Pub Date : 2024-09-18eCollection Date: 2024-01-01DOI: 10.1093/immadv/ltae007
Anthony T Tan, Shou Kit Hang, Nicole Tan, Thinesh L Krishnamoorthy, Wan Cheng Chow, Regina Wanju Wong, Lu-En Wai, Antonio Bertoletti
Introduction: The clinical efficacy of chimeric antigen and T cell receptor (TCR) T cell immunotherapies is attributed to their ability to proliferate and persist in vivo. Since the interaction of the engineered T cells with the targeted tumour or its environment might suppress their function, their functionality should be characterized not only before but also after adoptive transfer.
Materials and methods: We sought to achieve this by adapting a recently developed Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid whole blood T cell assay to stimulate engineered TCR T cells in small volumes of whole blood (<1 ml) without in vitro cellular purification. As a proof-of-concept, we used this method to longitudinally study two patients with primary Hepatitis B Virus (HBV)-related hepatocellular carcinoma who received multiple dose-escalating infusions of transiently functional mRNA-engineered HBV-TCR T cells.
Results: We demonstrated that a simple pulsing of whole blood with a peptide corresponding to the epitope recognized by the specific HBV-TCR elicited Th1 cytokine secretion in both patients only after HBV-TCR T cell treatment and not before. The amount of cytokines secreted also showed an infusion-dose-dependent association.
Discussions: These findings support the utility of the whole blood cytokine release assay in monitoring the in vivo function and quantity of engineered T cell products following adoptive transfer.
导言:嵌合抗原和T细胞受体(TCR)T细胞免疫疗法的临床疗效归功于它们在体内增殖和存活的能力。由于工程 T 细胞与目标肿瘤或其环境的相互作用可能会抑制它们的功能,因此不仅在采用性转移之前,而且在采用性转移之后都应该对它们的功能进行鉴定:为了实现这一目标,我们对最近开发的严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)快速全血 T 细胞检测方法进行了改良,以刺激小量全血(体外细胞纯化)中的工程 TCR T 细胞。作为概念验证,我们用这种方法对两名原发性乙型肝炎病毒(HBV)相关肝细胞癌患者进行了纵向研究,这两名患者接受了多剂量递增的瞬时功能性 mRNA 工程 HBV-TCR T 细胞输注:结果:我们发现,用与特异性 HBV-TCR 识别的表位相对应的多肽对全血进行简单脉冲,仅在 HBV-TCR T 细胞治疗后才会引起这两名患者分泌 Th1 细胞因子,而在治疗前则不会。细胞因子的分泌量也与输注剂量有关:讨论:这些研究结果支持全血细胞因子释放检测法在监测收养性转移后工程 T 细胞产品的体内功能和数量方面的实用性。
{"title":"A rapid method to assess the <i>in vivo</i> multi-functionality of adoptively transferred engineered TCR T cells.","authors":"Anthony T Tan, Shou Kit Hang, Nicole Tan, Thinesh L Krishnamoorthy, Wan Cheng Chow, Regina Wanju Wong, Lu-En Wai, Antonio Bertoletti","doi":"10.1093/immadv/ltae007","DOIUrl":"10.1093/immadv/ltae007","url":null,"abstract":"<p><strong>Introduction: </strong>The clinical efficacy of chimeric antigen and T cell receptor (TCR) T cell immunotherapies is attributed to their ability to proliferate and persist <i>in vivo</i>. Since the interaction of the engineered T cells with the targeted tumour or its environment might suppress their function, their functionality should be characterized not only before but also after adoptive transfer.</p><p><strong>Materials and methods: </strong>We sought to achieve this by adapting a recently developed Severe acute respiratory syndrome <i>coronavirus 2</i> (SARS-CoV-2) rapid whole blood T cell assay to stimulate engineered TCR T cells in small volumes of whole blood (<1 ml) without <i>in vitro</i> cellular purification. As a proof-of-concept, we used this method to longitudinally study two patients with primary Hepatitis B Virus (HBV)-related hepatocellular carcinoma who received multiple dose-escalating infusions of transiently functional mRNA-engineered HBV-TCR T cells.</p><p><strong>Results: </strong>We demonstrated that a simple pulsing of whole blood with a peptide corresponding to the epitope recognized by the specific HBV-TCR elicited Th1 cytokine secretion in both patients only after HBV-TCR T cell treatment and not before. The amount of cytokines secreted also showed an infusion-dose-dependent association.</p><p><strong>Discussions: </strong>These findings support the utility of the whole blood cytokine release assay in monitoring the <i>in vivo</i> function and quantity of engineered T cell products following adoptive transfer.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26eCollection Date: 2024-01-01DOI: 10.1093/immadv/ltae006
