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Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments

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中华医学杂志(英文版) 2024年第11期137卷 2023 Aug 28页

作者： Li Xudong Li Wei Xu Linping Song Yongping Department of Hematology The Affiliated Cancer Hospital of Zhengzhou University &amp Henan Cancer Hospital Zhengzhou Henan China Academy of Medical Sciences Zhengzhou University Zhengzhou Henan China Department of Hematology The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan China

The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an "off-the-shelf" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

关键词： Immunotherapy Chimeric antigen receptor-T cells Chimeric antigen receptor-NK cells Chimeric antigen receptor-macrophage solid tumors

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Challenges and interventions of chimeric antigen receptor-T cell therapy in solid tumors

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Chinese Journal of Cancer Research 2023年第3期35卷 239-244页

作者： Shasha Liu Yi Zhang Biotherapy Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Cancer Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou UniversityZhengzhou 450052China Henan Key Laboratory for Tumor Immunology and Biotherapy Zhengzhou 450052China

Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies.However,many challenges such as resistance,antigen heterogeneity,poor immune cell infiltration,immunosuppressive microenvironment,metabolic obstructive microenvironment,and T cell exhaustion remain as barriers to broader application especially in solid tumors.Encouragingly,the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers.Here,in this perspective,we focus on the most recent clinical advancements,challenges,and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy,to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.

关键词： Immunotherapy CAR-T cell solid tumors metabolism

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Multicellular tumor spheroids bridge the gap between two-dimensional cancer cells and solid tumors: The role of lipid metabolism and distribution

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Chinese Chemical Letters 2023年第2期34卷 259-262页

作者： Peisi Xie Jinghui Zhang Pengfei Wu Yongjiang Wu Yanjun Hong Jianing Wang Zongwei Cai State Key Laboratory of Environmental and Biological Analysis Department of ChemistryHong Kong Baptist UniversityHong KongChina College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China

Previous studies demonstrated that three-dimensional(3D) multicellular tumor spheroids(MCTS) could more closely mimic solid tumors than two-dimensional(2D) cancer cells in terms of the spatial structure, extracellular matrix-cell interaction, and gene expression pattern. However, no study has been reported on the differences in lipid metabolism and distribution among 2D cancer cells, MCTS, and solid tumors. Here, we used Hep G2 liver cancer cell lines to establish these three cancer models. The variations of lipid profiles and spatial distribution among them were explored by using mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging(MSI). The results revealed that MCTS, relative to 2D cells, had more shared lipid species with solid tumors. Furthermore,MCTS contained more comparable characteristics than 2D cells to solid tumors with respect to the relative abundance of most lipid classes and mass spectra patterns. MSI data showed that 46 of 71 lipids had similar spatial distribution between solid tumors and MCTS, while lipids in 2D cells had no specific spatial distribution. Interestingly, most of detected lipid species in sphingolipids and glycerolipids preferred locating in the necrotic region to the proliferative region of solid tumors and MCTS. Taken together, our study provides the evidence of lipid metabolism and distribution demonstrating that MCTS are a more suitable in vitro model to mimic solid tumors, which may offer insights into tumor metabolism and microenvironment.

关键词： Lipid metabolism Lipid distribution Two-dimensional cells Three-dimensional cell spheroids solid tumors

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Neoantigen cancer vaccines:a new star on the horizon

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Cancer Biology & Medicine 2024年第4期21卷 274-311页

作者： Xiaoling Li Jian You Liping Hong Weijiang Liu Peng Guo Xishan Hao Cell Biotechnology Laboratory Tianjin Cancer Hospital Airport HospitalTianjin 300308China National Clinical Research Center for Cancer Tianjin 300060China Haihe Laboratory of Synthetic Biology Tianjin 300090China Department of Thoracic Oncology Tianjin Cancer Hospital Airport HospitalTianjin 300308China Department of Thoracic Oncology Surgery Tianjin Medical University Cancer Institute&HospitalTianjin 300060China Tianjin Medical University Cancer Institute&Hospital Tianjin 300060China

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

关键词： Immunotherapy neoantigen cancer vaccine solid tumors high-throughput sequencing bioinformatics PDOs AI HLA TCR

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Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

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World Journal of Gastroenterology 2024年第21期30卷 2748-2750页

作者： Wei-Nung Liu Ming-Shen Dai Felicia Lin Gen-Min Lin Department of Medicine Tri-Service General HospitalTaipei 114Taiwan Division of Hematology/Oncology Department of Internal MedicineNational Defense Medical CenterTaipei 114Taiwan Community Care Minnesota OncologyMinneapolisMN 55404United States Department of Medicine Hualien Armed Forces General HospitalHualien City 970Taiwan

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

关键词： Hepatitis B virus reactivation Bruton tyrosine kinase inhibitors Hematologic malignancies solid tumors Prophylaxis guidelines

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Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

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Cancer Biology & Medicine 2021年第3期18卷 649-664页

作者： Brandon M.Bordeau Joseph P.Balthasar Department of Pharmaceutical Science University at BuffaloBuffaloNY 14214USA

Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been modest.Limited efficacy of m Ab in solid tumors likely relates to unique aspects of tumor physiology.solid tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of m Abs into and within tumors.For m Abs that are directed against cellular antigens,high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated m Ab,limiting m Ab distribution to portions of the tumor that are distant from functional vessels.Many preclinical investigations have reported strategies to improve m Ab uptake and distribution;however,to our knowledge,none have translated into the clinic.Here,we provide an overview of several barriers in solid tumors that limit m Ab uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.

