Journal Articles

A genome‑wide screen in E. coli reveals metabolic adaptations that enhance intratumoral fitness and bacterial cancer therapy efficacy

ABSTRACT: Despite decades of investigation, the fundamental molecular and cellular principles that enable bacteria to thrive within the tumor microenvironment have yet to be defined. Here, through a genome‑wide functional screen, we identify the bacterial genes and pathways that govern intratumoral fitness. Targeted deletion of nonglucose phosphotransferase systems to align bacterial metabolic preference with tumor metabolite availability promotes bacterial intratumoral fitness. Integrating multiple metabolic adaptations into a single tumor‑avid Escherichia coli strain (Ec‑TA) results in increased tumor colonization, not only after intratumoral delivery but also after intravenous delivery, leading to increased anti‑tumor efficacy when using Ec‑TA engineered to deliver an encoded immunostimulatory payload. Furthermore, Ec‑TA displaces wild‑type bacteria from pre‑colonized tumors when administered systemically, underscoring its potential for locally delivering therapeutics in the presence of resident tumor microbes. These data demonstrate that adapting bacteria to the unique characteristics of the tumor metabolic microenvironment can drive the development of safer and more effective chassis for next‑generation bacterial cancer therapies.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbi

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. (2) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. (3) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (4) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (5) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (6) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (7) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (8) Department of Biological Sciences, Columbia University, New York, NY, USA. (9) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. (10) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (11) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (12) Department of Biological Sciences, Department of Chemistry, and Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Irving Institute for Cancer Dynamics, Digestive and Liver Disease Research Center, Columbia University, New York, NY, USA. (13) Department of Environmental Science and Technology, Faculty of Engineering, Shinshu University, Nagano, Japan. (14) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Department of Biomedical Engineering, Columbia University, New York, NY, USA. Data Science Institute, Columbia University, New York, NY, USA. (15) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. na2697@cumc.columbia.edu. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. na2697@cumc.columbia.edu.

DC vaccine loaded with Bacteroides fragilis elicits functional cross-reactivity and enhances anti-PD-1 immunotherapy

The gut microbiome profoundly influences the clinical benefits of antitumor immunotherapy. Although various gut microbiota have been shown to enhance immunotherapy, their clinical application remains unexplored. In this study, a dendritic cell (DC) vaccine loaded with the gut commensal Bacteroides fragilis (DC-Bf) was used as a therapeutic cancer vaccine. DC-Bf elicited T cell responses that recognize both B. fragilis and tumor cells, primarily via major histocompatibility complex-I-mediated cross-presentation of B. fragilis antigens to prime CD8(+) T cells. DC-Bf treatment increased CD8(+) T cell infiltration and activation, expanded the diversity of the T cell receptor repertoire, and reduced the proportion of regulatory T cells and M2-type tumor-associated macrophages, thereby improving the immunosuppressive tumor microenvironment. In multiple tumor-bearing models, DC-Bf enhanced the therapeutic activity of programmed cell death protein 1 inhibitors by inducing interleukin-12-driven, CD8(+) T cell-dependent antitumor immune responses. This study confirms the potential of using bacteria-loaded DCs to augment immunotherapy efficacy and provides a new perspective for the clinical application of the gut microbiome. Targeting the gut microbiota holds promise as a novel avenue for developing antitumor vaccines.

Author Info: (1) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (2) Department of Biotherapy, Ca

Author Info: (1) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (2) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (3) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (4) Department of Oncology, West China Hospital, Sichuan University, Sichuan University West China Hospital Guang'an Hospital, Guang'an People's Hospital, Guang'an 638000, China. (5) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (6) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (7) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. (8) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: ping.cheng@foxmail.com. (9) Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: liujiyan1972@163.com.

Tumor-to-dendritic cell reprogramming induces immunogenic lymphoid structures across cancers

Ascic, Chatelain, et al. investigated TLSs initiated in various tumor models after PIB-transduction of tumor cells into cDC1s. Immunogenic TLSs formed in tumors and were associated with improved outcomes, immune memory, and, in some cases, synergized with ICB. TLS formation was dependent on T and B cells, and on MHC-I and CD40 signaling.

