Journal Articles

Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models

The extracellular matrix (ECM) plays a crucial role in supporting metastasis in solid malignancies, yet effective ECM-targeted therapies remain scarce. Here, we introduce a dual-targeting strategy to combat melanoma by leveraging bispecific agents that disrupt key ECM and tumor-associated pathways. Building on the inhibitory properties of lysyl oxidase-propeptide (LOX-PP), we engineered biselective decoys that simultaneously target the collagen cross-linking enzyme LOX and heat shock protein 70 (HSP70), both of which are up-regulated during melanoma progression in both human and mouse models. This dual-targeting strategy offers a new avenue for disrupting ECM-driven tumor progression and enhancing therapeutic efficacy. Administered to mouse models of melanoma, the decoys reduced tumor burden and circulating melanoma cells by inhibiting proliferation and lung metastasis. Mechanistically, the decoys suppressed cancer-supporting ECM organization, inhibited ECM-remodeling pathways and associated enzymes, and reshaped the tumor immune microenvironment. The treatment modulated immune responses by enhancing neutrophil, B cell, and CD8(+) T cell infiltration. In combination with immune check point inhibitor, the decoys further promoted melanoma killing by CD8(+) T cells. The decoys efficiently bound multiple human tumors expressing LOX(+)/HSP70(+) ex vivo. These findings highlight the potential of dual inhibition as a potential strategy for remodeling melanoma and other tumor microenvironments and enhancing immunotherapy efficacy.

Author Info: (1) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. Department of Agricultural Development, Agrofood an

Author Info: (1) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. Department of Agricultural Development, Agrofood and Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, Psachna 34400, Greece. (2) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (3) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (4) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (5) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (6) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (7) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (8) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (9) Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel. (10) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. (11) Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel. (12) Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. (13) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (14) Univ. Lyon, Institut de Chimie et Biochimie MolŽculaires et SupramolŽculaires (ICBMS), UMR 5246, University Lyon 1, CNRS, Villeurbanne F-69622, France. (15) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (16) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel.

Dendritic cell progenitors engineered to express extracellular-vesicle-internalizing receptors enhance cancer immunotherapy in mouse models

Cancer immunotherapy using dendritic cells (DC) pulsed ex vivo with tumour antigens is considered safe, but its clinical efficacy is generally modest. Here we engineer DC progenitors (DCP), which can replenish conventional type 1 DCs (cDC1) in mice, to constitutively express IL-12 together with a non-signalling chimeric receptor, termed extracellular vesicle-internalizing receptor (EVIR). By binding to a bait molecule (GD2 disialoganglioside) expressed on cancer cells and their EVs, the EVIR enforces EV internalization by cDC1 to promote their cross-dressing with preformed, tumour-derived MHCI-peptide complexes. Upon systemic deployment to mice, the engineered DCPs cause only mild and transient elevation of liver enzymes, acquire tumour-derived material, engage tumour-specific T cells, and enhance the efficacy of PD-1 blockade in an immunotherapy-resistant melanoma model comprising both GD2-positive and -negative cancer cells, without the need for ex vivo antigen pulsing. These results indicate that EVIR-engineered DCPs may avert the positive selection of antigen-negative cancer cells, potentially addressing a critical limitation of immunotherapies targeting defined tumour antigens.

Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer

Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (2) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (3) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (4) Laboratory of Metabolic Signaling, Institute of Bioengineering, EPFL, Lausanne, Switzerland. (5) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (6) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (7) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (8) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. (9) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (10) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (11) Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (12) Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. Department of Oncology, Geneva University Hospital (HUG), Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva (UNIGE), Geneva, Switzerland. (13) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. michele.depalma@epfl.ch. Agora Cancer Research Center, Lausanne, Switzerland. michele.depalma@epfl.ch. Swiss Cancer Center LŽman (SCCL), Lausanne, Switzerland. michele.depalma@epfl.ch.