关键词： solid tumors antibody uptake and distribution monoclonal antibody antibody-drug conjugate

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Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

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智能检验医学(英文) 2023年第1期1卷 29-43页

作者： Eric von Hofe Yanping Yang Moonsoo M.Jin AffyImmune Therapeutics Inc.NatickMassachusettsUSA Department of Radiology Molecular Imaging Innovations InstituteWeill Cornell MedicineNew YorkNew YorkUSA

Chimeric antigen receptor(CAR)T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies.It has been challenging to translate this success to solid tumors.Reasons for this include barriers to delivery,tumor heterogeneity,cancer cells'ability to evade the immune system as well as identifying the optimal target.Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation.Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement,but also caution,given instances of unacceptable toxicity.The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose.Here,we review those trials showing encouraging results in the context of target selection.It is clear that more specific tumor targeting is required,either by affinity tuning to avoid low‐level target expression in healthy cells,logic gating,or the identification of new targets that are more cancer specific.

关键词： CAR T cell clinical trials solid tumors targeted therapy

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Targeting the JAK/STAT pathway in solid tumors

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 287-304页

作者： Zoya Qureshy Daniel E.Johnson Jennifer R.Grandis Department of Otolaryngology-Head and Neck Surgery University of California San FranciscoSan Francisco 94158USA

Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to target directly.In this review,we summarize the role of targeting Janus kinases(JAKs),upstream activators of STATs,as a strategy for decreasing STAT activation in solid tumors.Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation,cell proliferation,and cell survival;in in vivo models,they also inhibit tumor growth.JAK inhibitors,particularly the JAK1/2 inhibitor ruxolitinib,sensitize cell lines and murine models to chemotherapy,immunotherapy,and oncolytic viral therapy.Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors;two of these inhibitors are already Food and Drug Administration(FDA)approved for the treatment of myeloproliferative disorders and rheumatoid arthritis,making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated.Four JAK inhibitors(two of which are FDA approved for other indications)have exhibited promising anti-cancer effects in preclinical studies;however,clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted.In summary,JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

关键词： Clinical trials Janus kinase/signal transducer and activator of transcription(JAK/STAT)pathway JAK inhibitors solid tumors STAT hyperactivation

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The potential prognostic and predictive roles of programmed cell death protein 1 expressed by tumor-infiltrating lymphocytes in solid tumors:a meta-analysis

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 199-209页

作者： Dong-Yun Zhang Rong-Zhi Liu Jian-Wei Ku Yu-Hong Ma Ying-Jie Yi Department of Basic Medicine Nanyang Medical CollegeNanyang 473061HenanChina Department of Medical Oncology The Second Affiliated Hospital of Nanyang Medical CollegeNanyang 473061HenanChina Department of Book Cataloguing Nanyang Medical CollegeNanyang 473061HenanChina

Aim:Several previous studies have evaluated the potential role of programmed cell death protein 1(PD-1)expressed by tumor-infiltrating lymphocytes(TILs)in various solid tumors and performed its prognosis role in patients’survival with inconsistent results.This study aims to further systematically evaluate the association of PD-1 by TILs with clinicopathological parameters and clinical outcomes in solid tumor patients.Methods:A comprehensive search was conducted in PubMed,Embase,Web of Science,CNKI and Wanfang databases for relevant studies.The potential prognostic and predictive roles of PD-1 were assessed by pooled hazard ratio(HR),odds ratio(OR)and 95%confidence intervals(CI).A total of 1863 patients were selected for in-depth analysis.Results:The results demonstrated that PD-1 by TILs was correlated to overall survival for ovarian cancer(HR=0.40,95%CI:0.26-0.61,Psolid tumors.

关键词： Programmed cell death protein 1 meta-analysis solid tumors prognosis

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HUMAN UMBILICAL CORD BLOOD TRANSPLANTATION IN 4 CASES WITH ADVANCED solid tumors

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山东大学学报(医学版) 1993年第1期 74-81页

作者：沈柏均侯怀水张洪泉隋星卫刘晓艳丁欣荣马秀峰时庆高宣 Dept.of Pediatrics and Cryomedicine Laboratory the Affiliated Hospital of Shandong Medical University

Four patients with solid tumors were treated by means of highdose chemotherapy and HLA-mismatched multi-cord blood transplantation.Ofthem,3 reached complete remission,1 got fair response with tolerant side-effects.No or a little graft-versus-host reaction(GVHR)were observed.Donor cellengraftments were documented in 2 patients by cytogenetic analysis and deter-mination of hemoglobin F of the peripheral blood.Recurrent diseases wereconfirmed clinically on day 210(4 year-old girl with liposarcoma)and day 90(11 year old boy with Non-Hodgkin′s Lymphoma).These results demonstratedthat HLA-mismatched multicord blood transfusion could rescue the marrowsuppression of patients treated with myeloablative chemotherapy with no or a littleGVHR,and suggested that muIticord blood stem cells might be engrafted in asingle patient without consideration of HLA-identical.Therefore,cord blood mayprovide a rich hematopoietic resources.Further studies are needed to confirmour observation.

关键词： Human Umbilical Cord Blood Transplantation solid tumors Children

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