Ascic, Chatelain, et al. investigated TLSs initiated in various tumor models after PIB-transduction of tumor cells into cDC1s. Immunogenic TLSs formed in tumors and were associated with improved outcomes, immune memory, and, in some cases, synergized with ICB. TLS formation was dependent on T and B cells, and on MHC-I and CD40 signaling.

ABSTRACT: Tertiary lymphoid structures (TLSs) in tumors are associated with improved responses to immunotherapy. Here, we examined the impact of type 1 conventional dendritic cells (cDC1s) in TLS formation. Reprogrammed tumor cells into cDC1-like cells remodeled the tumor microenvironment and induced immunogenic TLSs (imgTLSs) across melanoma, colon, bladder, breast, and pancreatic cancer models with distinct genetic backgrounds. cDC1-like cells activated lymphotoxin, TNF, and interferon programs and engaged early with T cells through MHC class I and CD40 signaling to induce imgTLSs containing BCL6(+) germinal centers, independently of endogenous cDC1s. Intratumoral positioning shaped distinct cDC1-like cell states, with DC-LAMP(+) CCR7(+) migratory cDC1s nucleating niches enriched in CD4(+), CD8(+) T cells, and B cells in mouse and human tumors. ImgTLSs sustained B and T cell responses and promoted systemic immunity through expansion of shared clonotypes in distant, untreated tumors. Our findings outline the spatial organization, signaling programs and interactions of cDC1-like cells that initiate intratumoral lymphoid structures and establish cellular reprogramming as a strategy toward overcoming resistance to immunotherapy.

Author Info: (1) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Lab

Author Info: (1) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (2) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (3) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (4) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (5) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (6) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (7) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (8) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (9) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (10) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (11) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (12) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (13) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (14) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden; Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (15) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (16) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (17) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (18) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (19) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (20) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (21) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (22) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (23) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (24) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden; Asgard Therapeutics AB, Medicon Village, Lund, Sweden; CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, Coimbra, Portugal; CiBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal. Electronic address: filipe.pereira@med.lu.se.

Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy

ABSTRACT: The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1(+) Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1(+)PD-1(+)CD8(+) T cells and enrichment of tumor-selective effector T cells. Stem-like CD8(+) T cells were clonally diverse and rapidly acquired a TCF1(-) differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12(+)CD34(+) Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8(+) T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (3) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (4) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (5) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (6) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (7) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (8) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (9) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (10) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (11) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (12) Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Stra§e 68, 51429 Bergisch Gladbach, Germany. (13) Genome Centre, Blizard Institute, Queen Mary University of London, London E1 2AT, UK. (14) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (15) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (16) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (17) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. Electronic address: james.arnold@kcl.ac.uk.

Antigen scaffolds drive preferential expansion of functional genetically engineered CAR and TCR T cells

T cells engineered to express recombinant T cell receptors (TCRs) or chimeric antigen receptors (CARs) can induce durable clinical responses in solid and hematological malignancies. However, manufacturing is resource intensive and often yields highly differentiated, exhausted T cell products. To address this, we developed an antigen-scaffold (Ag-scaffold) technology that presents cognate antigen alongside stimulatory cytokines to preferentially expand genetically engineered T cells. We expanded CRISPR-Cas9- and lentivirally engineered TCR T cells with peptide MHC (pMHC)-presenting Ag-scaffolds and anti-CD19 CAR T cells with CD19-presenting Ag-scaffolds. By applying cognate pMHC Ag-scaffolds, we achieved on average 69% (±22%) antigen-specific T cells after 14 days of culture with a cytotoxic, proliferative profile. Ag-scaffold expansion enhanced initial TCR and CAR cytotoxicity; repeated rechallenges showed sustained control. In vivo, Ag-scaffold-expanded CRISPR-Cas9-engineered NY-ESO-1-specific TCR T cells and anti-CD19 CAR T cells also showed improved tumor control in lymphoma and solid tumor xenograft models compared to cells expanded with IL2/7/15.