Katty Zeven, Yoline Lauwers, Lynn De Mey, Jens M Debacker, Tessa De Pauw, Timo W M De Groof, Nick Devoogdt
The evolving landscape of cancer immunotherapy has revolutionized cancer treatment. However, the dynamic tumor microenvironment has led to variable clinical outcomes, indicating a need for predictive biomarkers. Noninvasive nuclear imaging, using radiolabeled modalities, has aided in patient selection and monitoring of their treatment response. This approach holds promise for improving diagnostic accuracy, providing a more personalized treatment regimen, and enhancing the clinical response. Nanobodies or single-domain antibodies, derived from camelid heavy-chain antibodies, allow early timepoint detection of targets with high target-to-background ratios. To date, a plethora of nanobodies have been developed for nuclear imaging of tumor-specific antigens, immune checkpoints, and immune cells, both at a preclinical and clinical level. This review comprehensively outlines the recent advancements in nanobody-based nuclear imaging, both on preclinical and clinical levels. Additionally, the impact and expected future advancements on the use of nanobody-based radiopharmaceuticals in supporting cancer diagnosis and treatment follow-up are discussed.
{"title":"Advancements in nuclear imaging using radiolabeled nanobody tracers to support cancer immunotherapy.","authors":"Katty Zeven, Yoline Lauwers, Lynn De Mey, Jens M Debacker, Tessa De Pauw, Timo W M De Groof, Nick Devoogdt","doi":"10.1093/immadv/ltae006","DOIUrl":"https://doi.org/10.1093/immadv/ltae006","url":null,"abstract":"<p><p>The evolving landscape of cancer immunotherapy has revolutionized cancer treatment. However, the dynamic tumor microenvironment has led to variable clinical outcomes, indicating a need for predictive biomarkers. Noninvasive nuclear imaging, using radiolabeled modalities, has aided in patient selection and monitoring of their treatment response. This approach holds promise for improving diagnostic accuracy, providing a more personalized treatment regimen, and enhancing the clinical response. Nanobodies or single-domain antibodies, derived from camelid heavy-chain antibodies, allow early timepoint detection of targets with high target-to-background ratios. To date, a plethora of nanobodies have been developed for nuclear imaging of tumor-specific antigens, immune checkpoints, and immune cells, both at a preclinical and clinical level. This review comprehensively outlines the recent advancements in nanobody-based nuclear imaging, both on preclinical and clinical levels. Additionally, the impact and expected future advancements on the use of nanobody-based radiopharmaceuticals in supporting cancer diagnosis and treatment follow-up are discussed.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-19eCollection Date: 2024-01-01DOI: 10.1093/immadv/ltae004
Ashna Patel, Mikhail A Kutuzov, Michael L Dustin, P Anton van der Merwe, Omer Dushek
CD8+ T cells contribute to immune responses by producing cytokines when their T-cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome is a common toxicity observed in treatments that activate T cells, including chimeric antigen receptor (CAR)-T-cell therapy. While the engagement of costimulatory receptors is well known to enhance cytokine production, we have limited knowledge of their ability to regulate the kinetics of cytokine production by CAR-T cells. Here we compare early (0-12 h) and late (12-20 h) production of IFN-gg, IL-2, and TNF-a production by T cells stimulated via TCR or CARs in the presence or absence ligands for CD2, LFA-1, CD28, CD27, and 4-1BB. For T cells expressing TCRs and 1st-generation CARs, activation by antigen alone was sufficient to stimulate early cytokine production, while co-stimulation by CD2 and 4-1BB was required to maintain late cytokine production. In contrast, T cells expressing 2nd-generation CARs, which have intrinsic costimulatory signalling motifs, produce high levels of cytokines in both early and late periods in the absence of costimulatory receptor ligands. Losing the requirement for costimulation for sustained cytokine production may contribute to the effectiveness and/or toxicity of 2nd-generation CAR-T-cell therapy.
