Journal Articles

A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity Spotlight 

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

ABSTRACT: Cancer immunotherapies have achieved meaningful clinical benefit but remain limited by systemic toxicities that restrict the use of potent immune modulators. CD47-targeting antibodies promote tumor cell phagocytosis but are hindered by hematologic toxicity, while IL-2 activates cytotoxic lymphocytes but induces broad, dose-limiting immune activation. Here, we engineered a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) designed for tumor-selective activation. In this construct, a CD47-specific antibody (aCD47) and an IL-2/IL-2 receptor complex (IL2c) sterically and functionally suppress each other via protease-cleavable linkers, preventing CD47 blockade and IL-2 receptor engagement in circulation while enabling protease-dependent unmasking within the tumor microenvironment. A human construct demonstrated masking and protease-dependent restoration of both CD47-SIRP_ blockade and IL-2 signaling, with improved systemic tolerability in human hCD47/hSIRP_ transgenic mice, supporting translational potential. A murine analog enabled mechanistic and efficacy studies in immunocompetent tumor models. The tolerability of mouse aCD47/IL-2c was improved in comparison to individual components. Antitumor activity required both CD47 blockade and IL-2 activity, and resulted in a robust antitumor efficacy, including in an immune checkpoint-resistant melanoma model. The robust antitumor efficacy was associated with inflammatory macrophage polarization and increased numbers of effector CD8_ T cells inside the tumor. Unlike conventional CD47 antibodies or IL-2 therapies, this approach enabled coordinated, tumor-localized activation of innate and adaptive immunity while limiting systemic exposure. Together, these data highlight reciprocal masking as a clinically relevant strategy to expand the therapeutic index of immune modulators constrained by systemic toxicity.

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: http

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (3) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (4) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (5) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (6) Memorial Sloan Kettering Cancer Center New York City, New York United States. ROR: https://ror.org/02yrq0923 (7) Light Chain Bioscience. (8) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (9) Geneva Medical School Geneva Switzerland. (10) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (11) Light Chain Bioscience (Switzerland) Plan-les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132

Citation: Cancer Immunol Res 2026 Oct 5 Epub10/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42832640

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Bridging innate and adaptive immunity- A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance

Spotlight 

(1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

Cell reports. Medicine

Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

Contributed by Katherine Turner

(1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

Cell reports. Medicine

Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

Contributed by Katherine Turner

ABSTRACT: Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming-thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.

Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue,

Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (2) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (3) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (4) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (5) Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China. (6) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (7) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (8) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (9) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (10) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (11) Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: huax@pennmedicine.upenn.edu. (12) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: dianwenju@fudan.edu.cn. (13) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: xuyaozhang@fudan.edu.cn.

Citation: Cell Rep Med 2026 Oct 5 103087 Epub10/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42833217

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Antibodies against HLA-E-VL9 enhance NK cell and CD8+ T cell cytotoxicity against tumor cells and HIV-infected CD4+ T cells

Spotlight 

(1) Hwang JK (2) Tuyishime M (3) Marston DJ (4) Yang H (5) Wrapp D (6) Li D (7) Brackenridge S (8) Frazier M (9) Levering NP (10) Scearce R (11) Rhodes B (12) Harris C (13) Quastel M (14) Kapingidza AB (15) Kliszczak AE (16) Gater J (17) Borrow P (18) Ferrari G (19) Gillespie GM (20) McMichael AJ (21) Haynes BF (22) Azoitei ML

Science translational medicine

Hwang et al. engineered high-affinity antibodies against HLA-E–VL9 using structure-based design and high-throughput library screening to block inhibitory NKG2A/CD94 interactions. HLA-E–VL9 mAbs enhanced direct NK cell killing and NK-mediated ADCC against HLA-E–VL9+ tumors in vitro and K562HLA-E–VL9 tumors in vivo. HIV-infected primary CD4+ T cells expressed HLA-E–VL9, and HLA-E–VL9 mAbs mediated NK cell ADCC that selectively eliminated activated or infected CD4+ T cells over resting CD4+ T cells. HLA-E–VL9 blockade also enhanced NKG2A+CD8+ T cell-mediated HIV-specific cytotoxicity.