Author Info: (1) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Electron

Author Info: (1) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Electronic address: krisha@dtu.dk. (2) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (3) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (4) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (5) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (6) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (7) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (8) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (9) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (10) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (11) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (12) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (13) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (14) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (15) T Cells and Cancer, Experimental and Translational Immunology Section, Department for Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Electronic address: sirha@dtu.dk.

Personalized neoantigen-targeting cancer vaccines in ovarian cancer: a phase 1 trial Featured  

In a phase 1 clinical trial, Sellars et al. evaluated the adjuvant use of personalized cancer vaccines in combination with nivolumab in patients with high-grade ovarian cancer treated with standard-of-care platinum-based chemotherapy. Treatment was feasible and well tolerated, with evidence of vaccine-induced T cell responses and antitumor immunity. Immune escape through several mechanisms was also observed.

In a phase 1 clinical trial, Sellars et al. evaluated the adjuvant use of personalized cancer vaccines in combination with nivolumab in patients with high-grade ovarian cancer treated with standard-of-care platinum-based chemotherapy. Treatment was feasible and well tolerated, with evidence of vaccine-induced T cell responses and antitumor immunity. Immune escape through several mechanisms was also observed.

ABSTRACT: Personalized neoantigen-targeting cancer vaccines in the adjuvant setting are of increasing interest across malignancies. Here we report the results of a phase 1 clinical trial testing the feasibility and safety of personalized neoantigen-targeting cancer vaccines for high-grade epithelial ovarian cancer. 'NeoVax' consisted of pools of synthetic long peptides targeting patient-specific neoantigens admixed with the immunostimulant poly-ICLC, was combined with delayed administration of anti-PD-1 antibody, and was tested in ten patients (one newly diagnosed patient (Cohort A) and nine patients at first recurrence (Cohort B)) with platinum-sensitive ovarian cancer following standard-of-care platinum doublet chemotherapy. Nine of 12 evaluable Cohort B patients were vaccinated (75%, 90% CI 47-93%) and 1 of 9 Cohort A patients (11%, 90% CI 0.6-43%). No unexpected safety signals were encountered and no patients discontinued treatment due to toxicity. Across patients, >70% selected targets remained detectable by noninvasive cell-free DNA analysis despite a median of 6.5 months from the time of diagnostic biopsy to vaccine administration, during which, patients received standard-of-care chemotherapy. Biomarker analysis was suggestive of biologic activity of the vaccine in six of ten patients and this was associated with broader tumor and vaccine-specific immune responses in blood and tumor following vaccination. Resistant tumor clones reflected diverse mechanisms affecting antigen presentation, indicative of immune-selective pressure exerted by vaccination. Overall, the interplay between the repertoire of antigens presented by the tumor and the breadth of induced immunity seemed to dictate clinical efficacy following vaccination. ClinicalTrials.gov identifier: NCT04024878 .

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer I

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (26) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (28) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (29) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (30) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (34) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (35) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Department of Pathology, Harvard Medical School, Boston, MA, USA. (36) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (37) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (38) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (39) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (40) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Department of Medical Education and Biomedical Sciences, Methodist University CFVH School of Medicine, Fayetteville, NC, USA. (41) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. Mellen and Eisenson Family Center for BRCA and Related Genes, Dana-Farber Cancer Institute, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. (42) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Catherine_Wu@dfci.harvard.edu. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu.

Selective expansion of neoantigen-specific peripheral blood lymphocytes through antigen-presenting cell-T cell conjugate isolation Spotlight 

Khateb et al. developed NeoSelect to expand ultra-rare neoantigen-specific peripheral blood lymphocytes (NeoPBL) using two cycles of stimulation with neoantigen-specific peptides and enrichment of APC–T cell conjugates followed by a rapid expansion protocol. This strategy amplified NeoPBLs to high frequencies and absolute numbers, and even recovered neoantigen-specific TIL clonotypes that failed to expand ex vivo. NeoPBL clonotypes overlapped with those of highly differentiated and exhausted TILs. The on-target stimulation during NeoSelect shaped the transcriptional and epigenetic profile of NeoPBLs, resulting in polyfunctional, TPEX-like effectors.

