Journal Articles

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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Engineering CAR T cells to secrete VEGF-neutralizing scFvs enhances antitumor activity against solid tumors Spotlight 

(1) Gao TA (2) Shih RM (3) Clubb JD (4) Hung SH (5) Singh T (6) James-Allan LB (7) DiBernardo G (8) Shafer A (9) Bouren A (10) Ayala Ceja M (11) Ong S (12) Ball AB (13) Divakaruni AS (14) Memarzadeh S (15) Wu HC (16) Chen YY

Science translational medicine

To improve anti-angiogenic therapies in VEGF-overexpressing solid tumors, Gao et al. engineered CAR T cells to secrete anti-VEGF scFvs (CAR-αVEGF T cells) and compared their efficacy with standard CAR T cell therapy alone or combined with anti-VEGF Ab. αVEGF-scFv secretion resulted in superior CAR T cell efficacy in ovarian cancer and orthotopic glioma models. Mechanistically, CAR-αVEGF T cells prevented treatment-induced angiogenesis and hypoxia, promoted CD8+ T cell activation and mitochondrial fitness, and boosted immune-stimulatory myeloid phenotypes, while decreasing infiltration of suppressive, VEGF-expressing myeloid cells.

Contributed by Katherine Turner

(1) Gao TA (2) Shih RM (3) Clubb JD (4) Hung SH (5) Singh T (6) James-Allan LB (7) DiBernardo G (8) Shafer A (9) Bouren A (10) Ayala Ceja M (11) Ong S (12) Ball AB (13) Divakaruni AS (14) Memarzadeh S (15) Wu HC (16) Chen YY

Science translational medicine

To improve anti-angiogenic therapies in VEGF-overexpressing solid tumors, Gao et al. engineered CAR T cells to secrete anti-VEGF scFvs (CAR-αVEGF T cells) and compared their efficacy with standard CAR T cell therapy alone or combined with anti-VEGF Ab. αVEGF-scFv secretion resulted in superior CAR T cell efficacy in ovarian cancer and orthotopic glioma models. Mechanistically, CAR-αVEGF T cells prevented treatment-induced angiogenesis and hypoxia, promoted CD8+ T cell activation and mitochondrial fitness, and boosted immune-stimulatory myeloid phenotypes, while decreasing infiltration of suppressive, VEGF-expressing myeloid cells.

Contributed by Katherine Turner

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-_VEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-_VEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-_VEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.

Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Ge

Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. (3) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (4) Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115201, Taiwan. (5) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (6) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (7) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (12) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (13) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (14) Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. VA Greater Los Angeles Healthcare System, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. (15) Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115201, Taiwan. (16) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA 90095, USA.

Citation: Sci Transl Med 2026 Mar 4 18:eadw9286 Epub03/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41779870

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DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity

Spotlight 

(1) Stockmann AP (2) Vincent S (3) Herschelman L (4) Huang CS (5) Ma J (6) Fallon D (7) Kirby P (8) Gutierrez E (9) Talbot D (10) Hicks SW (11) Wagtmann N (12) Cheung AF

Cell reports. Medicine

Stockmann et al. engineered DF6215, comprised of two truncated IgG1 Fc chains (which bind FcRn, but not FcγR) fused at one Fc C terminus to an IL-2 mutein with reduced IL-2Rα (modest) and IL-2Rαβγ (23-fold) binding, increased IL-2Rβ binding (3.5-fold), and enhanced IL-2Rβγ signaling compared to WT IL-2. DF6215 preferentially expanded murine tumor-infiltrating CD8+ T and NK cells over Tregs, induced robust dose-dependent regression of solid tumors as monotherapy, and synergized with anti-PD-1. In NHPs, DF6215 showed an extended serum half-life and favorable safety and pharmacodynamics relative to aldesleukin. DF6215 is now in Phase 1/2 testing.

Contributed by Paula Hochman

(1) Stockmann AP (2) Vincent S (3) Herschelman L (4) Huang CS (5) Ma J (6) Fallon D (7) Kirby P (8) Gutierrez E (9) Talbot D (10) Hicks SW (11) Wagtmann N (12) Cheung AF

Cell reports. Medicine

Stockmann et al. engineered DF6215, comprised of two truncated IgG1 Fc chains (which bind FcRn, but not FcγR) fused at one Fc C terminus to an IL-2 mutein with reduced IL-2Rα (modest) and IL-2Rαβγ (23-fold) binding, increased IL-2Rβ binding (3.5-fold), and enhanced IL-2Rβγ signaling compared to WT IL-2. DF6215 preferentially expanded murine tumor-infiltrating CD8+ T and NK cells over Tregs, induced robust dose-dependent regression of solid tumors as monotherapy, and synergized with anti-PD-1. In NHPs, DF6215 showed an extended serum half-life and favorable safety and pharmacodynamics relative to aldesleukin. DF6215 is now in Phase 1/2 testing.

