Innovative Methods - ACIR Journal Articles

TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors

(1) Eggeb¿ MS (2) Heinzelbecker J (3) Palashati H (4) Chandler N (5) Tran TT (6) Li Y (7) Yang W (8) Laos M (9) Blaas I (10) Rustad EH (11) Bollineni RC (12) Delic-Sarac M (13) Lund-Johansen F (14) Nielsen MM (15) Olweus J

Nature immunology

CTNNB1^S37F (CTNNB1^WT encodes β-catenin) is a driver mutation found across solid tumors. Using an HLA⁺ cell line transduced with CTNNB1^S37F, Eggebø et al. used MS to identify two HLA-bound neopeptides that were also expressed naturally on CTNNB1^S37F⁺ tumor cells. Priming naive CD8⁺ T cells with these neoantigens identified 4 reactive TCRs that were highly specific, recognizing CTNNB1^S37F with pM-nM affinity, but not CTNNB1^WT or similar off-target peptides. TCR T cells expressing these TCRs eliminated patient-derived tumor organoids in vitro, and effectively treated CTNNB1^S37F⁺ melanoma and PDX endometrial adenocarcinoma in vivo.

Contributed by Alex Najibi

(1) Eggeb¿ MS (2) Heinzelbecker J (3) Palashati H (4) Chandler N (5) Tran TT (6) Li Y (7) Yang W (8) Laos M (9) Blaas I (10) Rustad EH (11) Bollineni RC (12) Delic-Sarac M (13) Lund-Johansen F (14) Nielsen MM (15) Olweus J

Nature immunology

CTNNB1^S37F (CTNNB1^WT encodes β-catenin) is a driver mutation found across solid tumors. Using an HLA⁺ cell line transduced with CTNNB1^S37F, Eggebø et al. used MS to identify two HLA-bound neopeptides that were also expressed naturally on CTNNB1^S37F⁺ tumor cells. Priming naive CD8⁺ T cells with these neoantigens identified 4 reactive TCRs that were highly specific, recognizing CTNNB1^S37F with pM-nM affinity, but not CTNNB1^WT or similar off-target peptides. TCR T cells expressing these TCRs eliminated patient-derived tumor organoids in vitro, and effectively treated CTNNB1^S37F⁺ melanoma and PDX endometrial adenocarcinoma in vivo.

Contributed by Alex Najibi

ABSTRACT: HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy.

Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department

Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (3) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (4) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (5) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. (6) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (7) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (8) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (9) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (10) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (11) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (12) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (13) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. fridtjl@medisin.uio.no. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. fridtjl@medisin.uio.no. (14) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. m.m.nielsen@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. m.m.nielsen@medisin.uio.no. (15) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no.

Citation: Nat Immunol 2025 Aug 27 Epub08/27/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40866620

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Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma

(1) Yang J (2) Wang C (3) Fu D (4) Ho LL (5) Galani K (6) Chen L (7) Gonzalez J (8) Fu J (9) Huang AY (10) Frederick DT (11) He L (12) Asnani M (13) Tacke R (14) Robitschek EJ (15) Yadav SK (16) Deng W (17) Burke KP (18) Sharova T (19) Sullivan RJ (20) Weiss S (21) Rai K (22) Liu D (23) Boland GM (24) Kellis M

Nature communications - Open Access | Free PMC Article

Yang, Wang, and Fu et al. profiled 15 responding and 21 non-responding metastatic melanoma tumors and identified 14 cell types and 55 subtypes, including a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC); correlation analysis identified six cellular programs. Higher relative abundance of mregDCs predicted responses to ICI treatment, which was validated in an independent ICI-treated cohort. High mregDC and TCF7⁺ CD8⁺ T cell proportions stratified patients’ survival across treatments. Transcriptional, epigenetic, and interactome analysis revealed unique immune-stimulatory and regulatory roles of mregDCs.

