Journal Articles

SYS6010, epidermal growth factor receptor-targeting antibody-drug conjugate for advanced non-small cell lung cancer: A phase 1 trial Spotlight 

(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S

Cancer cell

In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.

Contributed by Ute Burkhardt

(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S

Cancer cell

In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.

Contributed by Ute Burkhardt

ABSTRACT: SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ³ 3) occurred in 99.6%/57.2% of patients. Common grade ³3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030

Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (2) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (3) Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, P.R. China. (4) Department of Oncology, Xuzhou Center Hospital, Xuzhou 221000, P.R. China. (5) Department of Thoracic Oncology II, Beijing Cancer Hospital, Beijing 100142, P.R. China. (6) Department of Medical Oncology, Jiamusi Tumor Hospital, Jiamusi 154000 P.R. China. (7) Department of Critical Care Medicine, Jilin Cancer Hospital, Changchun 130000 P.R. China. (8) Clinical Pharmacology and Medical Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (9) Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (10) Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang 110000, P.R. China. (11) Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. (12) Phase I Ward, Chongqing University Cancer Hospital, Chongqing 400030, P.R. China. (13) Respiratory Medicine Ward 3, Cancer Hospital Affiliated to Harbin Medical University, Harbin 150000, P.R. China. (14) Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou 341001, P.R. China. (15) Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China. (16) Continuity of Care Unit, Shanghai Pulmonary Hospital, Shanghai 200433, P.R. China. (17) Department of Oro-maxillofacial Head and Neck Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430048, P.R. China. (18) Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding 071000, P.R. China. (19) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China. (20) Department of Medical Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. (21) Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China. (22) Department of Thoracic Tumor Radiotherapy, Jiangxi Cancer Hospital, Nanchang 330029 P.R. China. (23) Department of Oncology, The First Hospital of Jilin University, Changchun 130021, P.R. China. (24) Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou 350001, P.R. China. (25) Department of Oncology, Army Medical Center with Distinctive Features, Chongqing, 400010, P.R. China. (26) Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China. (27) Department of Internal Medicine No.2, Yunnan Cancer Hospital, Kunming 650106, P.R. China. (28) Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, P.R. China. (29) Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, P.R. China. (30) Preclinical Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (31) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (32) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (33) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (34) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (35) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (36) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. Electronic address: shunlu@sjtu.edu.cn.

Citation: Cancer Cell 2026 Aug 13 Epub08/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594871

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Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote antitumor immunity Spotlight 

(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R

Nature cancer

Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.

Contributed by Katherine Turner

(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R

Nature cancer

Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.

Contributed by Katherine Turner

ABSTRACT: Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.

Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Depa

Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (11) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (12) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. rony.dahan@weizmann.ac.il.

Citation: Nat Cancer 2026 Aug 5 Epub08/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42557403

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TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy

Spotlight 

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.

Contributed by Paula Hochman

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.

Contributed by Paula Hochman

ABSTRACT: The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named _TIGIT-IL12 (T-12), which fuses the 13G6 (_TIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8(+) T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8(+) T cells. T-12 preferentially activates tumor-infiltrating NK and CD8(+) T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedic

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, Guangxi, China. (3) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (4) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. (8) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: mahongdi@ustc.edu.cn. (9) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: tzg@ustc.edu.cn. (10) Department of Immunology, School of Basic Medical Sciences, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: haoyusun@ustc.edu.cn. (11) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: ustczxh@ustc.edu.cn.

Citation: Cell Rep Med 2026 Jun 16 102876 Epub06/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42302794

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MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial Spotlight 

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

ABSTRACT:IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401 (0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14% (8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% (8/41) was observed across 15 different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D, namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) CharitŽ UniversitŠtsmedizin Berlin, Berlin, Germany. (3)

