Experimental Immunotherapy - 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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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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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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Neoadjuvant immunotherapy promotes the formation of mature tertiary lymphoid structures in a remodeled pancreatic tumor microenvironment Spotlight

(1) Sidiropoulos DN (2) Shin SM (3) Wetzel M (4) Girgis AA (5) Bergman D (6) Danilova L (7) Perikala S (8) Shu D (9) Montagne JM (10) Deshpande A (11) Leatherman J (12) Dequiedt L (13) Jacobs V (14) Ogurtsova A (15) Mo G (16) Yuan X (17) Lvovs D (18) Stein-O'Brien G (19) Yarchoan M (20) Zhu Q (21) Harper EI (22) Weeraratna AT (23) Kiemen AL (24) Jaffee EM (25) Zheng L (26) Ho WJ (27) Anders RA (28) Fertig EJ (29) Kagohara LT

Cancer immunology research

Sidiropoulos et al. report state-of-the-art spatial genomics and proteomic profiling of PDAC tumors and tumor-adjacent lymph nodes from patients treated with GVAX and anti-PD-1 alone or in combination with a 41BB agonist in the neoadjuvant setting. Spatial transcriptomics identified TLS-specific spatial gene expression signatures associated with improved survival in TCGA PDAC samples. TLS-adjacent stroma of pathologic responders showed ECM remodeling with decreased desmoplasia. Neoadjuvant immunotherapy induced TLS formation in diverse spatial niches with mature B cell aggregates that disseminate IgG antibodies.

Contributed by Shishir Pant

(1) Sidiropoulos DN (2) Shin SM (3) Wetzel M (4) Girgis AA (5) Bergman D (6) Danilova L (7) Perikala S (8) Shu D (9) Montagne JM (10) Deshpande A (11) Leatherman J (12) Dequiedt L (13) Jacobs V (14) Ogurtsova A (15) Mo G (16) Yuan X (17) Lvovs D (18) Stein-O'Brien G (19) Yarchoan M (20) Zhu Q (21) Harper EI (22) Weeraratna AT (23) Kiemen AL (24) Jaffee EM (25) Zheng L (26) Ho WJ (27) Anders RA (28) Fertig EJ (29) Kagohara LT

Cancer immunology research

Sidiropoulos et al. report state-of-the-art spatial genomics and proteomic profiling of PDAC tumors and tumor-adjacent lymph nodes from patients treated with GVAX and anti-PD-1 alone or in combination with a 41BB agonist in the neoadjuvant setting. Spatial transcriptomics identified TLS-specific spatial gene expression signatures associated with improved survival in TCGA PDAC samples. TLS-adjacent stroma of pathologic responders showed ECM remodeling with decreased desmoplasia. Neoadjuvant immunotherapy induced TLS formation in diverse spatial niches with mature B cell aggregates that disseminate IgG antibodies.

Contributed by Shishir Pant

ABSTRACT: Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Herein, we report the generation of a spatial multi-omics atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning across distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that significantly associated with improved survival in PDAC patients. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Author Info: (1) Johns Hopkins Medicine, Baltimore, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Univers

Author Info: (1) Johns Hopkins Medicine, Baltimore, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins University, United States. (5) Johns Hopkins Medicine, United States. (6) Johns Hopkins Medicine, Baltimore, Maryland, United States. (7) Johns Hopkins University, United States. (8) University of Maryland Medical Center, Baltimore, MD, United States. (9) Johns Hopkins University, Baltimore, MD, United States. (10) Johns Hopkins Medicine, Baltimore, MD, United States. (11) Johns Hopkins University, Baltimore, MD, United States. (12) Johns Hopkins University, United States. (13) Johns Hopkins University, United States. (14) Johns Hopkins University, Baltimore, Maryland, United States. (15) Johns Hopkins Medicine, Baltimore, Maryland, United States. (16) Johns Hopkins Medicine, Baltimore, United States. (17) Johns Hopkins University, Baltimore, United States. (18) Johns Hopkins Medicine, Baltimore, MD, United States. (19) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States. (20) Johns Hopkins Medicine, Baltimore, MARYLAND, United States. (21) Johns Hopkins University, Baltimore, MD, United States. (22) Johns Hopkins University, Baltimore, MD, United States. (23) Johns Hopkins University, Baltimore, MD, United States. (24) Johns Hopkins University, Baltimore, MD, United States. (25) Johns Hopkins Medicine, Baltimore, Maryland, United States. (26) Johns Hopkins University, Baltimore, MD, United States. (27) Johns Hopkins Medicine, Baltimore, United States. (28) University of Maryland, Baltimore, Baltimore, Maryland, United States. (29) Johns Hopkins University, Baltimore, MD, United States.