当 CD8+ T 细胞的 T 细胞受体(TCR)识别 I 类主要组织相容性复合物上的肽抗原时,会产生细胞因子,从而促进免疫反应。例如,细胞因子释放综合征是激活T细胞(包括嵌合抗原受体(CAR)-T细胞疗法)的一种常见毒性。众所周知,共价受体的参与会促进细胞因子的产生,但我们对它们调节 CAR-T 细胞产生细胞因子的动力学的能力了解有限。在这里,我们比较了在CD2、LFA-1、CD28、CD27和4-1BB配体存在或不存在的情况下,通过TCR或CAR刺激的T细胞早期(0-12小时)和晚期(12-20小时)产生的IFN-gg、IL-2和TNF-a。对于表达 TCR 和第一代 CAR 的 T 细胞,仅抗原激活就足以刺激早期细胞因子的产生,而 CD2 和 4-1BB 共同刺激才能维持晚期细胞因子的产生。相反,表达第二代 CAR 的 T 细胞具有固有的成本刺激信号基团,在没有成本刺激受体配体的情况下,在早期和晚期都能产生高水平的细胞因子。失去了持续产生细胞因子的成本刺激要求,可能会影响第二代 CAR-T 细胞疗法的有效性和/或毒性。
{"title":"Regulation of temporal cytokine production by co-stimulation receptors in TCR-T cells is lost in CAR-T cells.","authors":"Ashna Patel, Mikhail A Kutuzov, Michael L Dustin, P Anton van der Merwe, Omer Dushek","doi":"10.1093/immadv/ltae004","DOIUrl":"10.1093/immadv/ltae004","url":null,"abstract":"<p><p>CD8+ T cells contribute to immune responses by producing cytokines when their T-cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome is a common toxicity observed in treatments that activate T cells, including chimeric antigen receptor (CAR)-T-cell therapy. While the engagement of costimulatory receptors is well known to enhance cytokine production, we have limited knowledge of their ability to regulate the kinetics of cytokine production by CAR-T cells. Here we compare early (0-12 h) and late (12-20 h) production of IFN-gg, IL-2, and TNF-a production by T cells stimulated via TCR or CARs in the presence or absence ligands for CD2, LFA-1, CD28, CD27, and 4-1BB. For T cells expressing TCRs and 1st-generation CARs, activation by antigen alone was sufficient to stimulate early cytokine production, while co-stimulation by CD2 and 4-1BB was required to maintain late cytokine production. In contrast, T cells expressing 2nd-generation CARs, which have intrinsic costimulatory signalling motifs, produce high levels of cytokines in both early and late periods in the absence of costimulatory receptor ligands. Losing the requirement for costimulation for sustained cytokine production may contribute to the effectiveness and/or toxicity of 2nd-generation CAR-T-cell therapy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumour-reactive plasma cells (TRPCs) have been reported to be positively associated with the long-term survival of patients with various cancers. However, unlike tumour-specific antigen (TSA)-induced T cells which have precise effects against tumours, plasma cells require TSA to obtain specific responses. Therefore, the search for a TSA suitable for B cell recognition is urgent. In this review, we discuss the functions of tumour-reactive plasma cells. Further, this review also explores the concept of screening for neoantigen-reactive plasma cells, drawing inspiration from T-cell screening methods. While challenges exist, such as epitope prediction and efficient screening, the development of novel techniques may lead to the discovery of highly specific plasma cells for adoptive cell therapy. In conclusion, tumour-reactive plasma cells are emerging as powerful players in cancer immunotherapy. Their ability to produce antibodies against a variety of antigens, especially neoantigens, opens new avenues for personalized treatments. Overcoming challenges in epitope prediction and screening will be crucial in harnessing the full potential of these plasma cells for the benefit of cancer patients.