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) CharitŽ UniversitŠtsmedizin Berlin, Berlin, Germany. (3) National Center for Tumor Diseases, Heidelberg, Germany. (4) Department of Hematology, Oncology, and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. (5) Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. (6) National Center for Tumor Diseases, Heidelberg, Germany. Thoraxklinik Heidelberg gGmbH, University Hospital Heidelberg, Heidelberg, Germany. (7) University Hospital WŸrzburg, Comprehensive Cancer Center Mainfranken, WŸrzburg, Germany. (8) Marien Hospital DŸsseldorf, DŸsseldorf, Germany. (9) Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany. (10) Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, School of Medicine and Health, Munich, Germany. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich (TUM), Munich, Germany. (11) University Hospital of TŸbingen, TŸbingen, Germany. (12) University Hospital Regensburg, Regensburg, Germany. (13) Immatics Biotechnologies GmbH, TŸbingen, Germany. (14) Immatics Biotechnologies GmbH, TŸbingen, Germany. (15) Immatics Biotechnologies GmbH, TŸbingen, Germany. (16) Immatics Biotechnologies GmbH, TŸbingen, Germany. (17) Immatics Biotechnologies GmbH, TŸbingen, Germany. (18) Immatics Biotechnologies GmbH, TŸbingen, Germany. (19) Immatics Biotechnologies GmbH, TŸbingen, Germany. (20) Immatics Biotechnologies GmbH, TŸbingen, Germany. (21) University Hospital Bonn, Bonn, Germany. (22) Nuremberg General Hospital, Nuremberg, Germany. (23) Department of Otorhinolaryngology and Head & Neck Surgery, Ulm University Medical Center, Ulm, Germany. (24) University Hospital, Goethe University Frankfurt, Frankfurt Cancer Institute, Frankfurt, Germany. (25) University Hospital Erlangen, Erlangen, Germany. (26) Immatics Biotechnologies GmbH, TŸbingen, Germany. (27) Immatics Biotechnologies GmbH, TŸbingen, Germany. Carsten.Reinhardt@immatics.com.

Citation: Nat Med 2026 May 31 Epub05/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42219399

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FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight 

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC. METHODS: Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing. RESULTS: Combination therapy induced dense intratumoral clusters of CD4(+) and CD8(+) T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4(+) and CD8(+) T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4(+) T cells toward a T helper cell 1 phenotype in combination-treated tumors. CONCLUSION: The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Ba

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (5) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (6) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Institute of Experimental Immunology, UniversitŠt ZŸrich, ZŸrich, Switzerland. Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany. (12) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (13) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland leo.kunz@roche.com.

Citation: J Immunother Cancer 2026 May 28 14: Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42208978

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Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot Spotlight 

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

ABSTRACT: Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, "cold" tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)-based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert "cold" tumors into inflamed "hot" lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed "hot" phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell-redirecting therapies, in challenging tumor settings.

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Swit

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Switzerland. (3) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (4) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (5) Philochem AG, Otelfingen, Switzerland. (6) Philochem AG, Otelfingen, Switzerland. (7) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (8) Philochem AG, Otelfingen, Switzerland. (9) Philochem AG, Otelfingen, Switzerland. Philogen SpA, Siena, Italy. (10) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 Philogen SpA, Siena, Italy. (11) Philochem AG, Otelfingen, Switzerland.

Citation: Cancer Immunol Res 2026 Apr 21 OF1-OF14 Epub04/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42012522

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Debio 1562M CD37-targeting ADC is highly active and well tolerated in preclinical models of AML and MDS Spotlight 

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

ABSTRACT: The leukocyte antigen CD37 is broadly expressed on acute myeloid leukemia (AML) blasts and associated with poor prognosis. We demonstrate that myelodysplastic syndrome (MDS) cells also express CD37, and both AML and MDS cells have favorable internalization properties of this receptor. Debio 1562M is a next-generation antibody-drug conjugate (ADC) that targets CD37 and is optimized to deliver more toxins to tumor cells than the first-generation ADC Debio 1562, while maintaining a good safety profile. Preclinically, Debio 1562M showed robust anti-leukemic activity in AML and MDS primary samples and in AML xenograft models, irrespective of disease stage or genotype. Debio 1562M was able to target leukemic stem cells in vitro and significantly decrease tumor burden in blood and bone marrow, resulting in survival prolongation compared with standard-of-care treatments. These data demonstrate that CD37 is a relevant target for both indications and that Debio 1562M is a promising therapeutic candidate.

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausann

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausanne, Switzerland. (4) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (5) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (6) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (7) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (8) Debiopharm International SA, 1006 Lausanne, Switzerland. (9) Debiopharm International SA, 1006 Lausanne, Switzerland. (10) Debiopharm International SA, 1006 Lausanne, Switzerland. (11) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (12) Debiopharm International SA, 1006 Lausanne, Switzerland. Electronic address: lisa.ivanschitz@debiopharm.com.

Citation: Cell Rep Med 2026 Apr 20 102749 Epub04/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42013843

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Developing a multimodal therapy for glioblastoma using oncolytic virus delivering CD19 and EGFRvIII antigens and bi-specific CARs

Spotlight 

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

ABSTRACT: Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duar

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (3) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (4) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (5) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (6) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (7) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (8) Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (9) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (10) Cellular Immunotherapy Program Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. yshi@coh.org.

