Journal Articles

CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors

Spotlight 

Gang Xu 1, Wei Liu 1, Ying Wang 1, Xiaoli Wei 2, Furong Liu 3, Yanyun He 1, Libo Zhang 1, Qin Song 1, Zhiyao Li 4, Changyu Wang 1, Ruihua Xu 5, Bo Chen 6

Cell Report Medicine

Xu, Liu, and Wang et al. summarized preclinical data supporting the ongoing phase 3 clinical investigation of CMG901 in patients with advanced gastric/gastroesophageal junction tumors. CMG901, a Claudin 18.2-targeted Ab (CM311) conjugated to the microtubule-targeting agent MMAE, was shown to specifically bind to and be internalized by Claudin 18.2+ tumor cells. Mechanisms of killing included direct cytotoxicity, ADCC, and CDC, as well as bystander killing of Claudin 18.2-negative tumor cells. In patient-derived xenograft (PDX) models, CMG901 had significant antitumor efficacy, while toxicity studies in primates and rats revealed reversible hematological changes.

Contributed by Katherine Turner

Gang Xu 1, Wei Liu 1, Ying Wang 1, Xiaoli Wei 2, Furong Liu 3, Yanyun He 1, Libo Zhang 1, Qin Song 1, Zhiyao Li 4, Changyu Wang 1, Ruihua Xu 5, Bo Chen 6

Cell Report Medicine

Xu, Liu, and Wang et al. summarized preclinical data supporting the ongoing phase 3 clinical investigation of CMG901 in patients with advanced gastric/gastroesophageal junction tumors. CMG901, a Claudin 18.2-targeted Ab (CM311) conjugated to the microtubule-targeting agent MMAE, was shown to specifically bind to and be internalized by Claudin 18.2+ tumor cells. Mechanisms of killing included direct cytotoxicity, ADCC, and CDC, as well as bystander killing of Claudin 18.2-negative tumor cells. In patient-derived xenograft (PDX) models, CMG901 had significant antitumor efficacy, while toxicity studies in primates and rats revealed reversible hematological changes.

Contributed by Katherine Turner

ABSTRACT: Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

Author Info: (1) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China.(2) Department of Medical Oncology, Sun Yat-Sen University Cancer Cent

Author Info: (1) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China.(2) Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, China. (3) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. (4) School of Biological Sciences, Nanyang Technological University 60 Nanyang Drive, Singapore 637551, Singapore. (5) Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong 510060, China. Electronic address: xurh@sysucc.org.cn. (6) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China. Electronic address: knybochen@keymedbio.com.

Citation: Cell Rep. Med. 2024 Aug 27

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/39232496/

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Alginate-based artificial antigen presenting cells expand functional CD8(+) T cells with memory characteristics for adoptive cell therapy

(1) Omotoso MO (2) Est-Witte SE (3) Shannon SR (4) Li S (5) Nair NM (6) Neshat SY (7) Kang SS (8) Tzeng SY (9) Green JJ (10) Schneck JP

Biomaterials

(1) Omotoso MO (2) Est-Witte SE (3) Shannon SR (4) Li S (5) Nair NM (6) Neshat SY (7) Kang SS (8) Tzeng SY (9) Green JJ (10) Schneck JP

Biomaterials

The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8(+) T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8(+) T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8(+) T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.

Author Info: (1) Department of Biomedical Engineering, School of Medicine, USA; Institute for Cell Engineering, School of Medicine, USA; Department of Pathology, School of Medicine, USA. (2) De

