Journal Articles

Perioperative pembrolizumab in locally advanced CSCC- A prospective phase 2 clinical trial

Spotlight 

Hugh Galloway1,13,16 ∙ Rodrigo X. Das Neves1,2,16 ∙ Florent Amatore1,2,16 ∙ Arivarasan Karunamurthy1,3 ∙ Samy Kotti1,2 ∙ Drew Hurd1,2 ∙ Shaum Sridharan4 ∙ Hong Wang1,5 ∙ Marion Joy6,7 ∙ Tanner Freeman6,7 ∙ Robert M. Morrison1,2 ∙ Mohammed A. Ghrib1,2 ∙ Terada Mitsuo1,2 ∙ Daniela Riccardi1,2 ∙ Anushri Kulkarni1,2 ∙ Ravi Patel1,8 ∙ Umamaheswar Duvvuri9 ∙ Seungwon Kim4 ∙ Kevin Contrera4 ∙ Haroon A. Choudry10 ∙ Matthew P. Holtzman10 ∙ James F. Pingpank10 ∙ Melissa Pugliano-Mauro11 ∙ Jeffrey R. Whiteaker12 ∙ Amy Rose1 ∙ Danielle Bednarz1 ∙ Amanda G. Paulovich12 ∙ John M. Kirkwood1,2 ∙ Yana G. Najjar1,2 ∙ Yufei Huang1,13,14 ∙ Hassane Zarour1,2,11,15,17 ∙ Diwakar Davar1,2,17,18

Cell Press Blue

In a phase 2 clinical trial for high-risk, resectable CSCC, Galloway, Das Neves, Amatore, et al. evaluated neoadjuvant treatment with two doses of pembrolizumab. Upon surgical resection, 56% of the 27 evaluable patients had a pathological complete response (PCR; no viable tumor remaining). While 81.5% patients continued on adjuvant pembrolizumab, 93.3% of those with PCR chose to forego adjuvant radiation, with no recurrences during a median follow-up of over 3 years. PCR was associated with post-treatment lymphoid aggregates of DCs, B cells, TCF1+CD8+ T cells, and HEVs. Non-response was associated with a TIME rich in PD-L1+ macrophages.

Contributed by Lauren Hitchings

Hugh Galloway1,13,16 ∙ Rodrigo X. Das Neves1,2,16 ∙ Florent Amatore1,2,16 ∙ Arivarasan Karunamurthy1,3 ∙ Samy Kotti1,2 ∙ Drew Hurd1,2 ∙ Shaum Sridharan4 ∙ Hong Wang1,5 ∙ Marion Joy6,7 ∙ Tanner Freeman6,7 ∙ Robert M. Morrison1,2 ∙ Mohammed A. Ghrib1,2 ∙ Terada Mitsuo1,2 ∙ Daniela Riccardi1,2 ∙ Anushri Kulkarni1,2 ∙ Ravi Patel1,8 ∙ Umamaheswar Duvvuri9 ∙ Seungwon Kim4 ∙ Kevin Contrera4 ∙ Haroon A. Choudry10 ∙ Matthew P. Holtzman10 ∙ James F. Pingpank10 ∙ Melissa Pugliano-Mauro11 ∙ Jeffrey R. Whiteaker12 ∙ Amy Rose1 ∙ Danielle Bednarz1 ∙ Amanda G. Paulovich12 ∙ John M. Kirkwood1,2 ∙ Yana G. Najjar1,2 ∙ Yufei Huang1,13,14 ∙ Hassane Zarour1,2,11,15,17 ∙ Diwakar Davar1,2,17,18

Cell Press Blue

In a phase 2 clinical trial for high-risk, resectable CSCC, Galloway, Das Neves, Amatore, et al. evaluated neoadjuvant treatment with two doses of pembrolizumab. Upon surgical resection, 56% of the 27 evaluable patients had a pathological complete response (PCR; no viable tumor remaining). While 81.5% patients continued on adjuvant pembrolizumab, 93.3% of those with PCR chose to forego adjuvant radiation, with no recurrences during a median follow-up of over 3 years. PCR was associated with post-treatment lymphoid aggregates of DCs, B cells, TCF1+CD8+ T cells, and HEVs. Non-response was associated with a TIME rich in PD-L1+ macrophages.

