Journal Articles

In vivo genome-wide CRISPR screens of human T cells in solid tumours Spotlight 

(1) Liu Q (2) Chen PA (3) Urs E (4) Zhang S (5) Arce MM (6) Wang CH (7) Yan J (8) Nguyen VQ (9) Li Z (10) Seo J (11) Kale N (12) Peng F (13) Luo Y (14) Goudy L (15) LaFlam TN (16) Zhong H (17) Modak C (18) Dann E (19) Jung JH (20) Kirane A (21) Warner AB (22) Quach BB (23) Good Z (24) Shy BR (25) Shifrut E (26) Bapat SP (27) Allen GM (28) Eyquem J (29) Fuh K (30) Dodgson SE (31) Cyster JG (32) Marson A (33) Carnevale J

Nature

Liu et al. developed a genome-wide in vivo CRISPR screening platform using a T cell-attracting anti-CD3 scFv-expressing A375 tumor model and primary human T cells to identify in vivo regulators of intratumoral T cell abundance and effector function. The abundance screen identified P2RY8-Gα13 as a negative regulator of T cell tumor infiltration, whereas the IFNγ-based functional screen identified GNAS as a key driver of intratumoral T cell dysfunction. GNAS deletion enhanced CAR- and TCR-T cell fitness and efficacy across solid tumor models. P2RY8 and GNAS dual-knockout CAR T cells showed increased infiltration and improved tumor control.

Contributed by Shishir Pant

(1) Liu Q (2) Chen PA (3) Urs E (4) Zhang S (5) Arce MM (6) Wang CH (7) Yan J (8) Nguyen VQ (9) Li Z (10) Seo J (11) Kale N (12) Peng F (13) Luo Y (14) Goudy L (15) LaFlam TN (16) Zhong H (17) Modak C (18) Dann E (19) Jung JH (20) Kirane A (21) Warner AB (22) Quach BB (23) Good Z (24) Shy BR (25) Shifrut E (26) Bapat SP (27) Allen GM (28) Eyquem J (29) Fuh K (30) Dodgson SE (31) Cyster JG (32) Marson A (33) Carnevale J

Nature

Liu et al. developed a genome-wide in vivo CRISPR screening platform using a T cell-attracting anti-CD3 scFv-expressing A375 tumor model and primary human T cells to identify in vivo regulators of intratumoral T cell abundance and effector function. The abundance screen identified P2RY8-Gα13 as a negative regulator of T cell tumor infiltration, whereas the IFNγ-based functional screen identified GNAS as a key driver of intratumoral T cell dysfunction. GNAS deletion enhanced CAR- and TCR-T cell fitness and efficacy across solid tumor models. P2RY8 and GNAS dual-knockout CAR T cells showed increased infiltration and improved tumor control.

Contributed by Shishir Pant

ABSTRACT: Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro(1,2). In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-G_13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, G_s, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

Author Info: (1) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. qi.liu3@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA

Author Info: (1) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. qi.liu3@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. qi.liu3@ucsf.edu. (2) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (3) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (4) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (6) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (7) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (8) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. UCSF CoLabs, University of California San Francisco, San Francisco, CA, USA. Department of Surgery, University of California San Francisco, San Francisco, CA, USA. Diabetes Center, University of California San Francisco, San Francisco, CA, USA. (9) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (10) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (11) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (12) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. (13) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (14) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (15) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. Division of Pediatric Rheumatology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA. (16) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. (17) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (18) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (19) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (20) Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. (21) Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (22) Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA. Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. (23) Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA. Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. (24) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. (25) Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (26) Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. Department of Pathology, University of California San Francisco, San Francisco, CA, USA. (27) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. (28) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. (29) Department of OB/Gyn, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA. (30) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (31) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. (32) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. Institute for Human Genetics (IHG), University of California San Francisco, San Francisco, CA, USA. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, USA. (33) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. julia.carnevale@ucsf.edu. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. julia.carnevale@ucsf.edu.