Contributed by Ute Burkhardt

Khateb et al. developed NeoSelect to expand ultra-rare neoantigen-specific peripheral blood lymphocytes (NeoPBL) using two cycles of stimulation with neoantigen-specific peptides and enrichment of APC–T cell conjugates followed by a rapid expansion protocol. This strategy amplified NeoPBLs to high frequencies and absolute numbers, and even recovered neoantigen-specific TIL clonotypes that failed to expand ex vivo. NeoPBL clonotypes overlapped with those of highly differentiated and exhausted TILs. The on-target stimulation during NeoSelect shaped the transcriptional and epigenetic profile of NeoPBLs, resulting in polyfunctional, TPEX-like effectors.

Contributed by Ute Burkhardt

BACKGROUND: Neoantigen-specific peripheral blood lymphocytes (NeoPBL) are the circulating counterparts of neoantigen-specific tumor-infiltrating lymphocytes (TILs). A recent study showed NeoPBL exist in a less differentiated state in vivo than TIL, which, along with their non-invasive potential, makes them attractive for cell therapy. However, NeoPBL circulate at ultra-low frequencies, usually less than 0.005%, posing a major translational barrier for their clinical use. METHODS: Here, we used NeoSelect, a peptide-based cyclic enrichment and expansion strategy that leverages magnetic selection of antigen-presenting cell-NeoPBL conjugates ex vivo to increase NeoPBL frequency by several thousand-fold over 28 days while also achieving large-scale expansion. We then evaluated expanded cells using functional, transcriptomic, and epigenetic profiling. RESULTS: Most NeoPBL clonotypes amplified by NeoSelect are detectable as exhausted TIL in vivo. In addition, neoantigen-specific TIL that failed to expand during ex vivo culture could be recovered as NeoPBL. Transcriptional and epigenetic analyses reveal that ex vivo NeoPBL have distinct transcriptional and epigenetic programs compared with TIL and retain expression of and chromatin accessibility at genes associated with stemness (TCF7, KLF2) and costimulation (CD28, CD40LG). CONCLUSIONS: NeoPBL encompass physiologically relevant antitumor clonotypes, can be rapidly expanded to clinically useful numbers and frequencies ex vivo, and can be used to expand the targetable neoantigen repertoire. By combining broad potential applicability and minimal invasiveness, these results position NeoPBL as a clinically streamlined and biologically distinct autologous cell platform that may be useful for adoptive cell transfer.

Author Info: (1) Surgery Branch, NCI, Bethesda, Maryland, USA. (2) Surgery Branch, NCI, Bethesda, Maryland, USA. (3) Surgery Branch, NCI, Bethesda, Maryland, USA. (4) Surgery Branch, NCI, Bethe

Author Info: (1) Surgery Branch, NCI, Bethesda, Maryland, USA. (2) Surgery Branch, NCI, Bethesda, Maryland, USA. (3) Surgery Branch, NCI, Bethesda, Maryland, USA. (4) Surgery Branch, NCI, Bethesda, Maryland, USA. (5) Surgery Branch, NCI, Bethesda, Maryland, USA. (6) Surgery Branch, NCI, Bethesda, Maryland, USA. (7) Surgery Branch, NCI, Bethesda, Maryland, USA. (8) Surgery Branch, NCI, Bethesda, Maryland, USA. (9) Surgery Branch, NCI, Bethesda, Maryland, USA. (10) Surgery Branch, NCI, Bethesda, Maryland, USA. (11) Surgery Branch, NCI, Bethesda, Maryland, USA. (12) Surgery Branch, NCI, Bethesda, Maryland, USA. (13) Surgery Branch, NCI, Bethesda, Maryland, USA. (14) Surgery Branch, NCI, Bethesda, Maryland, USA. (15) Surgery Branch, NCI, Bethesda, Maryland, USA. (16) Surgery Branch, NCI, Bethesda, Maryland, USA. (17) Surgery Branch, NCI, Bethesda, Maryland, USA. (18) Surgery Branch, NCI, Bethesda, Maryland, USA. (19) Surgery Branch, NCI, Bethesda, Maryland, USA. (20) Systems Biology Center, NHLBI, Bethesda, Maryland, USA. (21) Systems Biology Center, NHLBI, Bethesda, Maryland, USA. (22) Systems Biology Center, NHLBI, Bethesda, Maryland, USA. (23) Surgery Branch, NCI, Bethesda, Maryland, USA. (24) Surgery Branch, NCI, Bethesda, Maryland, USA. (25) Surgery Branch, NCI, Bethesda, Maryland, USA. (26) Surgery Branch, NCI, Bethesda, Maryland, USA. (27) NIDDK, Bethesda, Maryland, USA. (28) NCI/CCR, Bethesda, Maryland, USA. (29) Surgery Branch, NCI, Bethesda, Maryland, USA. (30) Surgery Branch, NCI, Bethesda, Maryland, USA nicholas.klemen@duke.edu.