Contributed by Lauren Hitchings

ABSTRACT: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer and a leading cause of non-melanoma skin cancer mortality. We conducted a phase 2 trial (NCT04808999) evaluating neoadjuvant pembrolizumab (200 mg intravenous [i.v.] every 3 weeks for 2 cycles) followed by surgery and adjuvant pembrolizumab in patients with high-risk resectable CSCC. The primary endpoint was pathologic complete response (PCR) by immune-related pathologic response criteria. Thirty patients were enrolled, and 27 underwent protocol-defined surgery and were evaluable for response. PCR was achieved in 15 patients (55.6%; 95% confidence interval [CI], 35.3%–74.5%) and was associated with a trend toward reduced 3-year recurrence risk (Gray’s p = 0.07). Adjuvant radiotherapy was omitted in 93.3% of PCR cases. Multiplex immunofluorescence and transcriptional analyses identified B cell- and dendritic cell-enriched lymphoid aggregates as correlates of PCR, whereas non-responders exhibited PD-L1-enriched macrophage- and tumor-dominant microenvironments. These findings support biomarker-driven treatment de-escalation strategies.

Author Info: (1)- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA (2)- Division of Malignant Hematology and Oncology, Department of Medicine, Universit

Author Info: (1)- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA (2)- Division of Malignant Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA (3)- Division of Dermatopathology, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA (4)- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA (5)- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA (6)- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA (7)- NSABP Foundation, Inc., Pittsburgh, PA, USA (8)- Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA (9)- Department of Otolaryngology and Head and Neck Surgery, NYU Grossman School of Medicine, New York, NY, USA (10)- Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA (11)- Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA (12)- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA (13)- Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA (14)- Department of Pharmaceutical Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (15)- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA (16)- These authors contributed equally (17)- Senior author (18)- Lead contact

Citation: 2026 Cell press blue

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    Relatlimab plus nivolumab versus nivolumab for advanced melanoma: 5-year survival and biomarker analyses of the phase 3 RELATIVITY-047 trial Spotlight 

    (1) Long GV (2) Dolfi S (3) Hodi FS (4) Lipson EJ (5) Schadendorf D (6) Ascierto PA (7) Matamala L (8) GutiŽrrez EC (9) Rutkowski P (10) Gogas HJ (11) Fecher LA (12) Lao CD (13) Janoski De Menezes J (14) Dalle S (15) Arance A (16) Gaudy-Marqueste C (17) Murillo E (18) Maio M (19) Rohde M (20) Garnett-Benson C (21) Jiang R (22) Chen B (23) Yu JX (24) Hollmann T (25) Zuchtriegel G (26) Tawbi H

    Nature medicine

    In a 5-year follow-up (minimum 57.3 months) of the RELATIVITY-047 trial, which led to the approval of nivolumab (anti-PD-1) plus relatlimab (anti-Lag3) for patients with metastatic, unresectable melanoma, Long et al. noted long-term benefits in progression-free, overall, and melanoma-specific survival versus nivolumab alone. In a subset of patients with PD-L1 ≥1%, survival curves separated after 3 years, and while those with high Lag3+ CD8+ T cells showed worse outcomes with nivolumab alone, they experienced greater late or post-progression benefits from relatlimab, suggesting mitigation of Lag3+ T cell-mediated primary resistance.