据报道,肿瘤反应性浆细胞(TRPCs)与各种癌症患者的长期存活率呈正相关。然而,与肿瘤特异性抗原(TSA)诱导的 T 细胞对肿瘤有精确作用不同,浆细胞需要 TSA 才能获得特异性反应。因此,寻找适合 B 细胞识别的 TSA 已迫在眉睫。在这篇综述中,我们讨论了肿瘤反应性浆细胞的功能。此外,本综述还从 T 细胞筛选方法中汲取灵感,探讨了筛选新抗原反应性浆细胞的概念。虽然存在表位预测和高效筛选等挑战,但新技术的开发可能会导致发现高度特异性的浆细胞,用于采用细胞疗法。总之,肿瘤反应性浆细胞正在成为癌症免疫疗法中的强大角色。它们能够产生针对各种抗原(尤其是新抗原)的抗体,为个性化治疗开辟了新途径。要充分利用这些浆细胞的潜力造福癌症患者,克服表位预测和筛选方面的挑战至关重要。
{"title":"Tumour-Reactive Plasma Cells in Antitumour Immunity: Current Insights and Future Prospects","authors":"Peng Chen, Yiwei Chu, Ronghua Liu","doi":"10.1093/immadv/ltae003","DOIUrl":"https://doi.org/10.1093/immadv/ltae003","url":null,"abstract":"\u0000 Tumour-reactive plasma cells (TRPCs) have been reported to be positively associated with the long-term survival of patients with various cancers. However, unlike tumour-specific antigen (TSA)-induced T cells which have precise effects against tumours, plasma cells require TSA to obtain specific responses. Therefore, the search for a TSA suitable for B cell recognition is urgent. In this review, we discuss the functions of tumour-reactive plasma cells. Further, this review also explores the concept of screening for neoantigen-reactive plasma cells, drawing inspiration from T-cell screening methods. While challenges exist, such as epitope prediction and efficient screening, the development of novel techniques may lead to the discovery of highly specific plasma cells for adoptive cell therapy. In conclusion, tumour-reactive plasma cells are emerging as powerful players in cancer immunotherapy. Their ability to produce antibodies against a variety of antigens, especially neoantigens, opens new avenues for personalized treatments. Overcoming challenges in epitope prediction and screening will be crucial in harnessing the full potential of these plasma cells for the benefit of cancer patients.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Farhana Khamarudin, M. Muhamad, Mohamad Johari I, Wan Nor I’zzah WMZ, Mardiana Abdul Aziz, Nurul Raudzah Adib Ridzuan, S. Ab-Rahim
Humanized xenograft models and cancer cell lines are widely used for preclinical drug evaluation, biological studies, and targeted therapy strategies in cancer research. A humanised mouse model is a laboratory mouse that has been genetically modified to contain specific human genes, cells, or tissues. By introducing human-specific elements into rodents, researchers can create a more accurate representation of human physiological and pathological processes. Lacking an appropriate animal model for osteosarcoma (OS), hindered understanding of underlying mechanisms in OS metastasis progression. Markedly, metastasis influences the prognosis and treatment of osteosarcoma. Gaining insight into the mechanisms and occurrences of metastasis could potentially facilitate oncologists in improving therapies. Hence, it is important to develop a lung metastatic OS model to study the basic biology of its progression. This study has established a tumour-bearing mouse model using HOS-143B cell line which was injected into male NOD.SCID gamma (NSG) mice at two locations; intramuscularly (hind leg) and subcutaneously (back) respectively. The primary and metastatic tumour size was monitored by palpating the area of tumour induced and quantified using digital calliper. H&E staining was performed by pathologist to confirm metastasis. Our results showed that mice injected with 1 million cancer cells were unable to produce tumours. Meanwhile, mice injected with 3 million cancer cells showed tumour development and lung metastasis after 25 days of cancer cell inoculation. In conclusion, this study has successfully established a lung metastatic OS mouse model that could be useful for biological studies of OS. These findings imply that this model is essential for safety and efficacy before clinical trials, accelerate the translation from basic research to therapeutic applications.