Author Info: (1) Department of Biomedical Engineering, School of Medicine, USA; Institute for Cell Engineering, School of Medicine, USA; Department of Pathology, School of Medicine, USA. (2) Department of Biomedical Engineering, School of Medicine, USA; Translational Tissue Engineering Center, USA; Institute for NanoBioTechnology, USA. (3) Department of Biomedical Engineering, School of Medicine, USA; Department of Pathology, School of Medicine, USA; Translational Tissue Engineering Center, USA; Institute for NanoBioTechnology, USA. (4) Department of Pathology, School of Medicine, USA; Institute for NanoBioTechnology, USA. (5) Department of Biomedical Engineering, Whiting School of Engineering, USA. (6) Department of Biomedical Engineering, School of Medicine, USA; Translational Tissue Engineering Center, USA; Institute for NanoBioTechnology, USA. (7) Department of Pathology, School of Medicine, USA. (8) Translational Tissue Engineering Center, USA; Department of Biomedical Engineering, Whiting School of Engineering, USA; Johns Hopkins Translational ImmunoEngineering Center, USA. (9) Department of Biomedical Engineering, School of Medicine, USA; Translational Tissue Engineering Center, USA; Institute for NanoBioTechnology, USA; Johns Hopkins Translational ImmunoEngineering Center, USA. Electronic address: green@jhu.edu. (10) Department of Biomedical Engineering, School of Medicine, USA; Institute for Cell Engineering, School of Medicine, USA; Department of Pathology, School of Medicine, USA; Johns Hopkins Translational ImmunoEngineering Center, USA; Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. Electronic address: jschnec1@jhmi.edu.

Citation: Biomaterials 2024 Aug 24 313:122773 Epub08/24/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39217794

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Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer

(1) Xue W (2) Xu C (3) Zhang K (4) Cui L (5) Huang X (6) Nan Y (7) Ju D (8) Chang X (9) Zhang X

Cell death discovery

(1) Xue W (2) Xu C (3) Zhang K (4) Cui L (5) Huang X (6) Nan Y (7) Ju D (8) Chang X (9) Zhang X

Cell death discovery

Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, the inconclusive underlying mechanisms pose a hurdle to extending the utility of these agents. In our study, _CLDN18.2-MMAE, an ADC composed of an anti-CLDN18.2 monoclonal antibody and the tubulin inhibitor MMAE, induced a dose-dependent apoptosis via the cleavage of caspase-9/PARP proteins in CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy was remarkably activated during the _CLDN18.2-MMAE treatment, which was characterized by the accumulation of autophagosomes, the conversion of autophagy marker LC3 from its form I to II, and the complete autophagic flux. Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced _CLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells. Combination with an autophagy inhibitor significantly potentiated the in vivo antitumoral efficacy of _CLDN18.2-MMAE. Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in _CLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.

Author Info: (1) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. (2) Department o

Author Info: (1) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. (2) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. (3) Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. (4) Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. (5) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. (6) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. (7) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. dianwenju@fudan.edu.cn. (8) Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. cxs20051014@163.com. (9) Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China. xuyaozhang@fudan.edu.cn.

Citation: Cell Death Discov 2024 Sep 3 10:393 Epub09/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39227365

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Therapeutic vaccine targeting dual immune checkpoints induces potent multifunctional CD8(+) T cell anti-tumor immunity

(1) Zheng Y (2) Lu Z (3) Zhu F (4) Zhao G (5) Shao Y (6) Lu B (7) Ding J (8) Wang G (9) Fang L (10) Zheng J (11) Chai D

International immunopharmacology

(1) Zheng Y (2) Lu Z (3) Zhu F (4) Zhao G (5) Shao Y (6) Lu B (7) Ding J (8) Wang G (9) Fang L (10) Zheng J (11) Chai D