    Contributed by Lauren Hitchings

    (1) Long GV (2) Dolfi S (3) Hodi FS (4) Lipson EJ (5) Schadendorf D (6) Ascierto PA (7) Matamala L (8) GutiŽrrez EC (9) Rutkowski P (10) Gogas HJ (11) Fecher LA (12) Lao CD (13) Janoski De Menezes J (14) Dalle S (15) Arance A (16) Gaudy-Marqueste C (17) Murillo E (18) Maio M (19) Rohde M (20) Garnett-Benson C (21) Jiang R (22) Chen B (23) Yu JX (24) Hollmann T (25) Zuchtriegel G (26) Tawbi H

    Nature medicine

    In a 5-year follow-up (minimum 57.3 months) of the RELATIVITY-047 trial, which led to the approval of nivolumab (anti-PD-1) plus relatlimab (anti-Lag3) for patients with metastatic, unresectable melanoma, Long et al. noted long-term benefits in progression-free, overall, and melanoma-specific survival versus nivolumab alone. In a subset of patients with PD-L1 ≥1%, survival curves separated after 3 years, and while those with high Lag3+ CD8+ T cells showed worse outcomes with nivolumab alone, they experienced greater late or post-progression benefits from relatlimab, suggesting mitigation of Lag3+ T cell-mediated primary resistance.

    Contributed by Lauren Hitchings

    ABSTRACT: Nivolumab plus relatlimab is approved for advanced melanoma based on the RELATIVITY-047 trial; however, long-term data are needed. Here we report data from RELATIVITY-047 with the longest follow-up at present. In this phase 2-3, double-blind trial, patients with metastatic/unresectable melanoma were randomized 1:1 to nivolumab 480 mg plus relatlimab 160 mg (n = 355) or nivolumab 480 mg (n = 359) intravenously every 4 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints were overall survival (OS), response and safety. Additional post hoc analyses, such as melanoma-specific survival (MSS) and exploratory biomarker analyses, are also reported. This analysis shows clear separation in survival curves with the largest absolute differences to date in PFS, OS and MSS. In this prespecified 5-year analysis, with a minimum follow-up of 57.3 months, nivolumab plus relatlimab demonstrated continued clinically significant benefit versus nivolumab for PFS (hazard ratio (HR) = 0.77; 95% confidence interval (CI): 0.65-0.92), OS (HR = 0.78; 95% CI: 0.64-0.95) and MSS (HR = 0.71; 95% CI: 0.57-0.88). The safety profile remained consistent with prior reports. Among biomarker-evaluable patients in the PD-L1 ≥1% subgroup, analyses revealed an association between worse outcomes with nivolumab and high peripheral or tumor LAG-3+ CD8 cell levels. The addition of relatlimab to nivolumab was associated with a lower prevalence of primary resistance than nivolumab alone. These data support the hypothesis that relatlimab can overcome LAG-3-mediated resistance to nivolumab and provide evidence for differential efficacy patterns observed across biomarker subgroups linked to primary versus acquired resistance states. ClinicalTrials.gov identifier: NCT03470922 .

    Author Info: (1) Melanoma Institute Australia, The University of Sydney Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. (2) Bristol Myers

    Author Info: (1) Melanoma Institute Australia, The University of Sydney Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. (2) Bristol Myers Squibb, Princeton, NJ, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Oncology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. (5) Department of Dermatology, University Hospital Essen, Essen, Germany. German Cancer Consortium, Campus Essen, Essen, Germany. National Center for Tumor Diseases (NCT-West), Campus Essen, Essen, Germany. Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Campus Essen, Essen, Germany. (6) University of Naples Federico II, Naples, Italy. Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. (7) Department of Oncology, Instituto Oncol—gico Fundaci—n Arturo L—pez PŽrez, Santiago, Chile. Department of Oncology, Instituto Nacional del C‡ncer, Santiago, Chile. (8) Department of Oncology, FAICIC Clinical Research, Veracruz, Mexico. (9) Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sk_odowska-Curie National Research Institute of Oncology, Warsaw, Poland. (10) Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece. (11) Department of Internal Medicine, Michigan Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. (12) Department of Internal Medicine, Michigan Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. (13) Department of Clinical Oncology, Hospital Nossa Senhora da Concei‹o, Porto Alegre, Brazil. (14) Department of Dermatology, Hospices Civils de Lyon, Cancer Research Center of Lyon, Pierre-BŽnite, France. (15) Department of Medical Oncology, Hospital Clinic de Barcelona and IDIBAPS, Barcelona, Spain. (16) Department of Dermatology and Skin Cancer, APHM, CHU Timone, Aix-Marseille University, Marseille, France. (17) Department of Oncology, iBiomed Clinical Research, Guadalajara, Mexico. (18) University of Siena, Siena, Italy. Department of Oncology, Center for Immuno-Oncology, University Hospital, Siena, Italy. (19) Bristol Myers Squibb, Princeton, NJ, USA. (20) Bristol Myers Squibb, Princeton, NJ, USA. (21) Bristol Myers Squibb, Princeton, NJ, USA. (22) Bristol Myers Squibb, Princeton, NJ, USA. (23) Bristol Myers Squibb, Princeton, NJ, USA. (24) Bristol Myers Squibb, Princeton, NJ, USA. (25) Bristol Myers Squibb, Boudry, Switzerland. (26) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