Autologous erythrocyte microparticles drive antitumour T cell immunity via haem-mediated dendritic cell activation Spotlight 

Tang, Liang, Sun et al. developed a process to prepare haem-containing erythrocyte-derived microparticles (EMPs) from UV-irradiated erythrocytes as DC adjuvants. EMPs mixed with tumor cell lysates simultaneously activated and delivered antigen to DCs in vivo, providing CD8+ T cell-dependent prophylactic and therapeutic tumor control and enhanced survival. EMPs functioned by haem binding the nuclear receptor REV-ERBα, thereby inhibiting PPARγ transcription and driving DC activation. Human erythrocyte-derived EMPs were active in stimulating human DC maturation, and demonstrated in vivo activity in a humanized model.

Contributed by Ed Fritsch

Tang, Liang, Sun et al. developed a process to prepare haem-containing erythrocyte-derived microparticles (EMPs) from UV-irradiated erythrocytes as DC adjuvants. EMPs mixed with tumor cell lysates simultaneously activated and delivered antigen to DCs in vivo, providing CD8+ T cell-dependent prophylactic and therapeutic tumor control and enhanced survival. EMPs functioned by haem binding the nuclear receptor REV-ERBα, thereby inhibiting PPARγ transcription and driving DC activation. Human erythrocyte-derived EMPs were active in stimulating human DC maturation, and demonstrated in vivo activity in a humanized model.

Contributed by Ed Fritsch

ABSTRACT: Current vaccine adjuvants, such as aluminum salts and emulsions, are limited by weak induction of cytotoxic T cell immunity and restricted ability to promote T helper type 1 responses, highlighting the need for safer and more effective alternatives. Here we show that microparticles generated from erythrocytes by controlled ultraviolet irradiation function as potent T helper type 1-skewing adjuvants that enhance tumour antigen-specific cytotoxic T cell responses in vitro and in multiple mouse tumour models. Following uptake by dendritic cells, these microparticles traffic to lysosomes and deliver haem cargo that is subsequently transported to the nucleus. Mechanistically, the particles elevate lysosomal pH, promoting lysosome movement towards the nucleus and enabling haem transfer, where haem activates REV-ERB_ and forms a co-repressor complex that suppresses peroxisome proliferator-activated receptor gamma, thereby relieving inhibition of dendritic cell maturation and antigen presentation. In vaccination settings, combining tumour antigens with erythrocyte-derived microparticles enhances cytotoxic T cell activation and suppresses tumour growth with minimal toxicity. These findings establish host-derived vesicles as a promising platform for next-generation cancer vaccine adjuvants.

Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ketang@hust.edu.cn. Department of Breast

Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ketang@hust.edu.cn. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China. ketang@hust.edu.cn. (2) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (3) School of Medicine, Xinxiang University, Xinxiang, China. (4) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (5) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (6) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (7) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (8) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (9) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (10) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (11) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (13) Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (14) Department of Immunology and State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (15) Department of Immunology and State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (16) Department of Immunology and State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. (17) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjhuangbo@hotmail.com. Department of Immunology and State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. tjhuangbo@hotmail.com.