International immunopharmacology

BACKGROUND: Vaccines targeting immune checkpoints represent a promising immunotherapeutic approach for solid tumors. However, the therapeutic efficacy of dual targeting immune checkpoints is still unclear in renal carcinoma. METHODS: An adenovirus (Ad) vaccine targeting B7H1 and B7H3 was developed and evaluated for its therapeutic efficacy in subcutaneous, lung metastasis or orthotopic renal carcinoma mouse and humanized models using flow cytometry, Enzyme-linked immunosorbent spot (ELISPOT), cytotoxic T lymphocyte (CTL) killing, cell deletion, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) assays. RESULTS: The Ad-B7H1/B7H3 immunization effectively inhibited tumor growth and increased the induction and percentages of CD8(+) T cells in subcutaneous tumor models. The vaccine enhanced the induction and maturation of CD11c(+) or CD8(+)CD11c(+) cells, promoting tumor-specific CD8(+) T cell immune responses. This was evidenced by increased proliferation of CD8(+) T cells and enhanced CTL killing activity. Deletion of CD8(+) T cells in vivo abolished the anti-tumor effect of the Ad-B7H1/B7H3 vaccine, highlighting the pivotal role of functional CD8(+) T cell immune responses. Moreover, significant therapeutic efficacy of the Ad-B7H1/B7H3 vaccine was observed in lung metastasis, orthotopic, and humanized tumor models through multifunctional CD8(+) T cell immune responses. CONCLUSIONS: The Ad vaccine targeting dual immune checkpoints B7H1 and B7H3 exerts a potent therapeutic effect for renal carcinoma and holds promise for solid tumor treatment.

Author Info: (1) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 2

Author Info: (1) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (2) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (3) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (4) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (5) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (6) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (7) Department of Oncology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu 221009, China. (8) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (9) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (10) Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: jnzheng@xzhmu.edu.cn. (11) Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: chaidafei@xzhmu.edu.cn.

Citation: Int Immunopharmacol 2024 Aug 31 142:113004 Epub08/31/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39217885

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Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends

(1) Im SJ (2) Lee K (3) Ha SJ

Experimental & molecular medicine

(1) Im SJ (2) Lee K (3) Ha SJ

Experimental & molecular medicine

IL-2 therapy, which enhances the function of CD8_+_T cells, was initially employed as the cornerstone of immunotherapy against cancer. However, the impact of this therapy extends beyond CD8_+_T cells to cells expressing IL-2R, such as endothelial cells and regulatory T cells (Tregs), resulting in various side effects. Consequently, IL-2 therapy has taken a step back from the forefront of treatment. Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies and CTLA-4 antibodies, are used because of their durable therapeutic responses and the reduced incidence of side effects. Nevertheless, only a small fraction of cancer patients respond to ICIs, and research on IL-2 as a combination treatment to improve the efficacy of these ICIs is ongoing. To mitigate side effects, efforts have focused on developing IL-2 variants that do not strongly bind to cells expressing IL-2R_ and favor signaling through IL-2R__. However, recent studies have suggested that, in the context of persistent antigen stimulation models, effective stimulation of antigen-specific exhausted CD8_+_T cells in combination with PD-1 inhibitors requires either 1) binding to IL-2R_ or 2) delivery via a fusion with PD-1. This review explores the historical context of IL-2 as an immunotherapeutic agent and discusses future directions for its use in cancer immunotherapy.

Author Info: (1) Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, Korea. sejinim@skku.edu. (2) Department of Immunology, Sungkyunkwan University School of Medicine,

Author Info: (1) Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, Korea. sejinim@skku.edu. (2) Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, Korea. (3) Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea. sjha@yonsei.ac.kr.

Citation: Exp Mol Med 2024 Sep 2 Epub09/02/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39218982

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Tumor-Homing Antibody-Cytokine Fusions for Cancer Therapy

(1) Prodi E (2) Neri D (3) De Luca R

OncoTargets and therapy | Free PMC Article

(1) Prodi E (2) Neri D (3) De Luca R

OncoTargets and therapy | Free PMC Article

Recombinant cytokine products have emerged as a promising avenue in cancer therapy due to their capacity to modulate and enhance the immune response against tumors. However, their clinical application is significantly hindered by systemic toxicities already at low doses, thus preventing escalation to therapeutically active regimens. One promising approach to overcoming these limitations is using antibody-cytokine fusion proteins (also called immunocytokines). These biopharmaceuticals leverage the targeting specificity of antibodies to deliver cytokines directly to the tumor microenvironment, thereby reducing systemic exposure and enhancing the therapeutic index. This review comprehensively examines the development and potential of antibody-cytokine fusion proteins in cancer therapy. It explores the molecular characteristics that influence the performance of these fusion proteins, and it highlights key findings from preclinical and clinical studies, illustrating the potential of immunocytokines to improve treatment outcomes in cancer patients. Recent advancements in the field, such as novel engineering strategies and combination strategies to enhance the efficacy and safety of immunocytokines, are also discussed. These innovations offer new opportunities to optimize this class of biotherapeutics, making them a more viable and effective option for cancer treatment. As the field continues to evolve, understanding the critical factors that influence the performance of immunocytokines will be essential for successfully translating these therapies into clinical practice.