人源化异种移植模型和癌细胞系被广泛用于癌症研究中的临床前药物评估、生物学研究和靶向治疗策略。人源化小鼠模型是一种经过基因改造的实验室小鼠,含有特定的人类基因、细胞或组织。通过在啮齿类动物中引入人类特异元素,研究人员可以更准确地再现人类的生理和病理过程。骨肉瘤(OS)缺乏合适的动物模型,这阻碍了对骨肉瘤转移进展内在机制的了解。转移对骨肉瘤的预后和治疗有显著影响。深入了解转移的机制和发生情况可能有助于肿瘤学家改进治疗方法。因此,建立肺转移性骨肉瘤模型以研究其进展的基本生物学特性非常重要。本研究利用HOS-143B细胞系建立了肿瘤小鼠模型,并将其分别注射到雄性NOD.SCID gamma(NSG)小鼠的两个部位:肌肉注射(后腿)和皮下注射(背部)。原发性和转移性肿瘤的大小通过触诊诱发肿瘤的区域进行监测,并使用数字卡尺进行量化。病理学家对转移瘤进行了 H&E 染色。结果表明,注射 100 万个癌细胞的小鼠无法产生肿瘤。同时,注射 300 万个癌细胞的小鼠在接种癌细胞 25 天后出现肿瘤发生和肺转移。总之,本研究成功建立了肺转移性 OS 小鼠模型,可用于 OS 的生物学研究。这些研究结果表明,该模型对临床试验前的安全性和有效性至关重要,可加速从基础研究到治疗应用的转化。
{"title":"Establishment of Humanised Xenograft Models as In Vivo Study for Lung Metastasis of Osteosarcoma","authors":"Farhana Khamarudin, M. Muhamad, Mohamad Johari I, Wan Nor I’zzah WMZ, Mardiana Abdul Aziz, Nurul Raudzah Adib Ridzuan, S. Ab-Rahim","doi":"10.1093/immadv/ltae002","DOIUrl":"https://doi.org/10.1093/immadv/ltae002","url":null,"abstract":"\u0000 Humanized xenograft models and cancer cell lines are widely used for preclinical drug evaluation, biological studies, and targeted therapy strategies in cancer research. A humanised mouse model is a laboratory mouse that has been genetically modified to contain specific human genes, cells, or tissues. By introducing human-specific elements into rodents, researchers can create a more accurate representation of human physiological and pathological processes. Lacking an appropriate animal model for osteosarcoma (OS), hindered understanding of underlying mechanisms in OS metastasis progression. Markedly, metastasis influences the prognosis and treatment of osteosarcoma. Gaining insight into the mechanisms and occurrences of metastasis could potentially facilitate oncologists in improving therapies. Hence, it is important to develop a lung metastatic OS model to study the basic biology of its progression. This study has established a tumour-bearing mouse model using HOS-143B cell line which was injected into male NOD.SCID gamma (NSG) mice at two locations; intramuscularly (hind leg) and subcutaneously (back) respectively. The primary and metastatic tumour size was monitored by palpating the area of tumour induced and quantified using digital calliper. H&E staining was performed by pathologist to confirm metastasis. Our results showed that mice injected with 1 million cancer cells were unable to produce tumours. Meanwhile, mice injected with 3 million cancer cells showed tumour development and lung metastasis after 25 days of cancer cell inoculation. In conclusion, this study has successfully established a lung metastatic OS mouse model that could be useful for biological studies of OS. These findings imply that this model is essential for safety and efficacy before clinical trials, accelerate the translation from basic research to therapeutic applications.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140386331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Kanegane, Akifumi Endo, Satoshi Okada, H. Ohnishi, Masataka Ishimura, R. Nishikomori, Kohsuke Imai, S. Nonoyama, Hideki Muramatsu, Taizo Wada, Atsushi Kuga, Ko Sakamoto, Sharon Russo-Schwarzbaum, Liang-Hui Chu, Barbara McCoy, Zhaoyang Li, L. Yel
This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200–600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50–200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100–400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5–69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/L: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03–9.12) g/L and 8.39 (7.89–8.91) g/L, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.
{"title":"Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study","authors":"H. Kanegane, Akifumi Endo, Satoshi Okada, H. Ohnishi, Masataka Ishimura, R. Nishikomori, Kohsuke Imai, S. Nonoyama, Hideki Muramatsu, Taizo Wada, Atsushi Kuga, Ko Sakamoto, Sharon Russo-Schwarzbaum, Liang-Hui Chu, Barbara McCoy, Zhaoyang Li, L. Yel","doi":"10.1093/immadv/ltae001","DOIUrl":"https://doi.org/10.1093/immadv/ltae001","url":null,"abstract":"\u0000 This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200–600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50–200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100–400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5–69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/L: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03–9.12) g/L and 8.39 (7.89–8.91) g/L, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140092390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The concept of a therapeutic cancer vaccine to activate anti-tumour immunity pre-dates innovations in checkpoint blockade immunotherapies. However, vaccination strategies have yet to show the hoped-for successes in patients, and unanswered questions regarding the underlying immunological mechanisms behind cancer vaccines have hampered translation to clinical practice. Recent advances in our understanding of the potential of tumour mutational burden and neo-antigen-reactive T cells for response to immunotherapy have re-ignited enthusiasm for cancer vaccination strategies, coupled with the development of novel mRNA-based vaccines following successes in prevention of COVID-19. Here we summarise current developments in cancer vaccines and discuss how advances in our comprehension of the cellular interplay in immunotherapy-responsive tumours may inform better design of therapeutic cancer vaccines, with a focus on the role of dendritic cells (DCs) as the orchestrators of anti-tumour immunity. The increasing number of clinical trials and research being funnelled into cancer vaccines has demonstrated the ‘proof-of-principle’, supporting the hypothesis that therapeutic vaccines have potential as an immuno-oncology agent. For efficacious and safe cancer vaccines to be developed, better understanding of the underpinning immunological mechanisms is paramount.