Contributed by Shishir Pant

(1) Yang J (2) Wang C (3) Fu D (4) Ho LL (5) Galani K (6) Chen L (7) Gonzalez J (8) Fu J (9) Huang AY (10) Frederick DT (11) He L (12) Asnani M (13) Tacke R (14) Robitschek EJ (15) Yadav SK (16) Deng W (17) Burke KP (18) Sharova T (19) Sullivan RJ (20) Weiss S (21) Rai K (22) Liu D (23) Boland GM (24) Kellis M

Nature communications - Open Access | Free PMC Article

Yang, Wang, and Fu et al. profiled 15 responding and 21 non-responding metastatic melanoma tumors and identified 14 cell types and 55 subtypes, including a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC); correlation analysis identified six cellular programs. Higher relative abundance of mregDCs predicted responses to ICI treatment, which was validated in an independent ICI-treated cohort. High mregDC and TCF7⁺ CD8⁺ T cell proportions stratified patients’ survival across treatments. Transcriptional, epigenetic, and interactome analysis revealed unique immune-stimulatory and regulatory roles of mregDCs.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet most patients fail to achieve durable responses. To better understand the tumor microenvironment (TME), we analyze single-cell RNA-seq (~189_K cells) from 36 metastatic melanoma samples, defining 14 cell types, 55 subtypes, and 15 transcriptional hallmarks of malignant cells. Correlations between cell subtype proportions reveal six distinct clusters, with a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC) linked to naive T and B cells. Importantly, mregDC abundance predicts progression-free survival (PFS) with ICIs and other therapies, especially when combined with the TCF7_+_/- CD8 T cell ratio. Analysis of an independent cohort (n_=_318) validates mregDC as a predictive biomarker for anti-CTLA-4 plus anti-PD-1 therapies. Further characterization of mregDCs versus conventional dendritic cells (cDC1/cDC2) highlights their unique transcriptional, epigenetic (single-nucleus ATAC-seq data for cDCs from 14 matched samples), and interaction profiles, offering new insights for improving immunotherapy response and guiding future combination treatments.

Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard,

Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. jackie.yang@rutgers.edu. Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. (2) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (8) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Division of Medical Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (11) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (13) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (15) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (18) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA. Division of Hematology and Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (20) Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ, USA. (21) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. GMBOLAND@MGH.HARVARD.EDU. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. GMBOLAND@MGH.HARVARD.EDU. (24) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. manoli@mit.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. manoli@mit.edu.

Citation: Nat Commun 2025 Sep 1 16:8151 Epub09/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40890106

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A novel CD3ε fusion receptor allows T cell engager use in TCR-less allogeneic CAR T cells to improve activity and prevent antigen escape

(1) Lu D (2) Chu HY (3) Park S (4) Landon M (5) Tsuda M (6) Avramis E (7) Dege C (8) Dailey T (9) Pan Y (10) Hanok SK (11) Denholtz M (12) Abujarour R (13) Lee T (14) Goulding J (15) Hosking M (16) Goodridge J (17) Peralta E (18) Valamehr B

Molecular therapy | Free PMC Article

TCR KO supports allogeneic CAR T cells, but also results in CD3 antigen loss from the cell surface. Lu et al. engineered a CD3ε fusion receptor (CD3FR) that could be expressed on TCR- cells and engaged with T cell engagers (TCEs) for T cell signaling and activation. Via CAR and TCEs, iPSC-derived TCR^- CD3FR⁺ CAR T cells could target one or multiple tumor antigens to improve cytotoxicity over control CAR T cells in vitro (especially at low E:T and with repeated stimulation) and in vivo, including against heterogeneous tumors. CD3FR⁺ CAR T cells secreting TCEs showed enhanced cytotoxicity and engaged bystander T cells. The CD3FR-TCE strategy also improved CAR iNK cell efficacy.

Contributed by Alex Najibi

(1) Lu D (2) Chu HY (3) Park S (4) Landon M (5) Tsuda M (6) Avramis E (7) Dege C (8) Dailey T (9) Pan Y (10) Hanok SK (11) Denholtz M (12) Abujarour R (13) Lee T (14) Goulding J (15) Hosking M (16) Goodridge J (17) Peralta E (18) Valamehr B