Contributed by Paula Hochman

ABSTRACT: DF6215 is a rationally engineered interleukin-2 (IL-2) Fc-fusion protein developed to overcome efficacy and safety limitations of traditional IL-2 cancer immunotherapy. Unlike non-alpha (non-α) IL-2 variants that eliminate CD25 binding and underperform clinically, DF6215 retains moderate IL-2 receptor α (IL-2Rα) affinity while enhancing IL-2Rβγ signaling and extending the half-life via an engineered immunoglobulin (Ig)G1 Fc domain. This design preferentially expands cytotoxic CD8+ T cells and natural killer cells over regulatory T cells, resulting in favorable effector-to-regulatory cell ratios, enhanced immune activation, and robust tumor regression in mouse models. In poorly immunogenic tumors, DF6215 synergized with PD-1 blockade to achieve durable responses without added toxicity. Cynomolgus monkey studies confirm DF6215's pharmacodynamics and favorable safety profile, with no signs of vascular leak syndrome or cytokine release syndrome. These findings position DF6215 as a differentiated IL-2 capable of modulating the tumor microenvironment and achieving potent anti-tumor immunity with improved tolerability, supporting its advancement into clinical trials for solid tumors.

Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dr

Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (5) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (6) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (7) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (8) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (9) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (10) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (11) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (12) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. Electronic address: ann.cheung@dragonflytx.com.

Citation: Cell Rep Med 2025 Dec 29 102518 Epub12/29/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41468896

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mRNA-engineered T lymphocytes secreting bispecific T cell engagers with therapeutic potential in solid tumors

(1) Zagorac I (2) Ram’rez-Fern‡ndez ç (3) Tapia-Galisteo A (4) Rubio-PŽrez L (5) G—mez-Rosel M (6) Grau M (7) Rodr’guez-Peralto JL (8) çlvarez-Vallina L (9) Blanco B

Frontiers in immunology | Free PMC Article

(1) Zagorac I (2) Ram’rez-Fern‡ndez ç (3) Tapia-Galisteo A (4) Rubio-PŽrez L (5) G—mez-Rosel M (6) Grau M (7) Rodr’guez-Peralto JL (8) çlvarez-Vallina L (9) Blanco B

Frontiers in immunology | Free PMC Article

BACKGROUND: In the last decade, chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of hematologic malignancies. However, antitumor responses in solid tumors remain poor, and the difficulty in finding truly tumor-specific target antigens leads to a high risk of on-target/off-tumor toxicity. Transient modification with mRNA is gaining momentum as an alternative approach to viral transduction in order to achieve a better safety profile. On the other hand, generation of T cells secreting bispecific T cell engagers (TCEs) has been reported to outperform the antitumor efficacy of T lymphocytes expressing membrane-anchored CARs, due to the ability of the soluble TCEs to recruit unmodified bystander T cells. METHODS: We have electroporated human primary T cells with in vitro transcribed mRNA encoding an anti-EGFR x anti-CD3 bispecific T cell engager. Such mRNA-modified T cells (STAR(EGFR)-T cells) have been analyzed for anti-EGFR bispecific TCE secretion and for their ability to drive anti-tumor responses against EGFR-expressing cells, both in vitro and in vivo. RESULTS: STAR(EGFR)-T cells transiently secrete bispecific TCEs capable of redirecting T lymphocytes to exert tumor cell-specific killing in in vitro assays. Moreover, STAR(EGFR)-T cells efficiently control tumor growth in in vivo xenograft models of solid malignancy. CONCLUSIONS: Our results strongly support mRNA-engineered TCE-secreting T cells as a promising therapeutic strategy for solid tumors.

Author Info: (1) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n San

Author Info: (1) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (2) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. (3) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (4) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (5) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. (6) Animal Facility, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. (7) Department of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain. Department of Pathology, Universidad Complutense, Madrid, Spain. Cutaneous Oncology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red en Oncolog’a (CIBERONC), Madrid, Spain. (8) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. Banc de Sang i Teixits, Barcelona, Spain. (9) Cancer Immunotherapy Unit, Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), Madrid, Spain. Centro Nacional de Investigaciones Oncol—gicas-Hospital del Mar Research Institute Barcelona (CNIO-HMRIB) Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncol—gicas (CNIO), Madrid, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain.