    Citation: Nat Med 2026 Oct 24 Epub10/24/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42926136

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

    Spotlight 

    (1) Chen N (2) Rouanne M (3) Yang Z (4) Mariuzza DL (5) Fabozzi M (6) Shin AE (7) Nishiwaki N (8) Rajbhandari P (9) Ringham OR (10) Schwabe AD (11) Zhu M (12) Stockwell BR (13) Mori H (14) Danino T (15) Arpaia N

    Nature cancer

    Utilizing a high-throughput barcoded KO screen targeting all non-essential E. coli genes, Chen et al. identified that KO of non-glucose phosphotransferase system genes enhanced intratumoral fitness and tumor colonization by increasing glucose avidity. A quadruple-mutant, tumor-avid E. coli strain (Ec-TA) outcompeted and displaced wild-type E. coli from pre-colonized tumors, demonstrated tumor specificity and a favorable safety profile, and increased delivery of an IFNγ payload upon intravenous administration. Ec-TA-IFNγ enhanced intratumoral IFNγ and effector T cell responses, and reduced tumor burden across colorectal tumor models.

    Contributed by Ute Burkhardt

    (1) Chen N (2) Rouanne M (3) Yang Z (4) Mariuzza DL (5) Fabozzi M (6) Shin AE (7) Nishiwaki N (8) Rajbhandari P (9) Ringham OR (10) Schwabe AD (11) Zhu M (12) Stockwell BR (13) Mori H (14) Danino T (15) Arpaia N

    Nature cancer

    Utilizing a high-throughput barcoded KO screen targeting all non-essential E. coli genes, Chen et al. identified that KO of non-glucose phosphotransferase system genes enhanced intratumoral fitness and tumor colonization by increasing glucose avidity. A quadruple-mutant, tumor-avid E. coli strain (Ec-TA) outcompeted and displaced wild-type E. coli from pre-colonized tumors, demonstrated tumor specificity and a favorable safety profile, and increased delivery of an IFNγ payload upon intravenous administration. Ec-TA-IFNγ enhanced intratumoral IFNγ and effector T cell responses, and reduced tumor burden across colorectal tumor models.

    Contributed by Ute Burkhardt

    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.

    Citation: Nat Cancer 2026 Oct 29 Epub10/29/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42957894

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

    (1) Hu S (2) Shi G (3) Zhao J (4) Long X (5) Tang L (6) Qi Z (7) Xu X (8) Cheng P (9) Liu J

    Molecular therapy

    In contrast to conventional tumor cell-targeting dendritic cell (DC) vaccines, Hu, Shi, and Zhao et al. explored the clinical potential of a therapeutic vaccine loaded with the gut commensal Bacteroides fragilis (DC-Bf). DC-Bf significantly enhanced infiltration of TILs and activation of diverse, cross-reactive CD8+ T cells that recognized and killed tumor cells while decreasing Tregs and immunosuppressive TAMs in the TIME. DC-Bf significantly enhanced the efficacy of anti-PD-1 via an IL-12-driven CD8+ T cell-dependent mechanism in both primary tumor and metastasis models, suggesting translational potential as an off-the-shelf cancer vaccine.