Molecular therapy | Free PMC Article

TCR KO supports allogeneic CAR T cells, but also results in CD3 antigen loss from the cell surface. Lu et al. engineered a CD3ε fusion receptor (CD3FR) that could be expressed on TCR- cells and engaged with T cell engagers (TCEs) for T cell signaling and activation. Via CAR and TCEs, iPSC-derived TCR^- CD3FR⁺ CAR T cells could target one or multiple tumor antigens to improve cytotoxicity over control CAR T cells in vitro (especially at low E:T and with repeated stimulation) and in vivo, including against heterogeneous tumors. CD3FR⁺ CAR T cells secreting TCEs showed enhanced cytotoxicity and engaged bystander T cells. The CD3FR-TCE strategy also improved CAR iNK cell efficacy.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in treating hematologic malignancies. However, heterogeneous target antigen expression can impair the durability of response. Combining CAR and T cell engagers (TCEs) targeting additional tumor antigens can address tumor heterogeneity and antigen escape. In allogeneic settings, eliminating the T cell receptor (TCR) of the adoptive T cell therapy prevents graft-versus-host disease. However, the absence of TCR leads to loss of surface CD3 expression, preventing cooperative activity with CD3-directed TCEs. We utilized induced pluripotent stem cells (iPSCs) to support the required multiplexed editing, establish a renewable starting material for off-the-shelf manufacture, and create the desired TCR-less CAR+ CD3+ T cells. Here, we illustrate surface expression of a CD3ε fusion receptor (CD3FR) in iPSC-derived CAR T (CAR iT) cells, enabling TCE-mediated targeting of diverse antigens. In vitro and in vivo, CD3FR+ CAR iT cells demonstrated potent cytotoxic response and cooperative activity against mixed tumor lines and multiple antigens. CD3FR+ iT cells were further engineered to secrete TCEs, eliminating the need for extra supplementation with TCEs. Collectively, the data highlight the ability to integrate TCEs with allogeneic CAR iT cells for multi-antigen targeting, overcoming tumor relapse, and supporting off-the-shelf therapy for patient access.

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therap

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (5) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (6) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (7) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (8) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (9) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (10) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (11) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (12) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (13) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (14) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (15) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (16) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (17) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: eigen.peralta@fatetherapeutics.com. (18) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: bob.valamehr@fatetherapeutics.com.

Citation: Mol Ther 2025 Sep 3 33:4570-4583 Epub05/28/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40443031

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Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors

(1) Abrantes R (2) Forcados C (3) Warren DJ (4) Santos-Ferreira L (5) Fleten KG (6) Senra E (7) Costa AF (8) Krpina K (9) Henrique R (10) Liberg AM (11) Rawat P (12) Gelebart P (13) McCormack E (14) Bj¿rge L (15) Davidson B (16) Greiff V (17) Costea DE (18) Pinto F (19) Flatmark K (20) Gomes C (21) Inderberg EM (22) Reis CA (23) Wlchli S

Cell reports. Medicine - Open Access

Abrantes and Forcados et al. generated and characterized AM52.1, a pan-carcinoma antibody with exclusive specificity for a truncated O-glycan structure Sialyl-Tn antigen (STn), which is found on various epithelial tumors, but not healthy tissues, and is associated with adverse outcomes. AM52.1 CAR T cells efficiently targeted STn-expressing cell lines and patient-derived organoids, and significantly extended survival in preclinical models of gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases. AM52.1 CAR T cells eradicated STn-positive tumor cells, even at low antigen density, with no evidence of toxicity.

Contributed by Katherine Turner

(1) Abrantes R (2) Forcados C (3) Warren DJ (4) Santos-Ferreira L (5) Fleten KG (6) Senra E (7) Costa AF (8) Krpina K (9) Henrique R (10) Liberg AM (11) Rawat P (12) Gelebart P (13) McCormack E (14) Bj¿rge L (15) Davidson B (16) Greiff V (17) Costea DE (18) Pinto F (19) Flatmark K (20) Gomes C (21) Inderberg EM (22) Reis CA (23) Wlchli S

Cell reports. Medicine - Open Access

Abrantes and Forcados et al. generated and characterized AM52.1, a pan-carcinoma antibody with exclusive specificity for a truncated O-glycan structure Sialyl-Tn antigen (STn), which is found on various epithelial tumors, but not healthy tissues, and is associated with adverse outcomes. AM52.1 CAR T cells efficiently targeted STn-expressing cell lines and patient-derived organoids, and significantly extended survival in preclinical models of gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases. AM52.1 CAR T cells eradicated STn-positive tumor cells, even at low antigen density, with no evidence of toxicity.

Contributed by Katherine Turner

ABSTRACT: Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.

Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Mole

Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (2) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (3) Department of Medical Biochemistry, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (4) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (5) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway. (6) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (7) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (8) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway. (9) ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Department of Pathology & Cancer Biology and Epigenetics Group - Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (P.CCC), Rua Dr. Antnio Bernardino de Almeida, 4200-072 Porto, Portugal. (10) Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (11) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (12) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (13) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Hematology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (14) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (15) Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway; Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (16) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (17) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Gade Laboratory for Pathology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (18) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (19) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Department of Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (20) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (21) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (22) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernni Monteiro, 4200-319 Porto, Portugal. Electronic address: celsor@i3s.up.pt. (23) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. Electronic address: sebastw@ous-hf.no.

Citation: Cell Rep Med 2025 Sep 1 102350 Epub09/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40925376

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Cytotoxic CD4⁺ T cells exhibit an immunosuppressive shift in checkpoint immunotherapy resistance in melanoma patients

(1) Bae HR (2) Son B (3) Hwang K (4) Kim S (5) Young HA (6) Kwon EY

Cancer immunology, immunotherapy - Open Access | Free PMC Article

Using scRNAseq data from patients with ICI-treated melanoma, Bae et al. profiled conventional CD4⁺ T cells (excluding Tregs and proliferative cells) at the lesion level. A cytotoxic cluster was enriched in responders, and an exhausted, Treg-like cluster was detected in all samples, and trended towards enrichment in non-responders (NRs). Two clusters dually enhanced in cytotoxicity and exhaustion genes also trended towards enrichment in NRs. Trajectory analysis suggested a cluster characterized by migratory genes as a precursor to the cytotoxic/exhausted clusters, along with a potential transition of a unique exhausted cluster to the Treg-like state.

Contributed by Morgan Janes

(1) Bae HR (2) Son B (3) Hwang K (4) Kim S (5) Young HA (6) Kwon EY

Cancer immunology, immunotherapy - Open Access | Free PMC Article

Using scRNAseq data from patients with ICI-treated melanoma, Bae et al. profiled conventional CD4⁺ T cells (excluding Tregs and proliferative cells) at the lesion level. A cytotoxic cluster was enriched in responders, and an exhausted, Treg-like cluster was detected in all samples, and trended towards enrichment in non-responders (NRs). Two clusters dually enhanced in cytotoxicity and exhaustion genes also trended towards enrichment in NRs. Trajectory analysis suggested a cluster characterized by migratory genes as a precursor to the cytotoxic/exhausted clusters, along with a potential transition of a unique exhausted cluster to the Treg-like state.

Contributed by Morgan Janes

ABSTRACT: Although checkpoint immunotherapy has primarily focused on CD8⁺ T cells, emerging evidence highlights an important role for cytotoxic CD4⁺ T cells in mediating therapeutic responses. However, research on the functional properties of cytotoxic CD4⁺ T cells in the context of immunotherapy is still at an early stage and remains insufficiently defined. Utilizing single-cell RNA-sequencing datasets obtained from metastatic melanoma patients treated with checkpoint inhibitors targeting PD-1 and/or CTLA-4, we performed transcriptomic profiling of conventional CD4⁺ T cells, excluding proliferative and regulatory (FOXP3⁺) subsets, and compared responders and non-responders as distinct groups. Importantly, our analysis identified distinct clusters that discriminate between responders and non-responders, with cytotoxic CD4⁺ T cells occupying a central position within these clusters. In responder-specific clusters, cytotoxic CD4⁺ T cells exhibited features of early activation, whereas clusters specific to non-responders were characterized by an exhausted phenotype. Notably, non-responder-specific clusters were positioned proximally to Treg-like clusters, suggesting a potential transition from cytotoxic to regulatory CD4⁺ T cell states in non-responders. Our findings reinforce the emerging concept that cytotoxic CD4⁺ T cells play a central role in mediating immunotherapy responses. These results provide a foundation for the development of predictive biomarkers and novel therapeutic strategies aimed at modulating CD4⁺ T cell differentiation.

Author Info: (1) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. Department of Food Science and Nutrition, Kyungpook National Universit

Author Info: (1) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea. Omixplus, LLC, Austin, TX, 78750, USA. (2) Department of Biology, Kyungpook National University, Daegu, 41566, Republic of Korea. (3) School of Artificial Intelligence, Kyungpook National University, Daegu, 41566, Republic of Korea. (4) Omixplus, LLC, Austin, TX, 78750, USA. (5) Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA. (6) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr. Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr. Center for Beautiful Aging, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr.