Citation: Cancer Immunol Res 2025 Aug 15 Epub08/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40815230

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Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy Spotlight

(1) Wu Z (2) Shi J (3) Lamao Q (4) Qiu Y (5) Yang J (6) Liu Y (7) Liang F (8) Sun X (9) Tang W (10) Chen C (11) Yang Q (12) Wang C (13) Li Z (14) Zhang H (15) Yang Z (16) Zhang Y (17) Yi Y (18) Zheng X (19) Sun Y (20) Ma K (21) Yu L (22) Yang H (23) Wang Z (24) Zheng W (25) Yang L (26) Zhang Z (27) Zhang Y (28) Wu Z (29) Wang Y (30) Wong CCL (31) Jin M (32) Yuan P (33) Han W (34) Wei W

Cell - Open Access

Deletion of the glycan regulator SPPL3 improved allo-CAR-T fitness by reducing T cell, NK cell, and FasL-mediated killing. SPPL3 KO increased TCR/CD3 glycosylation, reduced TCR detection and antigen recognition, and diminished GvHD in humanized mice, but did not affect the CAR molecule or functionality. In 10 patients with r/r B-NHL, SPPL3^KO TCR^KO allo-CAR-T were safe and efficacious, without severe GvHD. However, TCR- CAR-T persistence was limited compared to TCR⁺ CAR-T cells. Based on this result and further preclinical studies, 3 patients received SPPL3^KO TCR⁺ allo-CAR-T, which also showed safety and efficacy, despite TCR competence.

Contributed by Alex Najibi

(1) Wu Z (2) Shi J (3) Lamao Q (4) Qiu Y (5) Yang J (6) Liu Y (7) Liang F (8) Sun X (9) Tang W (10) Chen C (11) Yang Q (12) Wang C (13) Li Z (14) Zhang H (15) Yang Z (16) Zhang Y (17) Yi Y (18) Zheng X (19) Sun Y (20) Ma K (21) Yu L (22) Yang H (23) Wang Z (24) Zheng W (25) Yang L (26) Zhang Z (27) Zhang Y (28) Wu Z (29) Wang Y (30) Wong CCL (31) Jin M (32) Yuan P (33) Han W (34) Wei W

Cell - Open Access

Deletion of the glycan regulator SPPL3 improved allo-CAR-T fitness by reducing T cell, NK cell, and FasL-mediated killing. SPPL3 KO increased TCR/CD3 glycosylation, reduced TCR detection and antigen recognition, and diminished GvHD in humanized mice, but did not affect the CAR molecule or functionality. In 10 patients with r/r B-NHL, SPPL3^KO TCR^KO allo-CAR-T were safe and efficacious, without severe GvHD. However, TCR- CAR-T persistence was limited compared to TCR⁺ CAR-T cells. Based on this result and further preclinical studies, 3 patients received SPPL3^KO TCR⁺ allo-CAR-T, which also showed safety and efficacy, despite TCR competence.

Contributed by Alex Najibi

ABSTRACT: Despite the success of autologous chimeric antigen receptor (CAR)-T cell therapy, achieving persistence and avoiding rejection in allogeneic settings remains challenging. We showed that signal peptide peptidase-like 3 (SPPL3) deletion enabled glycan-mediated immune evasion in primary T cells. SPPL3 deletion modified glycan profiles on T cells, restricted ligand accessibility, and reduced allogeneic immunity without compromising the functionality of anti-CD19 CAR molecules. In a phase I clinical trial, SPPL3-null, T cell receptor (TCR)-deficient anti-CD19 allogeneic CAR-T cells reached the safety primary endpoint, with grade 3 or higher cytokine release syndrome (CRS) observed in 3 out of 9 patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (ClinicalTrials.gov: NCT06014073). Reverse translational research highlighted the pivotal role of TCR in sustaining T cell persistence. We therefore evaluated the safety of SPPL3-null, TCR-sufficient CAR-T therapy on three patients with lymphoma or leukemia for compassionate care and observed no clinical signs of graft-versus-host disease. Our findings suggest glycan shielding by SPPL3 deletion is a promising direction for optimizing universal CAR-T therapies.