Author Info: (1) Philochem AG, Otelfingen, 8112, Switzerland. University of Trento, Italy, CiBIO (Department of Cellular, Computational and Integrative Biology), Povo, 38123, Trento. (2) Philog

Author Info: (1) Philochem AG, Otelfingen, 8112, Switzerland. University of Trento, Italy, CiBIO (Department of Cellular, Computational and Integrative Biology), Povo, 38123, Trento. (2) Philogen Spa, Siena, 53100, Italy. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH ZŸrich), Zurich, Switzerland. (3) Philochem AG, Otelfingen, 8112, Switzerland.

Citation: Onco Targets Ther 2024 17:697-715 Epub08/29/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39224695

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Comparative assessment of autologous and allogeneic iNKT cell transfer in iNKT cell-based immunotherapy

(1) Takami M (2) Motohashi S

Frontiers in immunology | Free PMC Article

(1) Takami M (2) Motohashi S

Frontiers in immunology | Free PMC Article

Invariant natural killer T (iNKT) cells are a small subset of T lymphocytes that release large amounts of cytokines such as IFN-_ and exhibit cytotoxic activity upon activation, inducing strong anti-tumor effects. Harnessing the anti-tumor properties of iNKT cells, iNKT cell-based immunotherapy has been developed to treat cancer patients. In one of the iNKT cell-based immunotherapies, two approaches are utilized, namely, active immunotherapy or adoptive immunotherapy, the latter involving the ex vivo expansion and subsequent administration of iNKT cells. There are two sources of iNKT cells for adoptive transfer, autologous and allogeneic, each with its own advantages and disadvantages. Here, we assess clinical trials conducted over the last decade that have utilized iNKT cell adoptive transfer as iNKT cell-based immunotherapy, categorizing them into two groups based on the use of autologous iNKT cells or allogeneic iNKT cells.

Author Info: (1) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. (2) Department of Medical Immunology, Graduate School of Medicine, Chiba Universi

Author Info: (1) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. (2) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Citation: Front Immunol 2024 15:1457771 Epub08/19/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39224603

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Fratricide-resistant CD7-CAR T cells in T-ALL

(1) Oh BLZ (2) Shimasaki N (3) Coustan-Smith E (4) Chan E (5) Poon L (6) Lee SHR (7) Yeap F (8) Tan LK (9) Chai LYA (10) Le Bert N (11) Tan N (12) Bertoletti A (13) Chen SP (14) Del Bufalo F (15) Becilli M (16) Locatelli F (17) Yeoh AEJ (18) Campana D

Nature medicine

(1) Oh BLZ (2) Shimasaki N (3) Coustan-Smith E (4) Chan E (5) Poon L (6) Lee SHR (7) Yeap F (8) Tan LK (9) Chai LYA (10) Le Bert N (11) Tan N (12) Bertoletti A (13) Chen SP (14) Del Bufalo F (15) Becilli M (16) Locatelli F (17) Yeoh AEJ (18) Campana D

Nature medicine

T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7(-) T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7(+) immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.