Citation: Cancer Immunol Immunother 2025 Sep 4 74:297 Epub09/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40906211

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Engineered T cells stimulate dendritic cell recruitment and antigen spreading for potent anti-tumor immunity Spotlight

(1) Xiao Z (2) Wang J (3) He S (4) Wang L (5) Yang J (6) Li W (7) Ma K (8) Zhou Y (9) Liu X (10) Wang S (11) Yang Y (12) Ge M (13) Gao A (14) Tang K (15) Huang J (16) Wang C (17) Zhang L (18) Sun HX (19) Zhang L

Cell reports. Medicine - Open Access

Focusing on antigenic heterogeneity and antigen loss in solid tumors, Xiao, Wang, and He et al. engineered T cells to express FLT3L and XCL1 (FX). Adoptively transferred FX T cells improved DC recruitment and activation in the TME (increased IFNγ and IL-12), inducing antigen spreading and potent polyclonal T cell responses, and resulting in control and elimination of antigenic heterogeneous tumors and prevention of immune escape. XCL1 expression positively correlated with a CD8⁺ Tpex signature in mouse and human tumors, and with patient survival and response to ICB. FX-CAR T cells also exhibited superior tumor control in humanized mice.

Contributed by Katherine Turner

(1) Xiao Z (2) Wang J (3) He S (4) Wang L (5) Yang J (6) Li W (7) Ma K (8) Zhou Y (9) Liu X (10) Wang S (11) Yang Y (12) Ge M (13) Gao A (14) Tang K (15) Huang J (16) Wang C (17) Zhang L (18) Sun HX (19) Zhang L

Cell reports. Medicine - Open Access

Focusing on antigenic heterogeneity and antigen loss in solid tumors, Xiao, Wang, and He et al. engineered T cells to express FLT3L and XCL1 (FX). Adoptively transferred FX T cells improved DC recruitment and activation in the TME (increased IFNγ and IL-12), inducing antigen spreading and potent polyclonal T cell responses, and resulting in control and elimination of antigenic heterogeneous tumors and prevention of immune escape. XCL1 expression positively correlated with a CD8⁺ Tpex signature in mouse and human tumors, and with patient survival and response to ICB. FX-CAR T cells also exhibited superior tumor control in humanized mice.

Contributed by Katherine Turner

ABSTRACT: Current T cell-based immunotherapeutic strategies show limited success in treating solid tumors due to insufficient dendritic cell (DC) activity, particularly cross-presenting conventional type 1 dendritic cells (cDC1s). DC scarcity and dysfunction hinder T cell expansion and differentiation, greatly limiting anti-tumor responses. In this study, we propose a T cell engineering strategy to enhance interaction with XCR1(+) cDC1s. Adoptively transferred T cells engineered to secrete Flt3L and XCL1 (FX) promote DC trafficking and maturation and improve DC-T cell interaction, while maintaining a pool of TCF1(+)SlamF6(+) stem-like T cells. Importantly, FX-engineered T cells trigger robust antigen spreading and potent endogenous polyclonal T cell response, enabling the recognition and elimination of tumors with heterogeneous antigens and preventing immune escape. The therapeutic efficacy of FX-armed chimeric antigen receptor (CAR)-T cells is further validated in the Flt3KO&hFLT3LG humanized mouse model. This strategy offers a promising avenue for enhancing DC-T cell interactions, paving the way for more effective immunotherapy against solid tumors.

Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu

Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (2) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (3) College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (4) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (5) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (6) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (7) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (8) Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China. (9) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (10) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (11) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215123, China. (12) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (13) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (14) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (15) Nextvivo (Suzhou) Biotech Corp, Suzhou, Jiangsu 215123, China. (16) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: wc@ism.pumc.edu.cn. (17) Center for Cancer Diagnosis and Treatment, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China; PRAG Therapy Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zhangliyuan@suda.edu.cn. (18) College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: sunhaixi@genomics.cn. (19) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: zlj@ism.cams.cn.