Bispecific dual T cell agonist invikafusp alfa in solid tumors: the phase 1/2 START-001 trial Spotlight 

In a phase 1/2 clinical trial in patients with ICB-resistant, antigen-rich solid tumors, Sullivan, Tschernia, Friedman, et al. evaluated invika – IL-2 fused to a bispecific antibody targeting Vβ6 and Vβ10 TCRs (enriched in TILs and memory-like T cells). While 2 patients experienced reversible dose-limiting toxicities. iviika was generally well tolerated, with low-grade CRS as the most common trAE. At the optimal biological dose across phase 1 and 2 (52 patients), the ORR was 14.8% and the DCR was 59.3%. Dose-dependent increases in Vβ6/Vβ10 T cell expansion, IFNγ, and soluble CD25 were also observed. A phase 2 trial is currently ongoing.

Contributed by Lauren Hitchings

In a phase 1/2 clinical trial in patients with ICB-resistant, antigen-rich solid tumors, Sullivan, Tschernia, Friedman, et al. evaluated invika – IL-2 fused to a bispecific antibody targeting Vβ6 and Vβ10 TCRs (enriched in TILs and memory-like T cells). While 2 patients experienced reversible dose-limiting toxicities. iviika was generally well tolerated, with low-grade CRS as the most common trAE. At the optimal biological dose across phase 1 and 2 (52 patients), the ORR was 14.8% and the DCR was 59.3%. Dose-dependent increases in Vβ6/Vβ10 T cell expansion, IFNγ, and soluble CD25 were also observed. A phase 2 trial is currently ongoing.

Contributed by Lauren Hitchings

ABSTRACT: Invikafusp alfa (invika), a first-in-class, bispecific, dual T cell agonistic antibody selectively targeting Vβ6/Vβ10 T cell subsets, is being evaluated in START-001, a multicenter phase 1/2 monotherapy trial in participants with mostly immune checkpoint blockade (ICB)-resistant, antigen-rich solid tumors. Primary outcomes were safety/tolerability and recommended phase 2 dose (RP2D) in phase 1 and anti-tumor activity in phase 2. As of 12 March 2025, phase 1 completed dose escalation (n = 34) through dose levels of 0.01, 0.02, 0.04, 0.08, 0.12 and 0.16 mg kg-1 without reaching maximum tolerated dose, and initial phase 2 enrolled 18 participants. Two participants experienced reversible dose-limiting toxicities, one at each of the 0.08 mg kg-1 and 0.16 mg kg-1 dose levels. The most common treatment-related adverse event was cytokine release syndrome, mainly grades 1 and 2. No treatment-related deaths or non-laboratory grade 4 adverse events were reported. At the optimal biological doses (OBDs; 0.08 mg kg-1 and 0.12 mg kg-1) in combined phase 1 and phase 2 cohorts, the overall objective response rate was 14.8% (4/27), including confirmed partial responses in immunologically cold tumors, such as microsatellite stable colorectal cancer and programmed death-ligand 1 (PD-L1)-negative non-small cell lung cancer. No objective responses were seen at doses lower than 0.08 mg kg-1. Invika selectively and potently expanded peripheral and intratumoral Vβ6/Vβ10 T cells, of a predominantly memory-like phenotype, dose-dependently, peaking at the OBDs. Pharmacodynamic increases in interferon-γ and soluble CD25 followed a similar pattern. Integrated analyses from safety, pharmacokinetic, pharmacodynamic and preliminary anti-tumor data supported the selection of 0.08 mg kg-1 as the RP2D. In conclusion, phase 1 of START-001 met its primary outcomes by demonstrating the acceptable safety profile of invika consistent with its mechanism of action and selecting an RP2D. Initial phase 2 results further corroborated the safety of invika and expanded its preliminary evidence of clinically meaningful anti-tumor activity in ICB-resistant solid tumors, supporting further evaluation in the ongoing phase 2. ClinicalTrials.gov identifier: NCT05592626 .