Local delivery of IL-15 and anti-PD-L1 nanobody by in vitro-transcribed circILNb elicits superior antitumor immunity in cold tumors

The clinical translation of combined immunocytokine (IC) and immune checkpoint inhibitor (ICI) is constrained by relapse of advanced malignancies, systemic toxicities, and prohibitive research and synthesis costs. In this study, the circCV-B3 vector is constructed to enable scarless circular RNA (circRNA) engineering. The circILNb, engineered via the circCV-B3 vector, enables co-encoding of interleukin-15 (IL-15) and anti-PD-L1 nanobody (Nb). The circILNb is purified by biotin-avidin purification system (BAPS) and is encapsulated within lipid nanoparticles (LNPs). Intratumoral circILNb administration achieves in situ protein expression, achieving local tumor control. Furthermore, dendritic cells (DCs) load circILNb and migrate to tumor-draining lymph node (tdLN), where they prime antigen-specific CD8(+) T cell activation, eliciting a robust systemic immune response. These findings highlight the potential of circCV-B3 vector and BAPS as a methodology for circRNA engineering and substantiate circILNb as non-protein-based therapeutic strategy for tumor immunotherapy.

Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Fac

Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (3) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (4) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (5) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (6) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (7) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (8) College of Education and Science, Chongqing Normal University, Chongqing 400047, China. (9) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (10) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (11) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (12) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: yangmingzhen0807@126.com. (13) National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: qmzou2007@163.com. (14) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.

Serial multiomics uncovers anti-glioblastoma responses not evident by routine clinical analyses

Ling et al. provided a longitudinal multiomic view of human glioblastoma (GBM) evolution under intratumoral oncolytic viral therapy (CAN-3110), demonstrating the feasibility and importance of serial tumor sampling in studying therapeutic response. Spatial and temporal remodeling of the tumor microenvironment was mapped across 86 serial GBM biopsies from two patients. Multiomic analysis revealed therapeutic response, longitudinal and spatial reshaping of the tumor, expansion of HSV-reactive and tumor-specific T cell clonotypes, and enhanced HLA and cancer testis antigen presentation, despite indications of disease progression by MRI.

Contributed by Shishir Pant

Ling et al. provided a longitudinal multiomic view of human glioblastoma (GBM) evolution under intratumoral oncolytic viral therapy (CAN-3110), demonstrating the feasibility and importance of serial tumor sampling in studying therapeutic response. Spatial and temporal remodeling of the tumor microenvironment was mapped across 86 serial GBM biopsies from two patients. Multiomic analysis revealed therapeutic response, longitudinal and spatial reshaping of the tumor, expansion of HSV-reactive and tumor-specific T cell clonotypes, and enhanced HLA and cancer testis antigen presentation, despite indications of disease progression by MRI.

Contributed by Shishir Pant

ABSTRACT: Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM's microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)-presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM's evolution during administration of an investigational therapy.

Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical Sc

Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (2) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (3) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (4) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (7) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (8) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (9) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (10) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (11) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (12) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (13) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (14) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (15) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (17) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3AOG4, Canada. (18) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (19) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (20) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (21) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (22) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (23) Department of Radiation Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (24) Department of Pathology, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Neurosurgery, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (27) Department of Neuro-Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (28) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (29) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (30) Department of Neurology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (31) Division of Neuro-Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (32) Department of Neurosurgery, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (33) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (34) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (35) Department of Biostatistics, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (36) Candel Therapeutics Inc., Needham, MA 02494, USA. Accelerating GBM Therapies TeamLab, Cambridge, MA 02142, USA. (37) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. Department of Immunology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (38) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (39) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (40) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (41) Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (42) Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (43) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.

Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer

To systematically identify recurrent clonal neoepitopes in treatment-resistant patients, Gumbert and Sagie et al. developed and applied the “Spot Neoantigens in Metastases” (SpotNeoMet) pipeline to metastatic cancer samples from the Hartwig Medical Foundation, using primary tumor samples from TCGA as control. Focusing on the common androgen receptor (AR) H875Y mutation in castration-resistant prostate cancer, they identified three neopeptides and validated their presentation and immunogenicity. Two cloned cognate TCRs were highly specific and led to killing of prostate cancer cells endogenously expressing AR H875Y in vitro and in vivo.

Contributed by Ute Burkhardt

To systematically identify recurrent clonal neoepitopes in treatment-resistant patients, Gumbert and Sagie et al. developed and applied the “Spot Neoantigens in Metastases” (SpotNeoMet) pipeline to metastatic cancer samples from the Hartwig Medical Foundation, using primary tumor samples from TCGA as control. Focusing on the common androgen receptor (AR) H875Y mutation in castration-resistant prostate cancer, they identified three neopeptides and validated their presentation and immunogenicity. Two cloned cognate TCRs were highly specific and led to killing of prostate cancer cells endogenously expressing AR H875Y in vitro and in vivo.

Contributed by Ute Burkhardt

ABSTRACT: New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.

Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann In

Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann Institute of Science, Rehovot, Israel. (5) Weizmann Institute of Science, Rehovot, Israel. (6) Institute for Research in Biomedicine, Barcelona, Spain. (7) Princeton University, Princeton, NJ, United States. (8) Vall d'Hebron Institute of Oncology, Spain. (9) Weizmann Institute of Science, Rehovot, Israel. (10) Flatiron Institute, New York, NY, United States. (11) Weizmann Institute of Science, Rehovot, Israel. (12) Weizmann Institute of Science, Israel. (13) Weizmann Institute of Science, Rehovot, Israel. (14) Weizmann Institute of Science, Israel. (15) Weizmann Institute of Science, Rehovot, Israel, Israel. (16) University of Michigan-Ann Arbor, Ann Arbor, United States. (17) University of Michigan-Ann Arbor, Ann Arbor, United States. (18) Vall d'Hebron Institute of Oncology, Barcelona, Barcelona, Spain. (19) Vall d'Hebron Institute of Oncology, Spain. (20) Hadassah Medical Center, Jerusalem, Israel. (21) Weizmann Institute of Science, Israel. (22) Weizmann institute, Rehovot, Israel, Israel. (23) Weizmann Institute of Science, Rehovot, Israel, Israel. (24) Weizmann Institute of Science, Rehovot, Israel. (25) Princeton University, Princeton, NJ, United States. (26) University of British Columbia, Vancouver, British Columbia, Canada. (27) University of British Columbia, Vancouver, British Columbia, Canada. (28) University of Michigan-Ann Arbor, Ann Arbor, MI, United States. (29) University of California, San Francisco, San Francisco, CA, United States. (30) Dana-Farber Cancer Institute, Boston, MA, United States. (31) Weill Cornell Medicine, New York, NY, United States. (32) Vall d'Hebron Institute of Oncology, Barcelona, Spain. (33) Memorial Sloan Kettering Cancer Center, United States. (34) Vall d'Hebron Institute of Oncology, Spain. (35) Institute for Research in Biomedicine, Barcelona, Spain. (36) Weizmann Institute of Science, Rehovot, Israel.

Replacing cholesterol and PEGylated lipids with zwitterionic ionizable lipids in LNPs for spleen-specific mRNA translation

Zhao, Tian, Wang, et al. developed a new mRNA therapeutic cancer vaccine formulation that replaces cholesterol and PEGylated lipids in lipid nanoparticles (LNPs) with zwitterionic pyridine carboxybetaine ionizable lipids. This change increased spleen mRNA translation, reduced liver accumulation, and prevented immunogenicity against the vaccine upon repeat administration. The vaccine formulation induced specific CD8+ T cell responses, Tem and Tcm responses, and improved tumor control in murine models.