激活抗肿瘤免疫力的治疗性癌症疫苗的概念早于检查点阻断免疫疗法的创新。然而,疫苗接种策略尚未在患者身上取得预期的成功,癌症疫苗背后的潜在免疫学机制问题仍未得到解答,这阻碍了疫苗在临床实践中的应用。最近,我们对肿瘤突变负荷和新抗原反应 T 细胞对免疫疗法的潜在反应的认识有了新的进展,这重新点燃了人们对癌症疫苗接种策略的热情,同时,在成功预防 COVID-19 之后,基于 mRNA 的新型疫苗也得到了开发。在此,我们总结了癌症疫苗的当前发展,并讨论了我们对免疫疗法反应性肿瘤中细胞相互作用的理解所取得的进展如何为更好地设计治疗性癌症疫苗提供信息,重点是树突状细胞(DC)作为抗肿瘤免疫协调者的作用。越来越多的临床试验和研究被引入到癌症疫苗中,这证明了 "原理验证",支持了治疗性疫苗作为免疫肿瘤药物具有潜力的假设。要开发出有效、安全的癌症疫苗,就必须更好地了解其背后的免疫机制。
{"title":"Cancer Vaccines: From an immunology perspective","authors":"Shania Makker, Charlotte Galley, Clare L. Bennett","doi":"10.1093/immadv/ltad030","DOIUrl":"https://doi.org/10.1093/immadv/ltad030","url":null,"abstract":"\u0000 The concept of a therapeutic cancer vaccine to activate anti-tumour immunity pre-dates innovations in checkpoint blockade immunotherapies. However, vaccination strategies have yet to show the hoped-for successes in patients, and unanswered questions regarding the underlying immunological mechanisms behind cancer vaccines have hampered translation to clinical practice. Recent advances in our understanding of the potential of tumour mutational burden and neo-antigen-reactive T cells for response to immunotherapy have re-ignited enthusiasm for cancer vaccination strategies, coupled with the development of novel mRNA-based vaccines following successes in prevention of COVID-19. Here we summarise current developments in cancer vaccines and discuss how advances in our comprehension of the cellular interplay in immunotherapy-responsive tumours may inform better design of therapeutic cancer vaccines, with a focus on the role of dendritic cells (DCs) as the orchestrators of anti-tumour immunity. The increasing number of clinical trials and research being funnelled into cancer vaccines has demonstrated the ‘proof-of-principle’, supporting the hypothesis that therapeutic vaccines have potential as an immuno-oncology agent. For efficacious and safe cancer vaccines to be developed, better understanding of the underpinning immunological mechanisms is paramount.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138948858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathleen Richter, H. Haliduola, Jana Schockaert, Aurélie Mazy, N. Reznichenko, Eric Guenzi, Fausto Berti
Immunogenicity against biologic medicines is ubiquitous, and it is traditionally measured by the final humoral response. However, the onset of a sustained immunogenic response begins at the cellular level with activation of T cells and maturation of naïve B cells into plasma cells. Ex vivo comparative immunogenicity assessment (EVCIA) of cellular immunogenicity in participants with moderate-to-severe chronic plaque psoriasis in the AVT02-GL-302 study, who received either reference product (RP) alone (non-switching arm) or switched between RP and AVT02 (switching arm) after 1: 1 randomization at week 12. Peripheral blood mononuclear cells (PBMCs) were collected and cryopreserved from 28 participants at: baseline (before treatment) (week 1); pre-randomization (week 12); and week 16 and week 28 in both switching and non-switching arms. PBMCs were thawed and re-exposed to either medium alone (negative control), RP, AVT02, keyhole limpet hemocyanin (KLH) (positive control), RP+KLH, or AVT02+KLH. Samples from 10 participants (predetermined average cell viability of 75% across all timepoints) from each arm were analyzed for cytokine release after 24 hours and for Th-cell proliferation, 6 days post-seeding. Until week 28, cytokine release and Th-cell proliferation was similar at all time points in both switching and non-switching arms. Overall cellular immune response was elevated post-KLH re-exposure at all timepoints. The comparable ex vivo cellular immunogenicity between switching and non-switching arms complements the confirmation of interchangeability in the main study. Given the sensitivity of novel EVCIA, detecting cellular immunogenicity could be a potential outcome in predicting the immunogenicity of biologic medicines.
