘤固有耐药性则涵盖了抗原逃逸（丢失、突变或转换）、抑制性配体的表达上调、凋亡机制受损、系别转化（lineage switch）以及共辅助分子（co-accessory molecules）的缺乏等。在免疫抑制性肿瘤微环境层面，血管通透性缺陷、纤维细胞外基质（ECM）沉积等因素，均会阻碍CAR-T细胞的浸润。此外，免疫抑制性细胞/因子以及代谢因素的作用，也可能发挥一定作用。深入理解并解决这些挑战，对于提升CAR-T细胞疗法的疗效及患者预后具有重要意义。 （上下滑动查看更多） CAR-T的升级策略 2024 01 新靶点探索 为了应对CD19 CAR-T细胞疗法中出现的抗原逃逸现象，已开发出多种新型的单靶点及双靶点。在单靶点方面，针对CD20、CD22、CD70、ROR1、CD79、BAFF及κLC等靶点的CAR-T细胞疗法正处于积极的临床试验阶段。 部分临床试验已初步显现出积极成果。例如，在针对CD19 CAR-T治疗后复发的LBCL患者的1期临床试验中，CD20 CAR-T（C-CAR066）使得8/14例患者达到了CR。CD22 CAR-T在治疗CD19 CAR-T难治性LBCL方面也表现出显著疗效，ORR达68%，其中CR率为53%，中位生存期为14.1个月。此外，CD70 CAR-T在CD19缺失的淋巴瘤患者中也展现出了抗淋巴瘤活性。 02 双靶点设计 双靶CAR-T细胞疗法通过同时针对两个不同靶点，进一步增强了治疗效能，并有效降低了单靶耐药风险。目前，常见的双靶点组合涵盖CD19/20、CD19/22、CD19/70以及CD20/22等，不同双靶结构的设计各有优劣。 临床研究数据表明，Tandem CD19/CD20 CAR-T细胞疗法在R/R B细胞淋巴瘤中，≥3级的细胞因子释放综合征（CRS）发生率为14%，未见≥3级的免疫效应细胞相关神经毒性综合征（ICANS）。此外，Loop CD19/CD22 CAR-T细胞疗法，在LBCL患者中，ORR达到62%，CR率为29%；而在B细胞急性淋巴细胞白血病（B-ALL）患者中，ORR高达100%，CR率为88%，≥3级的CRS及ICANS发生率均在较低水平。 03 基因编辑改进 利用基因编辑技术对CD19 CAR-T进行改进，旨在提高功效和降低毒性。如第四代装甲型CAR-T（Truck CAR-T）和阻断PD-1信号的CAR-T可增强疗效；敲除IL-6可减少CRS，插入Toll样受体（TLR）可减轻ICANS等。 钱文斌教授团队的7×19 装甲型CAR-T在R/R LBCL的I/II期临床试验中，ORR、CR、PR分别为79.5%、56.4%、23.1%，mPFS达13个月，≥3级CRS12.8%，≥3级ICANS为10.3%。预期5年OS和PFS为43.6%、30.8%。 04 新一代CAR-T技术 新一代CAR-T技术正蓬勃发展，其中Allo CAR-T、FAST CAR-T及in vivo CAR-T等逐渐崭露头角。 Allo CAR-T技术以其多重优势而备受瞩目：它显著提升了产品的可及性，有效降低了生产失败的风险，拓宽了适用范围，实现了即需即用的便捷性，同时便于细胞类型的优化选择及规模化生产。然而，Allo CAR-T技术亦伴随着一系列挑战，包括移植物抗宿主病（GVHD）的风险上升、自身免疫反应的可能性增加、基因编辑过程中潜在的突变或脱靶毒性问题、体内持久性可能下降，以及在特定情境下可能需要辅以造血干细胞移植等局限。 