Citation: Front Immunol 2025 16:1684655 Epub11/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41341587

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Structural mechanism of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity

(1) Margulies D (2) Jiang J (3) Panda A (4) Natarajan K (5) Lei H (6) Sharma S (7) Boyd L (8) Towler R (9) Chempati S (10) Ahmad J (11) Morton A (12) Lang Z (13) Sun Y (14) Sgourakis N (15) Meier-Schellersheim M (16) Huang R (17) Shevach E

Research square | Free PMC Article

(1) Margulies D (2) Jiang J (3) Panda A (4) Natarajan K (5) Lei H (6) Sharma S (7) Boyd L (8) Towler R (9) Chempati S (10) Ahmad J (11) Morton A (12) Lang Z (13) Sun Y (14) Sgourakis N (15) Meier-Schellersheim M (16) Huang R (17) Shevach E

Research square | Free PMC Article

Anti-major histocompatibility complex class I (MHC-I) mAbs can stimulate immune responses to tumors and infections by blocking suppressive signals delivered via various immune inhibitory receptors. To understand such functions, we determined the structure of a highly cross-reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural models determined by the two methods were essentially identical revealing that B1.23.2 binds a conserved region on the _21 helix that overlaps the killer immunoglobulin-like receptor (KIR) binding site. Structural comparison to KIR/HLA complexes reveals a mechanism by which B1.23.2 blocks inhibitory receptor interactions, leading to natural killer (NK) cell activation. B1.23.2 treatment of the human KLM-1 pancreatic cancer model in humanized (NSG-IL15) mice provides evidence of suppression of tumor growth. Such anti-MHC-I mAb that block inhibitory KIR/HLA interactions may prove useful for tumor immunotherapy.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17)

Citation: Res Sq 2025 Oct 31 Epub10/31/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41333432

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Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy

(1) Wong JKM (2) Lam PY (3) Coleborn E (4) Jose J (5) Alim L (6) Tu C (7) Antczak M (8) Dietmair B (9) Hagh AG (10) Noronha L (11) Cheetham SW (12) Hooper J (13) Beavis PA (14) Merino D (15) Berthelet J (16) Aoude LG (17) McCart-Reed AE (18) Lakhani S (19) Simpson PT (20) Rossi GR (21) Brooks AJ (22) Jones ML (23) Simpson F (24) Souza-Fonseca-Guimaraes F

Molecular therapy

(1) Wong JKM (2) Lam PY (3) Coleborn E (4) Jose J (5) Alim L (6) Tu C (7) Antczak M (8) Dietmair B (9) Hagh AG (10) Noronha L (11) Cheetham SW (12) Hooper J (13) Beavis PA (14) Merino D (15) Berthelet J (16) Aoude LG (17) McCart-Reed AE (18) Lakhani S (19) Simpson PT (20) Rossi GR (21) Brooks AJ (22) Jones ML (23) Simpson F (24) Souza-Fonseca-Guimaraes F

Molecular therapy

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an emerging target in cancer immunotherapy, recognized for its consistent and elevated expression across several epithelial tumors, including triple-negative breast cancer (TNBC). TNBC is an aggressive and difficult-to-treat cancer, with limited effective therapeutic options currently available. Therapeutic approaches centered on targeting ROR1 have therefore become increasingly popular, with ROR1 chimeric antigen receptor (CAR) T cells currently in clinical trials to treat TNBC patients. While ROR1-targeting therapies have shown promising preclinical results, single arm treatment has often shown low efficacy as well as off-target toxicity. Natural killer (NK) cell-based immunotherapies, such as antibody-dependent cell cytotoxicity-inducing monoclonal antibodies and CAR NK cells, have also been shown to induce cancer cell cytotoxicity; however, with less toxicity compared with CAR T cells. Here, we developed and characterized a phage-derived single-chain fragment variable (scFv) against a highly specific ROR1 region and generated scFv-derived chimeric monoclonal antibodies and anti-ROR1-CAR NK cells, which show anti-cancer efficacy against TNBC cells. Additionally, we found TGF-_ inhibition using either small-molecule inhibitors or CRISPR-Cas9-edited NK cells could further enhance ROR1-targeting therapy persistence and efficacy in controlling TNBC tumor growth.

Author Info: (1) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (2) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (3)

Author Info: (1) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (2) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (3) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (4) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (5) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (6) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (7) Queensland Cyber Infrastructure Foundation Ltd (QCIF) Bioinformatics, Brisbane, QLD 4072, Australia. (8) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia; BASE Facility, University of Queensland, St Lucia, QLD 4067, Australia. (9) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia. (10) Laborat—rio de Patologia Experimental, Curitiba, Queensland 80215-901, Brazil. (11) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia; BASE Facility, University of Queensland, St Lucia, QLD 4067, Australia. (12) Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia. (15) Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia. (16) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (17) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia. (18) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia. (19) UQ Centre for Clinical Research, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Herston, QLD 4029, Australia; School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Saint Lucia, QLD 4067, Australia. (20) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (21) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; School of Science & Technology, University of New England, Armidale NSW 2351, Australia. (22) Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4067, Australia. (23) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. (24) Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia. Electronic address: f.guimaraes@uq.edu.au.

Citation: Mol Ther 2025 Dec 2 Epub12/02/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41338184

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