    Contributed by Katherine Turner

    (1) Hu S (2) Shi G (3) Zhao J (4) Long X (5) Tang L (6) Qi Z (7) Xu X (8) Cheng P (9) Liu J

    Molecular therapy

    In contrast to conventional tumor cell-targeting dendritic cell (DC) vaccines, Hu, Shi, and Zhao et al. explored the clinical potential of a therapeutic vaccine loaded with the gut commensal Bacteroides fragilis (DC-Bf). DC-Bf significantly enhanced infiltration of TILs and activation of diverse, cross-reactive CD8+ T cells that recognized and killed tumor cells while decreasing Tregs and immunosuppressive TAMs in the TIME. DC-Bf significantly enhanced the efficacy of anti-PD-1 via an IL-12-driven CD8+ T cell-dependent mechanism in both primary tumor and metastasis models, suggesting translational potential as an off-the-shelf cancer vaccine.

    Contributed by Katherine Turner

    ABSTRACT: 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.

    Citation: Mol Ther 2026 Nov 4 34:6294-6311 Epub08/13/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42596550

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

    (1) Ascic E (2) Chatelain C (3) Fontanari G (4) Pérez Bucio C (5) Zhang L (6) Thrasyvoulou M (7) Karali V (8) Ballocci T (9) de Rosa Torres M (10) Rabreau S (11) Hampton K (12) Lauss M (13) Phung B (14) Akerström F (15) Sundaramurthy AK (16) Catena X (17) Fan C (18) Jonathan S (19) Darabi A (20) Bengzon J (21) Rosa FF (22) Jönsson GB (23) Kurochkin I (24) Pereira CF

    Immunity

    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.

    (1) Ascic E (2) Chatelain C (3) Fontanari G (4) Pérez Bucio C (5) Zhang L (6) Thrasyvoulou M (7) Karali V (8) Ballocci T (9) de Rosa Torres M (10) Rabreau S (11) Hampton K (12) Lauss M (13) Phung B (14) Akerström F (15) Sundaramurthy AK (16) Catena X (17) Fan C (18) Jonathan S (19) Darabi A (20) Bengzon J (21) Rosa FF (22) Jönsson GB (23) Kurochkin I (24) Pereira CF

    Immunity

    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.

    Citation: Immunity 2026 Nov 4 Epub11/04/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42982037

    Tags:

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

    Spotlight 

    (1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

    Cell stem cell

    Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

    Contributed by Paula Hochman

    (1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

    Cell stem cell

    Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

    Contributed by Paula Hochman

    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.

    Citation: Cell Stem Cell 2026 Nov 4 Epub11/04/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42982040

    Tags:

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

    (1) Johansen KH (2) Ramanathan K (3) Rodriguez-Pardo C (4) Gjelstrup AK (5) Halld—rsd—ttir HR (6) Voss LF (7) Tvingsholm S (8) Grand LS (9) Dionisio E (10) Skriver AH (11) Frederiksen LP (12) Bj¿rnson M (13) Svensson-Frej M (14) Ormh¿j M (15) Hadrup SR

    Cell reports. Medicine

    To specifically expand NY-ESO-1 TCR-T and CD19 CAR-T cells following CRISPR-cas9 knock-inKI to the TRAC locus, Johansen et al. decorated dextran scaffolds with IL-2, IL-21, and either pMHC or CAR antigen, respectively. The scaffold increased TCR/CAR expression and expansion over stimulation with the soluble components. Compared to cytokine-expanded T cells, scaffold-expanded T cells had greater proliferative capacity, cytotoxicity through serial tumor rechallenge in vitro, and superior antitumor efficacy and expansion in vivo. Mixtures of scaffolds displaying several pMHCs expanded pooled TCR-T cells.