Author Info: (1) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and M

Author Info: (1) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China. (2) School of Medicine, Nankai University, Tianjin 300071, China; Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (3) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China. (4) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (5) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (6) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (7) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (8) School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; First School of Clinical Medicine, Peking University, Beijing 100871, China. (9) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (10) State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China. (11) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (12) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (13) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (14) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (15) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (16) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (17) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (18) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (19) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (20) Changping Laboratory, Beijing 102206, China. (21) Changping Laboratory, Beijing 102206, China. (22) Changping Laboratory, Beijing 102206, China. (23) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (24) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (25) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (26) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China. (27) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (28) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (29) Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. (30) First School of Clinical Medicine, Peking University, Beijing 100871, China; State Key Laboratory of Complex, Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China; Tsinghua-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. (31) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. (32) EdiGene Inc., Life Science Park, Changping District, Beijing 102206, China. Electronic address: pfyuan@edigene.com. (33) Changping Laboratory, Beijing 102206, China; School of Medicine, Nankai University, Tianjin 300071, China; Department of Bio-Therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: hanwdrsw@163.com. (34) Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China. Electronic address: wswei@pku.edu.cn.

Citation: Cell 2025 Aug 14 Epub08/14/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40845838

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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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Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency Spotlight

(1) Biederstdt A (2) Basar R (3) Park JM (4) Uprety N (5) Shrestha R (6) Reyes Silva F (7) Dede M (8) Watts J (9) Acharya S (10) Xiong D (11) Liu B (12) Daher M (13) Rafei H (14) Banerjee P (15) Li P (16) Islam S (17) Fan H (18) Shanley M (19) Jin J (20) Kumar B (21) Woods V (22) Lin P (23) Tiberti S (24) Nunez Cortes AK (25) Jiang XR (26) Biederstdt I (27) Zhang P (28) Li Y (29) Rawal S (30) Liu E (31) Muniz-Feliciano L (32) Deyter GM (33) Shpall EJ (34) Fowlkes NW (35) Chen K (36) Rezvani K

Cancer cell - Open Access

Biederstadt and Basar et al. developed a genome-wide CRISPR screen platform for primary human NK cells, and identified MED12, ARIH2, and CCNC as critical regulators of NK cell function under repeated tumor challenge and immunosuppressive pressure. Deletion of these genes enhanced NK cell metabolic fitness, proinflammatory cytokine secretion, and expansion of both innate and CAR-NK cells, and improved antitumor potency against multiple treatment-refractory human cancers xenografts. Dual ARIH2/CCNC editing augmented CAR-NK cell proliferation, activation, and inflammatory signaling, leading to enhanced tumor clearance.

Contributed by Shishir Pant

(1) Biederstdt A (2) Basar R (3) Park JM (4) Uprety N (5) Shrestha R (6) Reyes Silva F (7) Dede M (8) Watts J (9) Acharya S (10) Xiong D (11) Liu B (12) Daher M (13) Rafei H (14) Banerjee P (15) Li P (16) Islam S (17) Fan H (18) Shanley M (19) Jin J (20) Kumar B (21) Woods V (22) Lin P (23) Tiberti S (24) Nunez Cortes AK (25) Jiang XR (26) Biederstdt I (27) Zhang P (28) Li Y (29) Rawal S (30) Liu E (31) Muniz-Feliciano L (32) Deyter GM (33) Shpall EJ (34) Fowlkes NW (35) Chen K (36) Rezvani K

Cancer cell - Open Access

Biederstadt and Basar et al. developed a genome-wide CRISPR screen platform for primary human NK cells, and identified MED12, ARIH2, and CCNC as critical regulators of NK cell function under repeated tumor challenge and immunosuppressive pressure. Deletion of these genes enhanced NK cell metabolic fitness, proinflammatory cytokine secretion, and expansion of both innate and CAR-NK cells, and improved antitumor potency against multiple treatment-refractory human cancers xenografts. Dual ARIH2/CCNC editing augmented CAR-NK cell proliferation, activation, and inflammatory signaling, leading to enhanced tumor clearance.

Contributed by Shishir Pant

ABSTRACT: Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Inno

Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine III: Hematology & Oncology, School of Medicine, Technical University of Munich, Munich, Germany. (2) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Neurology, the University of Texas McGovern Medical School at Houston, Houston, TX, USA. (18) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. (26) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (34) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (36) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: krezvani@mdanderson.org.

Citation: Cancer Cell 2025 Aug 18 Epub08/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40845844

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

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Engineered bacteria launch and control an oncolytic virus Spotlight

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Neoadjuvant immunotherapy promotes the formation of mature tertiary lymphoid structures in a remodeled pancreatic tumor microenvironment Spotlight

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Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy Spotlight

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

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Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency Spotlight

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