Citation: Nature 2026 Aug 12 Epub08/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42587162

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Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors Spotlight 

(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L

Cell reports. Medicine

Zhu and Yu et al. developed and characterized a scalable, feeder-free, high-yield platform that generated allogeneic NY-ESO-1-specific cytotoxic T (AlloESO-T) cells from cord blood-derived hematopoietic stem and progenitor cells. Compared to PBMC-derived TCR-T cells, monospecific AlloESO-T cells showed superior cytotoxicity (with dual TCR and NKR targeting), solid tumor homing, HLA-independence, durable killing persistence (with IL-15), and enhanced efficacy in solid tumor models. AlloESO-T cells, which lack endogenous TCRs, exhibited an improved safety profile and minimal GvHD or /cytokine release syndrome risk in vitro and in vivo.

Contributed by Katherine Turner

(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L

Cell reports. Medicine

Zhu and Yu et al. developed and characterized a scalable, feeder-free, high-yield platform that generated allogeneic NY-ESO-1-specific cytotoxic T (AlloESO-T) cells from cord blood-derived hematopoietic stem and progenitor cells. Compared to PBMC-derived TCR-T cells, monospecific AlloESO-T cells showed superior cytotoxicity (with dual TCR and NKR targeting), solid tumor homing, HLA-independence, durable killing persistence (with IL-15), and enhanced efficacy in solid tumor models. AlloESO-T cells, which lack endogenous TCRs, exhibited an improved safety profile and minimal GvHD or /cytokine release syndrome risk in vitro and in vivo.

Contributed by Katherine Turner

ABSTRACT: Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T ((Allo)ESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. (Allo)ESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, (Allo)ESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived (Allo)ESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of (Allo)ESO-T cells across solid tumors.

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los A

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (12) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (13) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (14) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (15) Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA 90095, USA. (16) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (17) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (18) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (19) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (20) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (21) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu. (22) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

Citation: Cell Rep Med 2026 Aug 19 102998 Epub08/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617602

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Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function Spotlight 

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

ABSTRACT: Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford Univer

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (2) Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (8) Program in Immunology, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (15) Department of Pathology, Stanford University, Stanford, CA, USA. (16) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (20) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (21) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (22) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: troth@stanford.edu. (23) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.

Citation: Cell 2026 Aug 19 Epub08/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617595

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IL7-Receptor-Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia Spotlight 

(1) Hocine HR (2) Ganbaatar U (3) Amador-Molina A (4) Banerjee S (5) Misawa K (6) Rubino V (7) Ankola P (8) Fong C (9) Xiong Y (10) Vista WR (11) Bellis RY (12) Chintala NK (13) Curran KJ (14) Sulis ML (15) Park JH (16) Kung AL (17) Adusumilli PS

Nature communications

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

(1) Hocine HR (2) Ganbaatar U (3) Amador-Molina A (4) Banerjee S (5) Misawa K (6) Rubino V (7) Ankola P (8) Fong C (9) Xiong Y (10) Vista WR (11) Bellis RY (12) Chintala NK (13) Curran KJ (14) Sulis ML (15) Park JH (16) Kung AL (17) Adusumilli PS

Nature communications

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

ABSTRACT: On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL7 receptor (IL7R), which promotes resistance to chemotherapy and disease relapse, here we develop IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments. We establish the antitumor efficacy of CD127 CAR against T-ALL cells in vitro, in female mouse models of T-ALL, and against blasts from patients with T-ALL using the patients' own T cells transduced with CD127 CAR. Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells, albeit with fratricide of CAR T cells following eradication of CD127-overexpressing blasts. CRISPR-Cas9 knockout of CD127 eliminates fratricide at the risk of prolonged lymphopenia in vivo. To overcome fratricide, we investigate short-term ( < 7 days) co-culture with or without dasatinib, a tyrosine kinase inhibitor, versus a natural selection method (10 days) and demonstrate that co-culturing with dasatinib facilitates higher CAR T-cell yield, improved fitness, and preserved functionality. In vivo, dasatinib can be used to temporarily and reversibly suppress CAR T-cell activity. With this supporting translational data, we are initiating a trial with low-affinity CD127 CAR T cells for adult and pediatric patients with relapsed or refractory T-ALL.

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (9) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. (16) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (17) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org. Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. adusumip@mskcc.org.

Citation: Nat Commun 2026 Jul 15 Epub07/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42457686

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Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity

Spotlight 

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

ABSTRACT: Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFN-γ suppresses the expression of System Xc-, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1-specific TCR-T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2 microglobulin knockout counterparts. In NOG mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape variant tumor clones, offering a promising strategy for cancer treatment.