FAST CAR-T技术在临床试验中已显现出卓越的疗效与良好的耐受性，ORR高达80%，CR率亦达80%，CRS主要以1-2级为主（30%），3级ICANS的发生率为10%。 此外，众多in vivo CAR-T技术正处于临床试验的筹备阶段，预示着该领域研究的深入与拓展。同时，研究界正积极探索多种替代细胞类型的应用潜力，包括但不限于双阴性T细胞（DNT）、γδ T细胞、脐带血来源T细胞、NK细胞、巨噬细胞、恒定自然杀伤T细胞（iNKT细胞）/细胞因子诱导的杀伤细胞（CIK细胞），以及诱导多能干细胞（iPS细胞）来源的细胞等。每种细胞类型均展现出独特的优势，但同时也伴随着各自的潜在局限与不足。 桥接治疗 2024 目前，CAR-T细胞的制备流程颇为繁复，导致约有7%的患者无法耐受至治疗产品制备完成的阶段。同时，高肿瘤负荷亦是制约CAR-T细胞治疗效果的关键因素之一。与任一病灶最大径＜5厘米的患者相比，≥5厘米的患者在接受CAR-T细胞治疗后，缓解率、PFS以及OS均较差。因此，采取桥接治疗策略以降低肿瘤负荷显得尤为重要。 现有桥接治疗方案主要包括桥接化疗、桥接免疫以及桥接放疗，旨在为患者争取到更适合进行CAR-T细胞治疗的时机与条件，从而可能改善其治疗反应及长期生存状况。 01 桥接化疗 桥接化疗作为一种广泛应用的治疗手段，尽管在临床实践中占据一席之地，但其缺陷亦不容忽视。化疗作为桥接手段的效果并不理想，多数患者的肿瘤病灶并未见显著缩小。对比接受与未接受桥接化疗的患者群体发现，前者在PFS和OS方面往往更为不利。此外，尽管降低化疗剂量在一定程度上能够提升治疗的安全性，减少不良反应的发生，然而，截至目前，尚无确凿的临床证据能够表明低剂量的桥接化疗能够有效延长患者的OS。 02 桥接免疫 桥接免疫治疗药物涵盖了多种类型，其中包括单克隆抗体（如CD20、PD-1）、抗体偶联药物（ADC，如CD30、CD79、CD19、CD22）以及双特异性抗体（如CD20/CD3、CD19/CD3）。 然而，在实施桥接免疫治疗时，一个不容忽视的问题是所选药物靶点与后续CAR-T细胞治疗之间是否存在潜在的冲突。有研究表明，在B-ALL患者中，于CAR-T治疗之前使用CD19/CD3双抗贝林妥欧单抗，可能会导致缓解率降低，这一现象可能与抗原逃逸机制有关。但同样有研究显示，在R/R DLBCL中，患者即便先前接受过CD19 ADC治疗，后续接受CD19 CAR-T细胞治疗时仍能获得50%的ORR。Brinkmann团队的研究则进一步揭示了CD20/CD3双特异性抗体在改善体外淋巴瘤模型和体内慢性淋巴细胞白血病（CLL）模型对CD19 CAR-T细胞反应方面的积极作用。此外，在R/R LBCL患者的治疗中，若患者先前接受过双特异性抗体（CD20/CD3、CD22/CD3）治疗，后续的CAR-T细胞治疗依然有效（剔除曾使用过CD19/CD3双抗的患者）。在不靶向相同抗原的情况下，目前尚无确凿证据支持CAR-T细胞与双特异性抗体之间存在交叉耐药的现象。 03 桥接放疗 放射治疗作为一种经典治疗手段，在桥接过程中展现出其多重的治疗效益，不仅能够激活免疫系统功能，有效减轻肿瘤负荷，还对改善肿瘤免疫微环境具有积极作用，并且能够缓解CAR-T疗法相关毒副作用。这些积极作用共同确保了患者维持接受CAR-T细胞输注的资格，且有利于解决CAR-T治疗中的耐药性问题。 在169例接受了桥接放疗的LBCL患者中，其1年PFS相较于未接受桥接治疗的患者表现出明显优势，同时也超越了接受化疗、系统性治疗或激素治疗的患者群体。