Citation: Nat Commun 2026 Apr 9 Epub04/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41957020

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Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice Spotlight 

(1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

Nature communications

Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

Contributed by Katherine Turner

(1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

Nature communications

Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

Contributed by Katherine Turner

ABSTRACT: Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3(+)TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFN_-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFN_ and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.

Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beiji

Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (7) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (8) Changping Laboratory, Beijing, China. (9) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (10) Changping Laboratory, Beijing, China. (11) CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. (12) Guangzhou National Laboratory, Bio-Island, Guangzhou, China. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (13) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. (14) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Beijing, China. yangxinfu@tsinghua.edu.cn.

Citation: Nat Commun 2026 Mar 17 Epub03/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41844634

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A bispecific nanobody-drug conjugate targeting TROP2 and c-Met for low-concentration, single-dose treatment of pancreatic cancer Spotlight 

(1) Ning W (2) Liu H (3) Zeng H (4) Qin X (5) Xu L (6) Yang S (7) Wang Y (8) Chen F (9) Yuan N (10) Chen X (11) Xu T (12) Wu K (13) Wang P (14) Liu C (15) Chen Y (16) Xia N (17) Liu X (18) Luo W

Cell reports. Medicine

To address limitations of pancreatic cancer treatment, Ning, Liu, Liu, Zeng, and Qin et al. developed an internalizing, nanobody-based, bispecific ADC (B6ADC) that simultaneously bound TROP2 and c-MET, and was conjugated to the microtubule cytotoxic inhibitor MMAE. B6ADC demonstrated broad spectrum activity in multiple pancreatic models, and outperformed clinically approved ADCs for TROP2 and c-MET, both alone and in combination. B6ADC showed improved tumor selectivity with dual-positive or weakly positive Ag expression, had a favorable safety profile, and eradicated large tumors at a single low dose of 2.2 mg/kg in several models.

Contributed by Katherine Turner

(1) Ning W (2) Liu H (3) Zeng H (4) Qin X (5) Xu L (6) Yang S (7) Wang Y (8) Chen F (9) Yuan N (10) Chen X (11) Xu T (12) Wu K (13) Wang P (14) Liu C (15) Chen Y (16) Xia N (17) Liu X (18) Luo W

Cell reports. Medicine

To address limitations of pancreatic cancer treatment, Ning, Liu, Liu, Zeng, and Qin et al. developed an internalizing, nanobody-based, bispecific ADC (B6ADC) that simultaneously bound TROP2 and c-MET, and was conjugated to the microtubule cytotoxic inhibitor MMAE. B6ADC demonstrated broad spectrum activity in multiple pancreatic models, and outperformed clinically approved ADCs for TROP2 and c-MET, both alone and in combination. B6ADC showed improved tumor selectivity with dual-positive or weakly positive Ag expression, had a favorable safety profile, and eradicated large tumors at a single low dose of 2.2 mg/kg in several models.

Contributed by Katherine Turner

ABSTRACT: Pancreatic cancer remains highly lethal with limited treatment options. Although antibody-drug conjugates (ADCs) have emerged as promising therapeutic agents, their efficacy is often limited by heterogeneous antigen expression and poor tumor penetration. To address these limitations, we develop B6ADC, a nanobody-based bispecific ADC that simultaneously targets TROP2 and c-Met. In preclinical studies, B6ADC exhibits potent cytotoxicity in vitro across various TROP2/c-Met-expressing cancer cell lines and superior tumor inhibition in vivo compared with single-target ADC combination, including the clinically approved TROP2 ADC sacituzumab govitecan and c-Met ADC Teliso-V, as well as their combination. Notably, B6ADC eradicates giant tumors with a single dose at a low concentration of 2.2 mg/kg. We present a nanobody-based BsADC that simultaneously targets TROP2 and c-Met, with broad-spectrum antitumor activity, and improves selectivity for tumors with dual-positive or weakly positive antigen expression, offering a promising strategy for treating pancreatic cancer and other TROP2/c-Met-expressing malignancies.

Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute

Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (2) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (3) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (4) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (5) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (6) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (7) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (8) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (9) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (10) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (11) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (13) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (14) State Key Laboratory of Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. (15) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: yuanzhichen@xmu.edu.cn. (16) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: nsxia@xmu.edu.cn. (17) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: liuxue1108@xmu.edu.cn. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: wxluo@xmu.edu.cn.

Citation: Cell Rep Med 2026 Mar 18 102688 Epub03/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41856115

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