Zhao, Tian, Wang, et al. developed a new mRNA therapeutic cancer vaccine formulation that replaces cholesterol and PEGylated lipids in lipid nanoparticles (LNPs) with zwitterionic pyridine carboxybetaine ionizable lipids. This change increased spleen mRNA translation, reduced liver accumulation, and prevented immunogenicity against the vaccine upon repeat administration. The vaccine formulation induced specific CD8+ T cell responses, Tem and Tcm responses, and improved tumor control in murine models.

ABSTRACT: The spleen is emerging as a key vaccination target. However, existing lipid nanoparticles (LNPs) primarily accumulate in the liver, limiting their efficacy in vaccine therapy. The cholesterol in current LNP formulations promotes their uptake by hepatocytes, while the polyethylene glycol-modified (PEGylated) lipids induce PEG immunogenicity, further reducing the efficacy in the setting of repeated administrations. We develop a three-component (ThrCo) LNP by replacing cholesterol and PEGylated lipids in Pfizer-BioNTech LNPs with zwitterionic pyridine carboxybetaine (PyCB) ionizable lipids (ILs), achieving ~70% lower liver accumulation and a 4.5-fold increase in spleen-specific mRNA translation. PyCB ILs enhance LNP hydrophilicity, stabilizing the outer membrane to compensate for cholesterol removal. PyCB groups also exhibit strong protonation at endosomal pH, facilitating mRNA translation. The zwitterionic surface of ThrCo LNP reduces protein adsorption, thereby preventing the accelerated blood clearance effect caused by PEGylated lipids following repeated administrations. Thus, ThrCo LNP-based vaccines efficiently deliver mRNA to splenic antigen-presenting cells, boosting immune responses and improving therapeutic outcomes.

Author Info: (1) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (2) Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 1

Author Info: (1) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (2) Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA. (3) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (4) Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA. (5) Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA. (6) Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. (7) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (8) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. (9) Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. (10) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (11) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (12) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (13) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (14) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (15) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (16) Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA. (17) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (18) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.

Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment impacting colorectal liver metastases

Keenan and Qiao et al. showed in mouse models of colorectal liver metastases (CRLMs, which are CTLA-4high) that anti-CTLA-4 (but not anti-PD-1) treatment controlled LIGHT-overexpressing CRLMs by generating systemic and intratumoral immune activation. scRNAseq, CyTOF, and flow cytometry showed that the LIGHT/anti-CTLA-4 combination remodeled the TME; promoted TIL migration into metastases, TLS development, activation and effector functions of T cells and DC maturation; decreased T cell exhaustion; depleted suppressive myeloid cells; and reduced Treg functionality, with some corresponding data in human CRC.

Contributed by Paula Hochman

Keenan and Qiao et al. showed in mouse models of colorectal liver metastases (CRLMs, which are CTLA-4high) that anti-CTLA-4 (but not anti-PD-1) treatment controlled LIGHT-overexpressing CRLMs by generating systemic and intratumoral immune activation. scRNAseq, CyTOF, and flow cytometry showed that the LIGHT/anti-CTLA-4 combination remodeled the TME; promoted TIL migration into metastases, TLS development, activation and effector functions of T cells and DC maturation; decreased T cell exhaustion; depleted suppressive myeloid cells; and reduced Treg functionality, with some corresponding data in human CRC.

Contributed by Paula Hochman

ABSTRACT: Colorectal cancer and liver metastases are a leading cause of cancer-related mortality. Overexpression of the immunostimulatory cytokine TNFSF14/LIGHT associates with improved survival and correlates with increased tumor-infiltrating lymphocytes in patients and a clinically relevant model of colorectal liver metastases. We demonstrate that LIGHT monotherapy activates T cells, but also induces T cell exhaustion and the recruitment of immunosuppressive elements. As colorectal liver metastases exhibit high levels of CTLA-4 expression, we combined LIGHT overexpression with anti-CTLA-4, leading to complete tumor control. The combination functions by homing tumor-infiltrating lymphocytes, inducing tumor antigen-specific T cells, and reversing T cell exhaustion. Whereas both LIGHT overexpression and anti-CTLA-4 increase tumor-promoting macrophages, the combination eliminates this population. The ability of LIGHT overexpression combined with CTLA-4 inhibition to reverse T cell exhaustion and myeloid cell suppression is supported by analysis of complementary patient cohorts and has strong clinical relevance, especially given that liver metastases contribute to immunotherapy resistance across various cancer types.

Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical

Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (5) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (8) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (11) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (12) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. (13) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (14) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.

Collagen-disrupting attIL12 TIL therapy boosts deep T cell infiltration via dual signaling activation and CCKAR reduction in sarcomas

Across clinical sarcomas, collagen expression increased with tumor stage and associated with reduced patient survival. To treat ECM-rich tumors, Hu and Singh et al. modified TILs to express a cell-surface vimentin (CSV, sarcoma antigen)-targeting peptide linked to IL-12 (attIL12-TILs). Compared to standard TILs, attIL12-TILs improved IFNγ production, reduced tumor collagen expression, and boosted infiltration and tumor control in mouse sarcoma models. Inhibiting signaling by either TCRs or CSV abrogated these effects. Mechanistically, attIL12-TILs reduced tumor cell collagen levels via IFNγ inhibition of TGFβ-SMAD3 and CCKAR-pAKT pathways.

Contributed by Alex Najibi

Across clinical sarcomas, collagen expression increased with tumor stage and associated with reduced patient survival. To treat ECM-rich tumors, Hu and Singh et al. modified TILs to express a cell-surface vimentin (CSV, sarcoma antigen)-targeting peptide linked to IL-12 (attIL12-TILs). Compared to standard TILs, attIL12-TILs improved IFNγ production, reduced tumor collagen expression, and boosted infiltration and tumor control in mouse sarcoma models. Inhibiting signaling by either TCRs or CSV abrogated these effects. Mechanistically, attIL12-TILs reduced tumor cell collagen levels via IFNγ inhibition of TGFβ-SMAD3 and CCKAR-pAKT pathways.

Contributed by Alex Najibi

ABSTRACT: Tumor-targeted T cell therapies of various types have been booming, but T cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell-surface vimentin (CSV)-targeted and membrane-anchored interleukin 12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, but fail to reduce collagen expression by tumor cells, resulting in resistance to attIL12-T cell treatment. In this study, we found that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells by attIL12-TILs overcomes resistance to attIL12-T cell treatment and required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and human leukocyte antigen-T cell receptor on attIL12-TILs; When either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells induced interferon gamma production synergistically, which in combination with CCKAR downregulation reduced collagen expression through suppression of both transforminggrowth factor beta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T cell infiltration and improved tumor growth inhibition in PDX sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T cell infiltration in high-grade, collagen-rich tumors.

Author Info: (1) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Division of Pediatrics, Department of Pedia

Author Info: (1) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (3) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (4) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (5) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (6) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (7) Division of Cancer Medicine, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (8) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (9) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

Primate resident memory T cells activate humoral and stromal immunity

Joag et al. demonstrated that systemic T cell-based vaccines generate robust T cell surveillance throughout the body, integrating cellular and humoral immunity. Intravenous heterologous prime-boost vaccination in macaques established SIV-gag–specific CD8⁺ memory (including resident memory [Trm]), T cells across more than 30 lymphoid, mucosal, and visceral tissues. Local Trm reactivation in the reproductive tract mucosa activated stromal, endothelial, and innate lymphoid cells, amplifying interferon-driven antiviral programs. These signals recruited CD4⁺ T cells with host-defense signatures, and mobilized B and plasma cells.