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (4) Aichi Cancer Center Research Institute Chikusa-ku, Nagoya, Aichi Japan. (5) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (6) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (7) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (8) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (9) Takara Bio Inc. Kusatsu, Shiga Japan. (10) Takara Bio Inc. Otsu, Shiga Japan. (11) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (12) Nagasaki University Nagasaki, Nagasaki Japan. ROR: https://ror.org/058h74p94

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397036

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CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors Spotlight 

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

ABSTRACT: CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VI

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: emily.lelliott@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (3) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (8) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (10) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (13) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (15) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: shom.goel@petermac.org. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: jane.oliaro@petermac.org.

Citation: Mol Ther 2026 Jul 1 34:4021-4034 Epub03/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41883164

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An in vivo CRISPR screen unveils promising target genes to improve CAR-T cell efficacy in a solid tumor model Spotlight 

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

ABSTRACT: CAR-T cell therapies are revolutionizing the treatment of refractory or relapsed hematological malignancies, but many patients do not achieve durable responses, and these therapies remain ineffective against solid tumors. Therapeutic failure is closely associated with a poor persistence of CAR-T cells in patients, highlighting the need to identify strategies promoting in vivo expansion. Although numerous gene-editing strategies have been proposed, comparative studies to identify the most effective ones are still lacking. Here, using a focused CRISPR-knockout library targeting 50 selected gene candidates, we developed a competitive screening that revealed ZC3H12A, SOCS1, PTPN2, and CDKN2A as the most robust targets to improve persistence of EGFR CAR-T cells in human lung tumor-bearing mice. Surprisingly, disruption of other genes previously reported to improve CAR-T cell efficacy in other preclinical models-MED12, PRDM1, and BATF-had a detrimental effect in this context. These results suggest that some gene-editing strategies can yield beneficial, neutral, or even deleterious effects on CAR-T cell persistence, depending on specific conditions. Altogether, these findings highlight the importance of performing context-specific evaluations of genetic modifications to accelerate the clinical translation of the most promising editing strategies for optimizing CAR-T cell therapies.

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationa

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationale Contre le Cancer, Paris, France. Electronic address: fumatia97@gmail.com. (2) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (3) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (4) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (5) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (6) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (7) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (8) Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (9) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (10) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (11) Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (12) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (13) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (14) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy. (15) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (16) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (17) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (18) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. Electronic address: frederic.pendino@inserm.fr.

Citation: Mol Ther 2026 Jul 1 34:3976-4000 Epub04/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41935953

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The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM Spotlight 

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

ABSTRACT: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicin

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (5) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (9) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (13) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (14) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (17) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (18) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France. (19) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (20) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Clinical Immunology Laboratory, Institut Curie, Paris, France. (23) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (24) Department of Translational Research, PSL University, Institut Curie, Paris, France; INSERM U1330, PSL University, Institut Curie Research Center, Paris, France. (25) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (26) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France; Clinical Hematology Unit, Institut Curie, Saint-Cloud, France. (27) Departments of Dermatology and Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (29) Kite, a Gilead Company, Santa Monica, CA, USA. (30) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (31) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (32) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (33) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (34) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (35) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. (37) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (38) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (39) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (40) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (41) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (42) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (43) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (44) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (45) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (46) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (47) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (48) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: binderz@pennmedicine.upenn.edu. (49) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Clinical Laboratory, H™pital Foch, Suresnes, France. Electronic address: c.alanio@hopital-foch.com. (50) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dana.silverbush@pennmedicine.upenn.edu.

Citation: Cell 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42296961

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Reprogramming CAR with cytokine signaling increases the efficacy of CAR-T cell therapy in solid tumour treatment and confers sustained immune memory Spotlight 

(1) Sun R (2) Liu S (3) Yang X (4) Che C (5) Zhang Z (6) Zhang C (7) Wang Y (8) Yang Y (9) Li X (10) Wang J (11) Zheng H (12) Guo M (13) Yin H

Cancer immunology research

To improve CAR T cell efficacy for solid tumors, Sun and Liu et al. designed a series of CARs that enabled antigen-dependent “cytokine” co-activation, while preserving second-generation CAR structure. Incorporating compact IL-2/IL-15 receptor (IL2RB)-derived STAT5 docking motifs (Y392 and Y510) within the CD3ζITAM2/3 regions resulted in antigen-specific co-activation upon CAR engagement. The best candidate S71 CAR exhibited superior efficacy and dose-dependent memory in multiple xenograft tumor models (EDB-fibronectin, CD19, and CLDN), improved mitochondrial function, and supported durable and persistent T cell activity, with less exhaustion.