Citation: Cell Rep Med 2025 Aug 20 102307 Epub08/20/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40858102

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First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Spotlight

(1) Hong S (2) Wang Q (3) Cheng Y (4) Luo Y (5) Qu X (6) Zhu H (7) Ding Z (8) Li X (9) Wu L (10) Wang Y (11) Hu S (12) Wang E (13) Liu A (14) Sun Y (15) Fan Y (16) Ye F (17) Lu K (18) Fang J (19) Shen Y (20) Jin X (21) Ge J (22) Zhang L (23) Fang W

Nature medicine

Hong et al. investigated sac-TMT, a TROP2-targeted antibody–drug conjugate, in combination with tagitanlimab (anti-PD-L1) as a first-line therapy in advanced NSCLC without actionable genomic alterations. In cohorts 1A (q3w, n=40) and 1B (q2w, n=63) in the open-label trial, ORRs were 40% and 66.7%, with mPFS of 15.4 months and Not Reached, respectively. Treatment response did not differ by baseline TROP2 or PD-L1 expression, nor by histological subtype. The most common Grade 3+ AEs were hematologic (neutropenia, lymphopenia, anemia). Serious TRAEs occurred in 10.0% and 20.6% of patients, but TRAE-related discontinuation was minimal, and no deaths occurred.

Contributed by Morgan Janes

(1) Hong S (2) Wang Q (3) Cheng Y (4) Luo Y (5) Qu X (6) Zhu H (7) Ding Z (8) Li X (9) Wu L (10) Wang Y (11) Hu S (12) Wang E (13) Liu A (14) Sun Y (15) Fan Y (16) Ye F (17) Lu K (18) Fang J (19) Shen Y (20) Jin X (21) Ge J (22) Zhang L (23) Fang W

Nature medicine

Hong et al. investigated sac-TMT, a TROP2-targeted antibody–drug conjugate, in combination with tagitanlimab (anti-PD-L1) as a first-line therapy in advanced NSCLC without actionable genomic alterations. In cohorts 1A (q3w, n=40) and 1B (q2w, n=63) in the open-label trial, ORRs were 40% and 66.7%, with mPFS of 15.4 months and Not Reached, respectively. Treatment response did not differ by baseline TROP2 or PD-L1 expression, nor by histological subtype. The most common Grade 3+ AEs were hematologic (neutropenia, lymphopenia, anemia). Serious TRAEs occurred in 10.0% and 20.6% of patients, but TRAE-related discontinuation was minimal, and no deaths occurred.

Contributed by Morgan Janes

ABSTRACT: Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody-drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5_mg_kg(-1), every 3_weeks) plus tagitanlimab (1,200_mg, every 3_weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5_mg_kg(-1), every 2_weeks) plus tagitanlimab (900_mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63_years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ³3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3_months for cohort 1A and 13.0_months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4_months (95% confidence interval 6.7-17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration: NCT05351788 .

Author Info: (1) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, C

Author Info: (1) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China. (2) The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. Henan Cancer Hospital, Zhengzhou, China. Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China. (3) Jilin Cancer Hospital, Changchun, China. (4) Hunan Cancer Hospital, Changsha, China. (5) The First Hospital of China Medical University, Shenyang, China. (6) Shanxi Cancer Hospital, Taiyuan, China. (7) West China Hospital of Sichuan University, Chengdu, China. (8) The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. (9) Hunan Cancer Hospital, Changsha, China. (10) Harbin Medical University Cancer Hospital, Harbin, China. (11) Hubei Cancer Hospital, Wuhan, China. (12) Chongqing University Cancer Hospital, Chongqing, China. (13) The Second Affiliated Hospital of Nanchang University, Nanchang, China. (14) Shandong Cancer Hospital, Jinan, China. (15) Zhejiang Cancer Hospital, Hangzhou, China. (16) The First Affiliated Hospital of Xiamen University, Xiamen, China. (17) Jiangsu Province Hospital, Nanjing, China. (18) Beijing Cancer Hospital, Beijing, China. (19) Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China. (20) Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China. (21) Sichuan Kelun-Biotech Biopharmaceutical Co Ltd, Chengdu, China. National Engineering Research Center of Targeted Biologics, Chengdu, China. (22) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China. zhangli@sysucc.org.cn. (23) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China. fangwf@sysucc.org.cn.