Author Info: (1) Mass General Brigham Cancer Institute, Boston, MA, USA. (2) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Hea

Author Info: (1) Mass General Brigham Cancer Institute, Boston, MA, USA. (2) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (5) AdventHealth Cancer Institute, Orlando, FL, USA. (6) The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. (7) Institut BergoniŽ, Bordeaux, France. (8) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (9) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (10) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (11) Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (12) Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (13) START-FJD, Madrid, Spain. (14) Mass General Brigham Cancer Institute, Boston, MA, USA. (15) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) AdventHealth Cancer Institute, Orlando, FL, USA. (17) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Marengo Therapeutics Inc., Cambridge, MA, USA. (21) Marengo Therapeutics Inc., Cambridge, MA, USA. (22) Marengo Therapeutics Inc., Cambridge, MA, USA. (23) Marengo Therapeutics Inc., Cambridge, MA, USA. (24) Marengo Therapeutics Inc., Cambridge, MA, USA. (25) Marengo Therapeutics Inc., Cambridge, MA, USA. (26) Marengo Therapeutics Inc., Cambridge, MA, USA. (27) Marengo Therapeutics Inc., Cambridge, MA, USA. (28) Marengo Therapeutics Inc., Cambridge, MA, USA. kliu@marengotx.com. (29) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. lillian.siu@uhn.ca. (30) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. gulleyj@mail.nih.gov.

Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic cancer: the randomized phase 2 AMPLIFY-7P trial Spotlight 

In a phase 2 clinical trial, patients with stage I-III KRAS-mutated PDAC recently (<6 months) cleared by standard therapy were treated with either camupepimut (a lymph-node targeting, CpG-adjuvanted vaccine targeting KRAS G12D and G12R neoantigens; n=96) or standard-of-care/observation (n=48). DFS lasted a median of 23.8 versus 21.2 months, which did not meet the primary endpoint, but an improved 6-month DFS rate of 75.7% vs. 61.7% was significantly associated with treatment. In camupepimut-treated patients, mKRAS-specific T cell responses above 9.17-fold over baseline correlated with improved DFS (NR vs. 6.08 months), with evidence of epitope spreading.

Contributed by Lauren Hitchings

In a phase 2 clinical trial, patients with stage I-III KRAS-mutated PDAC recently (<6 months) cleared by standard therapy were treated with either camupepimut (a lymph-node targeting, CpG-adjuvanted vaccine targeting KRAS G12D and G12R neoantigens; n=96) or standard-of-care/observation (n=48). DFS lasted a median of 23.8 versus 21.2 months, which did not meet the primary endpoint, but an improved 6-month DFS rate of 75.7% vs. 61.7% was significantly associated with treatment. In camupepimut-treated patients, mKRAS-specific T cell responses above 9.17-fold over baseline correlated with improved DFS (NR vs. 6.08 months), with evidence of epitope spreading.