Contributed by Katherine Turner

(1) Sun R (2) Liu S (3) Yang X (4) Che C (5) Zhang Z (6) Zhang C (7) Wang Y (8) Yang Y (9) Li X (10) Wang J (11) Zheng H (12) Guo M (13) Yin H

Cancer immunology research

To improve CAR T cell efficacy for solid tumors, Sun and Liu et al. designed a series of CARs that enabled antigen-dependent “cytokine” co-activation, while preserving second-generation CAR structure. Incorporating compact IL-2/IL-15 receptor (IL2RB)-derived STAT5 docking motifs (Y392 and Y510) within the CD3ζITAM2/3 regions resulted in antigen-specific co-activation upon CAR engagement. The best candidate S71 CAR exhibited superior efficacy and dose-dependent memory in multiple xenograft tumor models (EDB-fibronectin, CD19, and CLDN), improved mitochondrial function, and supported durable and persistent T cell activity, with less exhaustion.

Contributed by Katherine Turner

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in hematologic malignancies but remains limited in solid tumors because of the immunosuppressive microenvironment, tumor heterogeneity, poor immune-cell infiltration, and progressive T-cell dysfunction. Because cytokine costimulation is critical for maintaining T-cell fitness, we developed a modular engineering strategy, distinct from previous approaches based on direct insertion of large cytokine receptor fragments, in which the intracellular CAR signaling domain was reconstructed to incorporate compact IL-2/IL-15 receptor-derived activation motifs, thereby enabling antigen-dependent coactivation while preserving the overall architecture of the parental CAR. Through systematic screening, we identified S71 as the optimal construct, with significantly greater antitumor activity than other mutants across multiple solid and hematologic tumor targets. Mechanistically, S71 rewired CAR signaling and reprogrammed tumor-induced metabolic responses through a self-sustaining mechanism, improving mitochondrial function and supporting durable T-cell activity. Functionally, S71 promoted enhanced persistence and robust immune memory responses against solid tumors. These findings demonstrate that modular integration of cytokine signaling motifs into CAR intracellular domains can improve CAR T-cell fitness and antitumor efficacy, and they establish S71 as a promising strategy for overcoming barriers to CAR T-cell therapy in solid tumors.

Author Info: (1) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (2) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (3) China Pharma

Author Info: (1) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (2) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (3) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (4) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (5) China Pharmaceutical University China. ROR: https://ror.org/01sfm2718 (6) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (7) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (8) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (9) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (10) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (11) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (12) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (13) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718

Citation: Cancer Immunol Res 2026 May 15 Epub05/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42139378

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Allogeneic CD19 CAR T cells armed with an anti-rejection CD70 CAR overcome antigen escape and evade alloimmune responses Spotlight 

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells eliminated B cells and CD70(+) T cells derived from patients with systemic lupus erythematosus in humanized mouse models, resulting in reduced immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore broaden clinical applicability while enabling the use of less intensive lymphodepleting conditioning regimens prior to CAR T cell infusion.

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA,

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA, USA. (4) Allogene Therapeutics Inc., South San Francisco, CA, USA. (5) Allogene Therapeutics Inc., South San Francisco, CA, USA. (6) Allogene Therapeutics Inc., South San Francisco, CA, USA. (7) Allogene Therapeutics Inc., South San Francisco, CA, USA. (8) Allogene Therapeutics Inc., South San Francisco, CA, USA. (9) Allogene Therapeutics Inc., South San Francisco, CA, USA. (10) Allogene Therapeutics Inc., South San Francisco, CA, USA. (11) Allogene Therapeutics Inc., South San Francisco, CA, USA. cesar.sommer@allogene.com. (12) Allogene Therapeutics Inc., South San Francisco, CA, USA. elvin.lauron@allogene.com.

Citation: Nat Commun 2026 Apr 12 Epub04/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41965340

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