Contributed by Shishir Pant

(1) Hwang JK (2) Tuyishime M (3) Marston DJ (4) Yang H (5) Wrapp D (6) Li D (7) Brackenridge S (8) Frazier M (9) Levering NP (10) Scearce R (11) Rhodes B (12) Harris C (13) Quastel M (14) Kapingidza AB (15) Kliszczak AE (16) Gater J (17) Borrow P (18) Ferrari G (19) Gillespie GM (20) McMichael AJ (21) Haynes BF (22) Azoitei ML

Science translational medicine

Hwang et al. engineered high-affinity antibodies against HLA-E–VL9 using structure-based design and high-throughput library screening to block inhibitory NKG2A/CD94 interactions. HLA-E–VL9 mAbs enhanced direct NK cell killing and NK-mediated ADCC against HLA-E–VL9+ tumors in vitro and K562HLA-E–VL9 tumors in vivo. HIV-infected primary CD4+ T cells expressed HLA-E–VL9, and HLA-E–VL9 mAbs mediated NK cell ADCC that selectively eliminated activated or infected CD4+ T cells over resting CD4+ T cells. HLA-E–VL9 blockade also enhanced NKG2A+CD8+ T cell-mediated HIV-specific cytotoxicity.

Contributed by Shishir Pant

ABSTRACT: A major natural killer (NK) cell and CD8(+) T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, human leukocyte antigen E (HLA-E) complexed with nine-amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high-throughput library screening to generate high-affinity antibodies that block NKG2A/CD94 interactions. These antibodies enabled direct NK and CD8(+) T cell cytotoxicity and mediated NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies enhanced human NK cell line NK-92 killing of HLA-E-VL9(+) human tumors in mice, demonstrating checkpoint inhibition activity in vivo. Moreover, HLA-E-VL9 was found to be expressed on primary human CD4(+) T cells infected with HIV in vitro, and its engagement by HLA-E-VL9 antibodies drove elimination of infected cells by NK cell-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94(+) CD8(+) T cells targeting an HIV Rev-derived epitope that complexes with HLA-E. Therefore, anti-HLA-E-VL9 antibodies represent a candidate therapeutic approach to eliminating pathogenic target cells by enhancing both NK cell and CD8(+) T cell function and by promoting ADCC.

Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department o

Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (3) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (4) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (5) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (6) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (7) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (8) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (9) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (10) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (11) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (12) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (13) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (14) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. (15) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (16) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (17) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (18) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (19) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (20) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (21) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA. (22) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.

Citation: Sci Transl Med 2026 Sep 16 18:eaea3879 Epub09/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42748220

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Identification of broadly tumour-reactive γδ TCRs from multiple myeloma

Spotlight 

(1) St Paul M (2) Hendrikse LD (3) Ying F (4) Snow BE (5) Luo P (6) Helke S (7) Smith LK (8) Hilal A (9) Abelman DD (10) Ramamurthy N (11) Nault H (12) Wei EN (13) Gold MJ (14) Tobin C (15) Lien SC (16) Liu Y (17) Zhou W (18) Zhang X (19) Nguyen D (20) Agbede O (21) Pedersen S (22) Eagles J (23) Saunders ME (24) Berger T (25) Wakeham A (26) Scott DS (27) Ly D (28) de Campos CB (29) Liang G (30) Zheng C (31) Wilson WV (32) Masih-Khan E (33) White D (34) McCurdy A (35) Louzada ML (36) Kotb R (37) Chu MP (38) Parkin S (39) Reece D (40) Gul E (41) Tiedemann R (42) Pugh TJ (43) Hirano N (44) Ohashi PS (45) Stewart AK (46) Trudel S (47) Mak TW

Nature

St. Paul and Hendrikse et al. used single-cell sequencing and developed a machine-learning algorithm (PreGame) to distinguish the enigmatic tumor-reactive γδ T cells (TRγδ T cells) from bystander cells and confirm their specificity. From MM patient bone marrow, PreGame identified TRγδ T cells that recognized broadly expressed tumor antigens in a TCR-dependent manner. Responsive patients treated with a BCMA-targeted ADC exhibited significant expansion of TRγδ T cells and of γδ TCRs in cfDNA, which correlated with favorable responses and served as an early response biomarker. A γδ TCR epitope in the ubiquitously expressed HLA-C protein was identified.

Contributed by Katherine Turner

(1) St Paul M (2) Hendrikse LD (3) Ying F (4) Snow BE (5) Luo P (6) Helke S (7) Smith LK (8) Hilal A (9) Abelman DD (10) Ramamurthy N (11) Nault H (12) Wei EN (13) Gold MJ (14) Tobin C (15) Lien SC (16) Liu Y (17) Zhou W (18) Zhang X (19) Nguyen D (20) Agbede O (21) Pedersen S (22) Eagles J (23) Saunders ME (24) Berger T (25) Wakeham A (26) Scott DS (27) Ly D (28) de Campos CB (29) Liang G (30) Zheng C (31) Wilson WV (32) Masih-Khan E (33) White D (34) McCurdy A (35) Louzada ML (36) Kotb R (37) Chu MP (38) Parkin S (39) Reece D (40) Gul E (41) Tiedemann R (42) Pugh TJ (43) Hirano N (44) Ohashi PS (45) Stewart AK (46) Trudel S (47) Mak TW