{"title":"Ex Vivo Comparative Immunogenicity Assessment (EVCIA) to Determine Relative Immunogenicity in Chronic Plaque Psoriasis in Participants Receiving Humira® or Undergoing Repeated Switches Between Humira® and AVT02","authors":"Kathleen Richter, H. Haliduola, Jana Schockaert, Aurélie Mazy, N. Reznichenko, Eric Guenzi, Fausto Berti","doi":"10.1093/immadv/ltad029","DOIUrl":"https://doi.org/10.1093/immadv/ltad029","url":null,"abstract":"\u0000 Immunogenicity against biologic medicines is ubiquitous, and it is traditionally measured by the final humoral response. However, the onset of a sustained immunogenic response begins at the cellular level with activation of T cells and maturation of naïve B cells into plasma cells. Ex vivo comparative immunogenicity assessment (EVCIA) of cellular immunogenicity in participants with moderate-to-severe chronic plaque psoriasis in the AVT02-GL-302 study, who received either reference product (RP) alone (non-switching arm) or switched between RP and AVT02 (switching arm) after 1: 1 randomization at week 12. Peripheral blood mononuclear cells (PBMCs) were collected and cryopreserved from 28 participants at: baseline (before treatment) (week 1); pre-randomization (week 12); and week 16 and week 28 in both switching and non-switching arms. PBMCs were thawed and re-exposed to either medium alone (negative control), RP, AVT02, keyhole limpet hemocyanin (KLH) (positive control), RP+KLH, or AVT02+KLH. Samples from 10 participants (predetermined average cell viability of 75% across all timepoints) from each arm were analyzed for cytokine release after 24 hours and for Th-cell proliferation, 6 days post-seeding. Until week 28, cytokine release and Th-cell proliferation was similar at all time points in both switching and non-switching arms. Overall cellular immune response was elevated post-KLH re-exposure at all timepoints. The comparable ex vivo cellular immunogenicity between switching and non-switching arms complements the confirmation of interchangeability in the main study. Given the sensitivity of novel EVCIA, detecting cellular immunogenicity could be a potential outcome in predicting the immunogenicity of biologic medicines.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138949370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natural killer (NK) cells are cytotoxic innate lymphoid cells that participate in anti-tumour and anti-viral immune responses. Their ability to rapidly destroy abnormal cells and to enhance the anti-cancer function of dendritic cells, CD8+ T cells and macrophages makes them an attractive target for immunotherapeutic strategies. The development of approaches which augment NK cell activation against cancer is currently under intense preclinical and clinical research and strategies include chimeric antigen receptor (CAR) NK cells, NK cell engagers, cytokines, and immune checkpoint inhibitors. In this review, we highlight recent advances in NK cell therapeutic development and discuss their potential to add to our armamentarium against cancer.