尽管在1年OS方面，桥接放疗组与未接受桥接治疗的患者之间未观察到统计学上的显著差异，但相较于化疗、系统性治疗或单独激素治疗，桥接放疗组仍然展现出了更优的获益。 CAR-T治疗的联合策略 2024 CAR-T耐药机制主要涉及CAR-T细胞功能障碍、肿瘤固有耐药和免疫抑制性肿瘤微环境，为了显著提升CAR-T细胞疗法的治疗效果并减少毒副作用，研究者们探索了多种联合治疗策略。 01 联合策略及机制 小分子药物如布鲁顿酪氨酸激酶抑制剂（BTKi）通过靶向抑制性受体，有效促进了细胞因子的生成、Th1极化和免疫突触的形成，而来那度胺则能进一步促进细胞因子的产生、Th1极化、免疫突触的增强以及CAR-T细胞的激活。 免疫检查点阻断剂在增强CAR-T细胞活化方面发挥着重要作用。抗程序性死亡受体-1（Anti-PD-1）通过阻断PD-1与PD-L1的结合，显著增强了CAR-T细胞的活化水平，从而加速癌细胞的死亡。同样，抗细胞毒性T淋巴细胞相关抗原4（Anti-CTLA-4）也能有效提升CAR-T细胞的活化状态，助力癌细胞被更有效地清除。 放疗作为一种物理治疗手段，通过促使损伤相关分子模式（DAMPs）的释放，加速了树突状细胞（DC）的成熟与激活，进而增加了促炎细胞因子的产生，增强了CAR-T细胞的浸润和激活能力，最终导致了癌细胞的死亡。 溶瘤病毒则利用其独特的溶瘤特性，在癌细胞内复制并引发细胞裂解，释放DAMPs和肿瘤抗原，这些物质进一步促进了DC的成熟与激活，诱导了M1极化，增加了促炎细胞因子的释放，从而显著增强了CAR-T细胞的浸润和激活，有效致使癌细胞死亡。 此外，抗肿瘤抗体、双特异性T细胞衔接器（BiTEs）及疫苗也为CAR-T细胞疗法提供了新的治疗思路。抗CD20抗体通过其靶向作用，有效杀灭癌细胞，而CD19 CAR-T联合CD3×CD20 BiTE则实现了更为精准的靶向。疫苗策略通过将肿瘤抗原传递给抗原呈递细胞（APC），显著增强了CAR-T细胞的扩增能力， 综上所述，这些联合治疗策略有望从不同层面和角度发挥协同作用，为增强CAR-T细胞疗效提供多维度的途径，展现了血液肿瘤治疗领域的广阔前景和无限可能。 02 临床研究进展 当前，医学界已在多个领域开展了广泛的CAR-T细胞联合临床研究，旨在进一步探索和优化其治疗效果。例如，在DLBCL中，采用来那度胺联合CD19 CAR-T细胞的治疗方案相较于单独的CAR-T治疗，展现出了更为显著的临床效益：1年OS从33.3%大幅提升至100%，ORR从77.8%提高到85.7%，CR率也从33.3%增加至42.9%，有力地证明了联合治疗方案的潜在价值。 在非霍奇金淋巴瘤（NHL）的治疗领域，纳武利尤单抗与CD19 CAR-T细胞的联合应用同样取得了成果。研究显示，该联合治疗方案的ORR达到了81.81%，CR率为45.45%，PFS达到6个月，ICANS的发生率为9%。 在R/R NHL中，CD19/CD22 CAR-T细胞联合PD-1抑制剂的治疗方案也展现出了一定优势。与单独的CAR-T治疗相比，该联合治疗方案的ORR从60%提高到了82.9%，2年PFS也从21.3%大幅提升至59.8%，为R/R NHL患者提供了新的治疗希望。 此外，众多类型的联合治疗方案正在不断探索之中，相关的临床试验也在积极推进，包括去甲基化药物、组蛋白去乙酰化酶（HDAC）抑制剂、酪氨酸激酶抑制剂（TKI）、BTKi、磷脂酰肌醇-3-激酶（PI3K）抑制剂、Janus激酶（JAK）抑制剂、单克隆抗体以及免疫检查点抑制剂等与CAR-T细胞的联合应用。