Citation: Nat Med 2025 Aug 19 Epub08/19/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40830660

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Engineered bacteria launch and control an oncolytic virus Spotlight

(1) Singer ZS (2) Pabn J (3) Huang H (4) Sun W (5) Luo H (6) Grant KR (7) Obi I (8) Coker C (9) Rice CM (10) Danino T

Nature biomedical engineering

Singer and Pabón et al. developed a Salmonella typhimurium bacterial platform that delivered non-spreading, self-replicating viral RNA, even into cell types beyond the virus’s natural tropism. S. typhimurium “encapsidating” full-length oncolytic Senecavirus A delivered i.t. into s.c. engrafted tumors cleared treated and distal tumors in athymic mice, as did i.v. treatment of immunocompetent mice (even in the presence of pre-existing circulating viral-neutralizing antibodies), without adverse effects. Additional virus engineering aimed to control viral spread and persistence and to mitigate RNA mutational escape by requiring that virion maturation depend on bacterially delivered TEV protease.

Contributed by Paula Hochman

(1) Singer ZS (2) Pabn J (3) Huang H (4) Sun W (5) Luo H (6) Grant KR (7) Obi I (8) Coker C (9) Rice CM (10) Danino T

Nature biomedical engineering

Singer and Pabón et al. developed a Salmonella typhimurium bacterial platform that delivered non-spreading, self-replicating viral RNA, even into cell types beyond the virus’s natural tropism. S. typhimurium “encapsidating” full-length oncolytic Senecavirus A delivered i.t. into s.c. engrafted tumors cleared treated and distal tumors in athymic mice, as did i.v. treatment of immunocompetent mice (even in the presence of pre-existing circulating viral-neutralizing antibodies), without adverse effects. Additional virus engineering aimed to control viral spread and persistence and to mitigate RNA mutational escape by requiring that virion maturation depend on bacterially delivered TEV protease.

Contributed by Paula Hochman

ABSTRACT: The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice. Finally, we engineer the virus to require a bacterially delivered protease to achieve virion maturation, demonstrating bacterial control over the virus. Together, we refer to this platform as 'CAPPSID' for Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery. This work extends bacterially delivered therapeutics to viral genomes, and shows how a consortium of microbes can achieve a cooperative aim.

Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2)

Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (3) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (4) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (5) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (6) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (7) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (9) Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (10) Department of Biomedical Engineering, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Data Science Institute, Columbia University, New York, NY, USA. tal.danino@columbia.edu.

Citation: Nat Biomed Eng 2025 Aug 15 Epub08/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40817284

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Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer Featured

(1) Aznar MA (2) Good CR (3) Barber-Rotenberg JS (4) Agarwal S (5) Wilson W (6) Watts A (7) Zhang Z (8) Gonzales D (9) Donahue G (10) Hwang WT (11) Rennels AK (12) Rech AJ (13) Kuramitsu S (14) Huang H (15) Glastad KM (16) Alexander KA (17) Plesa G (18) Dowd E (19) Brennan A (20) Siegel DL (21) Tanyi J (22) Haas A (23) Torigian DA (24) Nadolski G (25) Gonzalez VE (26) Hexner EO (27) Fraietta JA (28) Jadlowsky JK (29) Young RM (30) Berger SL (31) June CH (32) O'Hara MH

Cell reports. Medicine - Open Access

Aznar and Good et al. reported on a Phase I study assessing a mesothelin-targeting CAR T cell product (huCART-meso) in patients with advanced PDAC. Treatment was feasible and safe, but lacked efficacy. Biopsy and ascites analysis showed limited persistence of the CAR-T and remaining CAR-T upregulated transcription factors SOX4 and ID3, related to dysfunction. Murine studies showed limited effects of ID3KO in CART, while SOX4KO improved antitumor efficacy, but tumors relapsed. Double KO of ID3 and SOX4 in the CAR-T prevented relapses and improved relapse-free survival.