Nature

St. Paul and Hendrikse et al. used single-cell sequencing and developed a machine-learning algorithm (PreGame) to distinguish the enigmatic tumor-reactive γδ T cells (TRγδ T cells) from bystander cells and confirm their specificity. From MM patient bone marrow, PreGame identified TRγδ T cells that recognized broadly expressed tumor antigens in a TCR-dependent manner. Responsive patients treated with a BCMA-targeted ADC exhibited significant expansion of TRγδ T cells and of γδ TCRs in cfDNA, which correlated with favorable responses and served as an early response biomarker. A γδ TCR epitope in the ubiquitously expressed HLA-C protein was identified.

Contributed by Katherine Turner

ABSTRACT: γδ T cells are becoming increasingly appreciated for their antitumour capacity and role in mediating responses to immune checkpoint blockade1-3. Unlike classical αβ T cells, the degree to which γδ T cells rely on their T cell receptors (TCRs) to induce antitumour responses remains unclear. The challenge of distinguishing γδ T cells with tumour-reactive TCRs from bystander γδ T cells limits our understanding of tumour-reactive γδ T cell biology and the translation of their TCRs into immunotherapeutics. Here we present PreGame, a machine-learning algorithm capable of identifying tumour-reactive γδ T cells from single-cell CITE sequencing data. We use PreGame to identify tumour-reactive γδ T cells from patients with multiple myeloma or other solid cancers, and confirm the specificity of their TCRs to tumour cells. Clinically, we demonstrate that expansion of tumour-reactive γδ T cells is an early biomarker of response in patients with multiple myeloma receiving combination therapy with belantamab mafodotin. We also identify a γδ TCR epitope in the ubiquitously expressed HLA-C protein and a logic gate that enables tumour immunosurveillance. Thus, PreGame is a versatile tool that can accelerate our understanding of γδ T cell biology and facilitate the translation of γδ TCRs into universal therapeutics.

Author Info: (1) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. michael.stpaul@uhn.ca. (2) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. liam.hendrikse@uhn.ca. (3) Prin

Author Info: (1) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. michael.stpaul@uhn.ca. (2) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. liam.hendrikse@uhn.ca. (3) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (4) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (5) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Computer Science and Mathematics, Faculty of Computer Science and Technology, Algoma University, Brampton, Ontario, Canada. (6) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (7) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (8) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (9) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (10) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (11) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (12) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (13) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (14) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (15) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (16) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (17) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (18) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (19) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (20) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (21) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (22) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (23) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (24) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (25) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (26) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (27) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (28) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (29) Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. (30) Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. (31) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (32) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (33) Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada. (34) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (35) London Health Sciences Centre, London, Ontario, Canada. (36) CancerCare Manitoba, Winnipeg, Manitoba, Canada. (37) Cross Cancer Institute, Edmonton, Alberta, Canada. (38) Vancouver General Hospital, Vancouver, British Columbia, Canada. (39) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (40) Canadian Myeloma Research Group (CMRG), Vaughan, Ontario, Canada. (41) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (42) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. (43) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (44) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (45) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (46) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. suzanne.trudel@uhn.ca. (47) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. tak.mak@uhn.ca. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. tak.mak@uhn.ca. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. tak.mak@uhn.ca.

Citation: Nature 2026 Sep 16 Epub09/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42749802

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Intratumoral injection of EpCAM BITE, IL-12, and GM-CSF mRNA-LNPs blocks the growth of local treated and distant untreated tumors Spotlight 

(1) Golubovskaya V (2) Hu L (3) Zhang S (4) Sienkiewicz J (5) Zhou H (6) Berahovich R (7) Sun J (8) Li L (9) Bodmer W (10) Wu L

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Golubovskaya et al. showed that intratumoral delivery of an anti-human EpCAM-CD3 BiTE mRNA-LNP stops growth of only directly injected EpCAM+ human tumor xenografts in immuno-incompetent mice (with i.v. human T cells). When added to the BiTE-LNPs, IL-12+GM-CSF led to control of both injected and distal tumors. Combined treatment increased the expansion of injected human T cells, expression of T cell cytolysis pathway genes, and HLA class II- and APC-associated gene expression in tumors. In blood, GM-CSF, IL-12, and the BiTE peaked between 4 and 72 hrs post-delivery, and were minimally expressed in normal tissues.