这些研究有望为未来的治疗领域开辟更为广阔的道路，为患者带来更多的治疗选择。 CAR-T治疗的毒副作用及管理 2024 CAR-T治疗的毒副作用可分为急性和慢性两类：急性毒副作用包括CRS、ICANS、肿瘤细胞溶解症（TLS）、噬血综合征（HLH/MAS）。慢性毒副作用包括免疫效应细胞相关血液毒性（ICAHT）血液学毒性、低免疫球蛋白血症、感染和第二肿瘤。全面认识并妥善处理CAR-T治疗相关的毒副作用，对于确保患者治疗安全及提升整体疗效具有不可忽视的意义。 CRS管理：根据症状严重程度分为I - IV级及难治性CRS。对于I - II级，主要采取对症支持治疗，如退热、补液等；III - IV级需使用糖皮质激素、托珠单抗等，必要时转入ICU进行密切监测和生命体征支持，对于难治性CRS可考虑使用环磷酰胺治疗。 ICANS管理：同样根据严重程度分级，诊断方法包括神经系统检查、脑电图（EEG）、影像学检查（MRI 或 CT）等。治疗上，轻度给予支持治疗，中重度需使用糖皮质激素，必要时预防癫痫发作或转入ICU，对于类固醇难治性ICANS可考虑使用阿那白滞素（anakinra）、环磷酰胺等。 TLS管理：治疗前应评估G6PD缺乏情况，高风险患者可预防性使用别嘌醇、拉布立酶或非布司他等药物，治疗期间密切监测TLS相关实验室指标，并根据情况给予水化和电解质管理等支持治疗。 HLH/MAS管理：国外一线治疗推荐阿那白滞素±糖皮质激素，但中国患者的一线治疗方案仍需进一步探索。 血液学毒性管理：建议根据CAR-HEMATOTOX评分进行风险分层，治疗期间监测血常规。对于严重血细胞减少患者可考虑输血支持、生长因子治疗或自体干细胞回输等，同时预防性使用抗菌药物，必要时进行异基因造血干细胞移植。 低免疫球蛋白血症及感染管理：治疗前建议排查感染病原体，治疗期间监测免疫球蛋白水平和感染症状，并根据情况给予抗感染治疗和免疫球蛋白替代治疗。对于特定病毒感染（如HBV、HCV）需进行相应监测和抗病毒治疗，延迟治疗或调整治疗方案应根据患者具体情况决定。 继发性肿瘤管理：减少继发性肿瘤的策略包括早期治疗、监测克隆造血、减少危险因素和密切疾病监测。对于继发性髓系肿瘤，可采用异基因造血干细胞移植、去甲基化药物、非格司亭、输血和支持治疗等方法。克隆造血风险评分（CHRS）可预测相关风险，中高CHRS的患者在CAR-T治疗后的前9个月内发生治疗相关的髓系肿瘤的风险增加。 CAR-T治疗预后相关的生物标记物 2024 CAR-T治疗相关的生物标记物在评估治疗预后、毒性及感染风险方面扮演着至关重要的角色。其中，CAR-HEMATOTOX评分是一个关键指标，它基于血小板计数、血红蛋白水平、绝对中性粒细胞计数、CRP以及铁蛋白含量等参数综合得出，与CAR-T治疗的预后、可能产生的毒性以及感染风险密切相关。 除了CAR-HEMATOTOX评分外，18F-FDG PET/CT相关指标也是一个重要工具。在大B细胞淋巴瘤患者中，CAR-T治疗前降低肿瘤代谢体积（MTV）有助于改善患者的生存结果。此外，外周血嗜酸性粒细胞计数、循环肿瘤DNA（ctDNA）、预后营养指数（PNI）等指标同样值得关注。这些多样化的生物标志物共同构成了CAR-T治疗个体化策略与预后评估的坚实基础，为临床决策提供了更加全面、精准的参考依据。 - END - （来源：《肿瘤瞭望–血液时讯》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。