Contributed by Lauren Hitchings

ABSTRACT: Camupepimut (ELI-002 7P) drives mutated KRAS (mKRAS)-specific T cell responses that correlated with disease-free survival (DFS) and overall survival (OS) in patients with mKRAS pancreatic adenocarcinoma (PDAC) in the phase 1 AMPLIFY-201 trial. In the phase 2 AMPLIFY-7P trial, patients with stage I-III KRAS-mutated PDAC without recurrence within 6 months of standard therapy were randomized 2:1 to camupepimut (n = 96) or standard-of-care/observation (n = 48). Stratification balanced nodal status. The primary DFS endpoint was not met (median 23.8 versus 21.2 months; HR 0.85, P = 0.5329). However, prespecified and exploratory analyses were informative. A numerical DFS advantage at 6 months of 14.0% (75.7% versus 61.7%; HR 0.55, P = 0.0557) corresponded to camupepimut dosing. Post hoc multivariate Cox regression analysis of DFS indicated an improved outcome for camupepimut (adjusted HR 0.47, P = 0.0086), a worse outcome for stage III disease (adjusted HR 2.29, P = 0.0127), an elevated baseline CA19-9 (adjusted HR 3.16, P < 0.0001) and baseline circulating tumor DNA (ctDNA) positivity (adjusted HR 5.99, P < 0.0001). Prespecified subgroup analyses addressing prognostic and predictive factors suggested DFS benefit for camupepimut (ctDNA negative: HR 0.51, P = 0.0280; no prior radiation: HR 0.59, P = 0.0221). Exploratory analysis demonstrated that ex vivo mKRAS-specific T cell responses were robust (98.9%, 89/90) and associated with antigen spreading (86.7%, 13/15). In camupepimut-treated patients, mKRAS-specific T cell response >9.17-fold over baseline (82.2%, 74/90) correlated with improved DFS (HR 0.22, P < 0.0001), with the median DFS not reached versus 6.08 months for above and below 9.17-fold, respectively. Camupepimut safety was similar to observation, with grade ≥3 adverse events in 10.4% (10/96) versus 14.6% (7/48), and few serious AEs (6.3%, 6/96 versus 8.3%, 4/48; reflecting progression/surgical complication). These efficacy and immunogenicity signals will inform a refined strategy for a confirmatory phase 3 trial. ClinicalTrials.gov identifier: NCT05726864 .

Author Info: (1) Medical College of Wisconsin, Milwaukee, WI, USA. george.ben@mayo.edu. Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. george.ben@mayo.edu. (2) Dana Farber Cancer

Author Info: (1) Medical College of Wisconsin, Milwaukee, WI, USA. george.ben@mayo.edu. Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. george.ben@mayo.edu. (2) Dana Farber Cancer Institute, Boston, MA, USA. (3) Northwell Health Cancer Institute, New Hyde Park, NY, USA. (4) City of Hope, Duarte, CA, USA. (5) Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. (6) Samuel Oschin Cancer Center, Cedars Sinai, Los Angeles, CA, USA. (7) Moffitt Cancer Center, Tampa, FL, USA. (8) University of California, Irvine, Orange, CA, USA. (9) Mayo Clinic, Phoenix, AZ, USA. (10) Vanderbilt-Ingram Cancer Center, Vanderbilt Health, Nashville, TN, USA. (11) Weill-Cornell Medicine, New York, NY, USA. NYU Langone Health, New York, NY, USA. (12) City of Hope, Duarte, CA, USA. Weill-Cornell Medicine, New York, NY, USA. (13) University of Colorado School of Medicine, Aurora, CO, USA. (14) Sarah Cannon Research Institute, Nashville, TN, USA. (15) University of Iowa, Iowa City, IA, USA. (16) Mass General Hospital, Boston, MA, USA. (17) University of Pennsylvania, Philadelphia, PA, USA. (18) University of Florida, Gainesville, FL, USA. (19) UT Southwestern, Dallas, TX, USA. (20) Ochsner Health, New Orleans, LA, USA. (21) Lehigh Valley Topper Cancer Institute, Jefferson Health, Allentown, PA, USA. (22) Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, MN, USA. (23) Elicio Therapeutics, Boston, MA, USA. (24) Elicio Therapeutics, Boston, MA, USA. (25) Elicio Therapeutics, Boston, MA, USA. (26) Elicio Therapeutics, Boston, MA, USA. (27) Elicio Therapeutics, Boston, MA, USA. (28) Elicio Therapeutics, Boston, MA, USA. (29) Elicio Therapeutics, Boston, MA, USA. (30) Elicio Therapeutics, Boston, MA, USA. (31) Elicio Therapeutics, Boston, MA, USA. (32) Elicio Therapeutics, Boston, MA, USA. (33) Elicio Therapeutics, Boston, MA, USA. chris.haqq@elicio.com. (34) University of Texas, MD Anderson Cancer Center, Houston, TX, USA. (35) University of California, Los Angeles, Los Angeles, CA, USA. (36) Memorial Sloan Kettering Cancer Center, New York, NY, USA. oreillye@mskcc.org.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.