Contributed by Paula Hochman

(1) Golubovskaya V (2) Hu L (3) Zhang S (4) Sienkiewicz J (5) Zhou H (6) Berahovich R (7) Sun J (8) Li L (9) Bodmer W (10) Wu L

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Golubovskaya et al. showed that intratumoral delivery of an anti-human EpCAM-CD3 BiTE mRNA-LNP stops growth of only directly injected EpCAM+ human tumor xenografts in immuno-incompetent mice (with i.v. human T cells). When added to the BiTE-LNPs, IL-12+GM-CSF led to control of both injected and distal tumors. Combined treatment increased the expansion of injected human T cells, expression of T cell cytolysis pathway genes, and HLA class II- and APC-associated gene expression in tumors. In blood, GM-CSF, IL-12, and the BiTE peaked between 4 and 72 hrs post-delivery, and were minimally expressed in normal tissues.

Contributed by Paula Hochman

ABSTRACT: We have previously shown that a T cell engaging bispecific humanized anti-human EpCAM-CD3 antibody efficiently kills a human EpCAM positive human xenograft in an NSG partially humanized mouse injected intravenously with human T cells when the anti-EpCAM-CD3 was delivered intratumorally as an mRNA-LNP. To extend these results we tested the effects of combining the anti-human EpCAM-CD3 with various cytokines injected into a tumor on the left side of NSG mice and an uninjected tumor on the right side of the mice. Combining both IL-12 and GM-CSF with anti-EpCAM-CD3 increased the number of T cells and the expression of genes and pathways that mediated T cell-based killing in the neighborhood of both the injected and the uninjected tumor and substantial increases in the expression of HLA Class II and associated genes in both tumors. This turned the cancer cells into potentially antigen-presenting cells. The effect of combining intratumoral injection of anti-EpCAM-CD3 with cytokines IL-12 and GM-CSF on tumor growth distal to the injection site avoids serious side effects on normal tissue, and suggests this technology offers a major approach to immunotherapy for treatment of a wide range of cancers from early to severe late stages.

Author Info: (1) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (2) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (3) Promab Biotechnologies

Author Info: (1) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (2) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (3) Promab Biotechnologies, Richmond, CA 94564. (4) Promab Biotechnologies, Richmond, CA 94564. (5) Promab Biotechnologies, Richmond, CA 94564. (6) Promab Biotechnologies, Richmond, CA 94564. (7) Promab Biotechnologies, Richmond, CA 94564. (8) IntraAb, Richmond, CA 94564. (9) Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom. ROR: https://ror.org/052gg0110 (10) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564.

Citation: Proc Natl Acad Sci U S A 2026 Sep 8 123:e2616059123 Epub09/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42696537

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Enfortumab vedotin induces immunogenic cell death and shows enhanced preclinical antitumor activity when combined with a PD-1 inhibitor Featured  

(1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

Cell reports. Medicine

Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

(1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

Cell reports. Medicine

Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

ABSTRACT: Enfortumab vedotin is a Nectin-4-directed antibody-drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4-positive tumor cells, indirect bystander effect on neighboring Nectin-4-negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells results in protection against tumor rechallenge in mice, consistent with antitumor immunity. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical findings provide mechanistic hypotheses that may be relevant to the improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy.

Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer,

Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer, Inc., Bothell, WA 98021, USA. (6) Pfizer, Inc., Bothell, WA 98021, USA. (7) Pfizer, Inc., Bothell, WA 98021, USA. (8) Seagen, Inc., Bothell, WA 98021, USA. (9) Pfizer, Inc., Bothell, WA 98021, USA. (10) Pfizer, Inc., Bothell, WA 98021, USA. (11) Pfizer, Inc., Bothell, WA 98021, USA. (12) Seagen, Inc., Bothell, WA 98021, USA. (13) Seagen, Inc., Bothell, WA 98021, USA. (14) Pfizer, Inc., Bothell, WA 98021, USA. (15) Pfizer, Inc., Bothell, WA 98021, USA. (16) Seagen, Inc., Bothell, WA 98021, USA. (17) Seagen, Inc., Bothell, WA 98021, USA. (18) Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. (19) Astellas Research Institute of America LLC, Northbrook, IL 60062, USA. (20) Pfizer, Inc., Bothell, WA 98021, USA. (21) Pfizer, Inc., Bothell, WA 98021, USA. (22) Pfizer, Inc., Bothell, WA 98021, USA. Electronic address: sharsti.sandall@pfizer.com.

Citation: Cell Rep Med 2026 Sep 2 103021 Epub09/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42685702

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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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