(1) Aznar MA (2) Good CR (3) Barber-Rotenberg JS (4) Agarwal S (5) Wilson W (6) Watts A (7) Zhang Z (8) Gonzales D (9) Donahue G (10) Hwang WT (11) Rennels AK (12) Rech AJ (13) Kuramitsu S (14) Huang H (15) Glastad KM (16) Alexander KA (17) Plesa G (18) Dowd E (19) Brennan A (20) Siegel DL (21) Tanyi J (22) Haas A (23) Torigian DA (24) Nadolski G (25) Gonzalez VE (26) Hexner EO (27) Fraietta JA (28) Jadlowsky JK (29) Young RM (30) Berger SL (31) June CH (32) O'Hara MH

Cell reports. Medicine - Open Access

Aznar and Good et al. reported on a Phase I study assessing a mesothelin-targeting CAR T cell product (huCART-meso) in patients with advanced PDAC. Treatment was feasible and safe, but lacked efficacy. Biopsy and ascites analysis showed limited persistence of the CAR-T and remaining CAR-T upregulated transcription factors SOX4 and ID3, related to dysfunction. Murine studies showed limited effects of ID3KO in CART, while SOX4KO improved antitumor efficacy, but tumors relapsed. Double KO of ID3 and SOX4 in the CAR-T prevented relapses and improved relapse-free survival.

ABSTRACT: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK(+) phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).

Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Unive

Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (2) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (4) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (6) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (9) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (10) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (12) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (13) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (14) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (15) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (16) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (17) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (19) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (20) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (21) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (23) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (26) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (28) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ryoung@upenn.edu. (30) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: bergers@pennmedicine.upenn.edu. (31) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: cjune@upenn.edu. (32) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: mark.ohara@pennmedicine.upenn.edu.

Citation: Cell Rep Med 2025 Aug 13 102301 Epub08/13/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40829595

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Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency Spotlight

(1) Wang W (2) Bunyatov M (3) Moffat D (4) Lopez-Barbosa N (5) DeLisa MP

Cell chemical biology

Wang et al. focused on improving the potency and specificity of mAbs targeting cancer- and infection-associated carbohydrates. Using structure-based rational design and directed evolution, variants of mAb735 – a modest-affinity, polysialic acid (polySia)-specific antibody – were generated (scFv and IgG formats) with significantly increased affinity (4- to 7-fold) compared to parental mAb735. Affinity-matured mAb735 IgG variants bound more avidly to polySia-positive tumor cell lines, and demonstrated increased functional potency and tumor cell killing, including ADCC and CDC, providing a framework for enhancing the promise of anti-glycan Abs.

Contributed by Katherine Turner

(1) Wang W (2) Bunyatov M (3) Moffat D (4) Lopez-Barbosa N (5) DeLisa MP

Cell chemical biology

Wang et al. focused on improving the potency and specificity of mAbs targeting cancer- and infection-associated carbohydrates. Using structure-based rational design and directed evolution, variants of mAb735 – a modest-affinity, polysialic acid (polySia)-specific antibody – were generated (scFv and IgG formats) with significantly increased affinity (4- to 7-fold) compared to parental mAb735. Affinity-matured mAb735 IgG variants bound more avidly to polySia-positive tumor cell lines, and demonstrated increased functional potency and tumor cell killing, including ADCC and CDC, providing a framework for enhancing the promise of anti-glycan Abs.

Contributed by Katherine Turner

ABSTRACT: Monoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for basic research and clinical applications. However, high-quality anti-glycan mAbs with sufficiently high affinity and specificity remain scarce, highlighting the need for strategies that enable optimization of antigen-binding properties. To this end, we engineered the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which possesses only modest affinity. Using a combination of rational design and directed evolution, we isolated several affinity-matured IgG variants with _5- to 7-fold stronger affinity for polySia relative to mAb735. The higher affinity IgG variants opsonized polySia-positive cancer cells more avidly and triggered greater antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Collectively, these results demonstrate the effective application of molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition and uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.

Author Info: (1) Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA. (2) Robert F. Smith School of Chemical and Biomolecular E

Author Info: (1) Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA. (2) Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA. (3) Nancy E. and Peter C. Meinig School of Biomedical Engineering School of Biomedical Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA. (4) Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA. (5) Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA; Nancy E. and Peter C. Meinig School of Biomedical Engineering School of Biomedical Engineering, Cornell University, Olin Hall, Ithaca, NY 14853, USA; Cornell Institute of Biotechnology, Cornell University, 130 Biotechnology Building, Ithaca, NY 14853, USA. Electronic address: md255@cornell.edu.

Citation: Cell Chem Biol 2025 Aug 21 32:1042-1057.e6 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40845830

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