    Contributed by Alex Najibi

    (1) Johansen KH (2) Ramanathan K (3) Rodriguez-Pardo C (4) Gjelstrup AK (5) Halld—rsd—ttir HR (6) Voss LF (7) Tvingsholm S (8) Grand LS (9) Dionisio E (10) Skriver AH (11) Frederiksen LP (12) Bj¿rnson M (13) Svensson-Frej M (14) Ormh¿j M (15) Hadrup SR

    Cell reports. Medicine

    To specifically expand NY-ESO-1 TCR-T and CD19 CAR-T cells following CRISPR-cas9 knock-inKI to the TRAC locus, Johansen et al. decorated dextran scaffolds with IL-2, IL-21, and either pMHC or CAR antigen, respectively. The scaffold increased TCR/CAR expression and expansion over stimulation with the soluble components. Compared to cytokine-expanded T cells, scaffold-expanded T cells had greater proliferative capacity, cytotoxicity through serial tumor rechallenge in vitro, and superior antitumor efficacy and expansion in vivo. Mixtures of scaffolds displaying several pMHCs expanded pooled TCR-T cells.

    Contributed by Alex Najibi

    ABSTRACT: 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.

    Citation: Cell Rep Med 2026 Nov 5 103128 Epub11/05/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42987830

    Tags:

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

    (1) Sellars MC (2) Frank JA (3) Shim B (4) Vanasse A (5) Liu R (6) Forman C (7) Tu CR (8) Tabata KK (9) Kowelewski A (10) Cheng SC (11) Song C (12) Xiong K (13) Jain P (14) Crnjac A (15) Sax HE (16) Chea V (17) Lu W (18) Janes JT 3rd (19) Rickles-Young M (20) Sud A (21) Sarolkar S (22) Hayes M (23) Olive O (24) Greenslade H (25) Cibulskis C (26) Hacohen N (27) Fritsch EF (28) Li S (29) Livak KJ (30) Tayob N (31) Stover EH (32) Krasner C (33) Porter R (34) Matulonis U (35) Getz G (36) Oliveira G (37) Ott PA (38) Simon JM (39) Adalsteinsson VA (40) Keskin DB (41) Konstantinopoulos PA (42) Wu CJ

    Nature medicine

    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.

    (1) Sellars MC (2) Frank JA (3) Shim B (4) Vanasse A (5) Liu R (6) Forman C (7) Tu CR (8) Tabata KK (9) Kowelewski A (10) Cheng SC (11) Song C (12) Xiong K (13) Jain P (14) Crnjac A (15) Sax HE (16) Chea V (17) Lu W (18) Janes JT 3rd (19) Rickles-Young M (20) Sud A (21) Sarolkar S (22) Hayes M (23) Olive O (24) Greenslade H (25) Cibulskis C (26) Hacohen N (27) Fritsch EF (28) Li S (29) Livak KJ (30) Tayob N (31) Stover EH (32) Krasner C (33) Porter R (34) Matulonis U (35) Getz G (36) Oliveira G (37) Ott PA (38) Simon JM (39) Adalsteinsson VA (40) Keskin DB (41) Konstantinopoulos PA (42) Wu CJ

    Nature medicine

    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.

    Citation: Nat Med 2026 Oct 14 Epub10/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42875558

    Tags:

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

    (1) Khateb M (2) Jung R (3) Hadley P (4) Leibou S (5) Yu Z (6) Dinerman AJ (7) Dulemba V (8) Gasmi B (9) Levin N (10) Kim SP (11) Bhasin A (12) Bhat D (13) Sindiri S (14) Gartner JJ (15) Prickett TD (16) Benzine T (17) Farid S (18) Parkhurst M (19) Halas H (20) Ge G (21) Cao Y (22) Zhao K (23) Yang JC (24) Robbins P (25) Lowery FJ (26) Krishna S (27) Heller T (28) Mcvicar D (29) Rosenberg SA (30) Klemen ND

    Journal for immunotherapy of cancer | Free PMC Article

    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

    (1) Khateb M (2) Jung R (3) Hadley P (4) Leibou S (5) Yu Z (6) Dinerman AJ (7) Dulemba V (8) Gasmi B (9) Levin N (10) Kim SP (11) Bhasin A (12) Bhat D (13) Sindiri S (14) Gartner JJ (15) Prickett TD (16) Benzine T (17) Farid S (18) Parkhurst M (19) Halas H (20) Ge G (21) Cao Y (22) Zhao K (23) Yang JC (24) Robbins P (25) Lowery FJ (26) Krishna S (27) Heller T (28) Mcvicar D (29) Rosenberg SA (30) Klemen ND

    Journal for immunotherapy of cancer | Free PMC Article

    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.