Contributed by Shishir Pant

Joag et al. demonstrated that systemic T cell-based vaccines generate robust T cell surveillance throughout the body, integrating cellular and humoral immunity. Intravenous heterologous prime-boost vaccination in macaques established SIV-gag–specific CD8⁺ memory (including resident memory [Trm]), T cells across more than 30 lymphoid, mucosal, and visceral tissues. Local Trm reactivation in the reproductive tract mucosa activated stromal, endothelial, and innate lymphoid cells, amplifying interferon-driven antiviral programs. These signals recruited CD4⁺ T cells with host-defense signatures, and mobilized B and plasma cells.

Contributed by Shishir Pant

ABSTRACT: CD8(+) resident memory T (Trm) cells comprise a small population of frontline sentinels compared with the large tissues they surveil, making outsized contributions to immune protection from infection. Here, we interrogated mechanisms of Trm cell function in primates. Intravenous immunization of macaques with a simian immunodeficiency virus (SIV)-gag-containing heterologous prime-boost-boost vaccine established memory T cells in >30 tissues, including visceral and mucosal compartments. Upon in vivo reactivation in the reproductive tract, antigen-sensing CD8(+) Trm activated local stromal, parenchymal, and innate and adaptive immune cells. Stromal and parenchymal cells accentuated leukocyte migration and antiviral defenses. B and plasma cells mobilized into the vaginal mucosa, and bloodborne CD4(+) T cells were recruited and adopted a host-defense program. Our findings demonstrate that systemic vaccination promotes a Trm cell response in barrier compartments and that Trm cells repurpose abundant neighboring stromal, parenchymal, and immune cells to amplify alarm signals and activate diverse host defenses.

Author Info: (1) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vineet.joag@seattlechildrens.org. (2)

Author Info: (1) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vineet.joag@seattlechildrens.org. (2) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (3) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (4) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (5) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (6) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (7) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (8) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (9) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (10) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (11) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (12) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (13) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (14) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (15) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (16) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (17) Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. (18) Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6G 2V4, Canada. (19) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (20) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (21) Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA. (22) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (23) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (24) Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. (25) Center for Innate Immunity and Inflammation, Pelotonia Institute for Immuno-oncology, the James Comprehensive Cancer Center, Department of Surgery, Ohio State University, Columbus, OH, USA. (26) Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA. (27) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (28) Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA. (29) Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA. (30) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (31) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: masopust@umn.edu.

Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density Spotlight 

To treat neuroblastoma expressing the oncofetal antigen GPC2, Quan and Huo et al. generated "AbTCR-T cells" expressing (1) anti-GPC2 Fab linked to TCRγδ and (2) anti-GPC2 scFv linked to a CD30 costimulatory domain. The GPC2-binding domain was humanized from the murine CT3 antibody, and retained specific GPC2 binding. Compared to CAR-T, AbTCR-T had superior cytotoxicity, tumor T cell infiltration, and in vivo efficacy against tumors with high or, in particular, low antigen expression. AbTCR-T also maintained a less exhausted and more stem-like phenotype, improving serial cytotoxicity, and augmented endogenous TCR and NFAT signaling.

Contributed by Alex Najibi

To treat neuroblastoma expressing the oncofetal antigen GPC2, Quan and Huo et al. generated "AbTCR-T cells" expressing (1) anti-GPC2 Fab linked to TCRγδ and (2) anti-GPC2 scFv linked to a CD30 costimulatory domain. The GPC2-binding domain was humanized from the murine CT3 antibody, and retained specific GPC2 binding. Compared to CAR-T, AbTCR-T had superior cytotoxicity, tumor T cell infiltration, and in vivo efficacy against tumors with high or, in particular, low antigen expression. AbTCR-T also maintained a less exhausted and more stem-like phenotype, improving serial cytotoxicity, and augmented endogenous TCR and NFAT signaling.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to _/_ T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8(+) T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.

Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular

Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (3) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (4) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (5) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (7) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (8) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (9) Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (10) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (11) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (12) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (13) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (14) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (15) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (16) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (17) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (18) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (19) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (20) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. Electronic address: homi@mail.nih.gov.

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