自然杀伤(NK)细胞是细胞毒性先天性淋巴细胞,参与抗肿瘤和抗病毒免疫反应。自然杀伤细胞能迅速消灭异常细胞,并增强树突状细胞、CD8+ T 细胞和巨噬细胞的抗癌功能,因此成为免疫治疗策略中极具吸引力的靶点。目前,临床前和临床研究正在大力开发增强 NK 细胞活化抗癌功能的方法,其中包括嵌合抗原受体 (CAR) NK 细胞、NK 细胞啮合剂、细胞因子和免疫检查点抑制剂。在这篇综述中,我们将重点介绍 NK 细胞疗法开发的最新进展,并讨论它们为我们的抗癌武器库增添新成员的潜力。
{"title":"Harnessing natural killer cell effector function against cancer","authors":"Matthew D. Blunt, S. Khakoo","doi":"10.1093/immadv/ltad031","DOIUrl":"https://doi.org/10.1093/immadv/ltad031","url":null,"abstract":"\u0000 Natural killer (NK) cells are cytotoxic innate lymphoid cells that participate in anti-tumour and anti-viral immune responses. Their ability to rapidly destroy abnormal cells and to enhance the anti-cancer function of dendritic cells, CD8+ T cells and macrophages makes them an attractive target for immunotherapeutic strategies. The development of approaches which augment NK cell activation against cancer is currently under intense preclinical and clinical research and strategies include chimeric antigen receptor (CAR) NK cells, NK cell engagers, cytokines, and immune checkpoint inhibitors. In this review, we highlight recent advances in NK cell therapeutic development and discuss their potential to add to our armamentarium against cancer.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138950993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-11eCollection Date: 2024-01-01DOI: 10.1093/immadv/ltad028
J Guillaume, A Perzolli, M Boes
Immunotherapy has made significant advancements in cancer treatments, improving patients' survival rates and quality of life. Several challenges still need to be addressed, which include the considerable fraction of incomplete curative responses in cancer patients, the development of therapy resistance by tumours, and the occurrence of adverse effects, such as inflammatory and autoimmune complications. Paediatric tumours usually exhibit lower responsiveness to immunotherapies compared to adult tumours. Although the underlying reasons are not yet fully understood, one known mechanism by which tumours avoid immune recognition is through reduced cell surface expression of major histocompatibility complex class I (MHC-I) complexes. Accordingly, the reduced presentation of neoantigens by MHC-I hinders the recognition and targeting of tumour cells by CD8+ T cells, impeding T-cell-mediated cytotoxic anti-tumour responses. MHC-I downregulation indeed often correlates with a poorer prognosis and diminished response to immunotherapy. Understanding the mechanisms underlying MHC-I downregulation in different types of paediatric and adult tumours is crucial for developing strategies to restore MHC-I expression and enhance anti-tumour immune responses. We here discuss progress in MHC-I-based immunotherapies against cancers.
免疫疗法在癌症治疗方面取得了重大进展,提高了患者的生存率和生活质量。但仍有一些挑战需要解决,其中包括癌症患者中存在相当大比例的不完全治愈反应、肿瘤产生抗药性以及出现炎症和自身免疫并发症等不良反应。与成人肿瘤相比,儿童肿瘤对免疫疗法的反应性通常较低。虽然其根本原因尚不完全清楚,但肿瘤避免免疫识别的一个已知机制是细胞表面主要组织相容性复合物 I 类(MHC-I)复合物的表达减少。因此,MHC-I 对新抗原的呈现减少,阻碍了 CD8+ T 细胞对肿瘤细胞的识别和靶向,从而阻碍了 T 细胞介导的细胞毒性抗肿瘤反应。事实上,MHC-I的下调往往与预后较差和对免疫疗法的反应减弱相关。了解不同类型儿童和成人肿瘤中 MHC-I 下调的机制对于制定恢复 MHC-I 表达和增强抗肿瘤免疫反应的策略至关重要。我们在此讨论基于 MHC-I 的癌症免疫疗法的进展。
{"title":"Strategies to overcome low MHC-I expression in paediatric and adult tumours.","authors":"J Guillaume, A Perzolli, M Boes","doi":"10.1093/immadv/ltad028","DOIUrl":"10.1093/immadv/ltad028","url":null,"abstract":"<p><p>Immunotherapy has made significant advancements in cancer treatments, improving patients' survival rates and quality of life. Several challenges still need to be addressed, which include the considerable fraction of incomplete curative responses in cancer patients, the development of therapy resistance by tumours, and the occurrence of adverse effects, such as inflammatory and autoimmune complications. Paediatric tumours usually exhibit lower responsiveness to immunotherapies compared to adult tumours. Although the underlying reasons are not yet fully understood, one known mechanism by which tumours avoid immune recognition is through reduced cell surface expression of major histocompatibility complex class I (MHC-I) complexes. Accordingly, the reduced presentation of neoantigens by MHC-I hinders the recognition and targeting of tumour cells by CD8+ T cells, impeding T-cell-mediated cytotoxic anti-tumour responses. MHC-I downregulation indeed often correlates with a poorer prognosis and diminished response to immunotherapy. Understanding the mechanisms underlying MHC-I downregulation in different types of paediatric and adult tumours is crucial for developing strategies to restore MHC-I expression and enhance anti-tumour immune responses. We here discuss progress in MHC-I-based immunotherapies against cancers.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10787372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}