Author Info: (1) Viva-University Children's Cancer Center, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Sing

Author Info: (1) Viva-University Children's Cancer Center, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (2) Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (3) Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (4) National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore. (5) National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore. (6) Viva-University Children's Cancer Center, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (7) Viva-University Children's Cancer Center, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (8) National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore. (9) Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore. (10) Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore, Singapore. (11) Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore, Singapore. (12) Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore, Singapore. (13) Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. (14) Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Ges, Rome, Italy. (15) Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Ges, Rome, Italy. (16) Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Ges, Rome, Italy. franco.locatelli@opbg.net. Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy. franco.locatelli@opbg.net. (17) Viva-University Children's Cancer Center, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore. paeyej@nus.edu.sg. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. paeyej@nus.edu.sg. National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore. paeyej@nus.edu.sg. Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. paeyej@nus.edu.sg. (18) Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore. Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Citation: Nat Med 2024 Sep 3 Epub09/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39227445

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A study on the efficacy and Safety Evaluation of a novel PD-1/CTLA-4 bispecific antibody

(1) Song Q (2) Jiang M (3) Pan X (4) Zhou G (5) Zhang X

Immunobiology

(1) Song Q (2) Jiang M (3) Pan X (4) Zhou G (5) Zhang X

Immunobiology

Tumors constitute a significant health concern for humans, and PD-1 and CTLA-4 monoclonal antibodies have been proven effective in cancer treatment. Some researchers have identified that the combination of PD-1 and CTLA-4 dual blockade demonstrates superior therapeutic efficacy. However, the development of PD-1/CTLA-4 bispecific antibodies faces challenges in terms of both safety and efficacy. The present study discloses a novel PD-1/CTLA-4 bispecific antibody, designated as SH010. Experimental validation through surface plasmon resonance (SPR) confirmed that SH010 exhibits favorable binding activity with both PD-1 and CTLA-4. Flow cytometry analysis demonstrated stable binding of SH010 antibody to CHOK1 cells overexpressing human or cynomolgus monkey PD-1 protein and to 293F cells overexpressing human or cynomolgus monkey CTLA-4 protein. Moreover, it exhibited excellent blocking capabilities in protein binding between human PD-1 and PD-L1, as well as human CTLA-4 and CD80/CD86. Simultaneously, in vitro experiments indicate that SH010 exerts a significant activating effect on hPBMCs. In murine transplant models of human prostate cancer (22RV1) and small cell lung cancer (NCI-H69), administration of varying concentrations of the bispecific antibody significantly inhibits tumor growth. MSD analysis revealed that stimulation of hPBMCs from three different donors with SH010 did not induce the production of cytokine release syndrome. Furthermore, Single or repeated intravenous administrations of SH010 in cynomolgus monkeys show favorable systemic exposure without noticeable drug accumulation or apparent toxicity. In conclusion, SH010 represents a novel cancer therapeutic drug poised to enter clinical trials and obtain market approval.

Author Info: (1) Department of Pharmacology, SanHome, Nanjing, PR China; College of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China. (2) Department of Pharmacolo

Author Info: (1) Department of Pharmacology, SanHome, Nanjing, PR China; College of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China. (2) Department of Pharmacology, SanHome, Nanjing, PR China. (3) Department of Pharmacology, SanHome, Nanjing, PR China. (4) Department of Pharmacology, SanHome, Nanjing, PR China. (5) Department of Pharmacology, SanHome, Nanjing, PR China. Electronic address: zhangxm@sanhome.com.

Citation: Immunobiology 2024 Aug 30 229:152844 Epub08/30/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39226691

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Targeted Delivery of Circular Single-Stranded DNA Encoding IL-12 for the Treatment of Triple-Negative Breast Cancer

(1) Zhang Y (2) Cao X (3) Hu G (4) Ye R (5) Zhang L (6) Song J

Advanced healthcare materials

(1) Zhang Y (2) Cao X (3) Hu G (4) Ye R (5) Zhang L (6) Song J

Advanced healthcare materials

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.

Author Info: (1) School of Life Sciences, Tianjin University, Tianjin, 300072, China. Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. (2) Institu

Author Info: (1) School of Life Sciences, Tianjin University, Tianjin, 300072, China. Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. (2) Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China. (3) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410082, China. (4) Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China. (5) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. (6) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.

Citation: Adv Healthc Mater 2024 Sep 3 e2401376 Epub09/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39226527

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