    Citation: J Immunother Cancer 2026 Oct 15 14: Epub10/15/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42880819

    Tags:

    Lower airway microbiome transcriptional and metabolic activities influence responsiveness to immunotherapy in NSCLC

    (1) Darawshy F (2) Tsay JJ (3) Sanchez E (4) Jin DM (5) Kim Y (6) Li Q (7) Chung M (8) Becker AS (9) Sulaiman I (10) Barnett C (11) Wu BG (12) Pillai R (13) Kwok B (14) Wong KK (15) Kugler MC (16) Li Y (17) Schluger R (18) Collazo D (19) Kyeremateng Y (20) Bain A (21) Chang M (22) Bessich JL (23) DeMaio A (24) Laniado I (25) O'Neill DK (26) Shum E (27) Chachoua A (28) Hall JJ (29) Sanders J (30) Thurston G (31) Goncalves MD (32) Dantas EC (33) Vanguri RS (34) Wong KK (35) Sterman DH (36) Tsirigos A (37) Morton J (38) Li H (39) Ghedin E (40) Segal LN

    Cancer immunology research

    (1) Darawshy F (2) Tsay JJ (3) Sanchez E (4) Jin DM (5) Kim Y (6) Li Q (7) Chung M (8) Becker AS (9) Sulaiman I (10) Barnett C (11) Wu BG (12) Pillai R (13) Kwok B (14) Wong KK (15) Kugler MC (16) Li Y (17) Schluger R (18) Collazo D (19) Kyeremateng Y (20) Bain A (21) Chang M (22) Bessich JL (23) DeMaio A (24) Laniado I (25) O'Neill DK (26) Shum E (27) Chachoua A (28) Hall JJ (29) Sanders J (30) Thurston G (31) Goncalves MD (32) Dantas EC (33) Vanguri RS (34) Wong KK (35) Sterman DH (36) Tsirigos A (37) Morton J (38) Li H (39) Ghedin E (40) Segal LN

    Cancer immunology research

    ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.

    Author Info: (1) NYU Langone Medical Center New York, New York United States. (2) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (3) New York University Ne

    Author Info: (1) NYU Langone Medical Center New York, New York United States. (2) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (3) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (4) New York University NY, NY United States. ROR: https://ror.org/0190ak572 (5) NYU Langone Medical Center New York, New York United States. (6) New York University New York, NY United States. ROR: https://ror.org/0190ak572 (7) National Institutes of Health Bethsada, MD United States. ROR: https://ror.org/01cwqze88 (8) New York University Grossman School of Medicine New York, NY United States. (9) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (10) NYU Langone Medical Center New York, New York United States. (11) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (12) NYU Langone Health New York, New York United States. ROR: https://ror.org/005dvqh91 (13) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (14) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (15) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (16) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (17) NYU Langone Medical Center New York, New York United States. (18) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (19) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (20) New York University Grossman School of Medicine New York, New York United States. (21) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (22) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (23) NYU Langone Medical Center New York, New York United States. (24) NYU Langone Medical Center New York, New York United States. (25) NYU Langone Medical Center New York, New York United States. (26) NYU Langone's Laura and Isaac Perlmutter Cancer Center New York, NY United States. ROR: https://ror.org/00sa8g751 (27) NYU Langone's Laura and Isaac Perlmutter Cancer Center New York, NY United States. ROR: https://ror.org/00sa8g751 (28) Gutz Analytics BOULDER, CO United States. (29) Gutz Analytics United States. (30) New York University Grossman School of Medicine New York, New York United States. (31) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (32) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (33) NYU Langone Health New York, NY United States. ROR: https://ror.org/005dvqh91 (34) NYU Langone's Laura and Isaac Perlmutter Cancer Center New York, ny United States. ROR: https://ror.org/00sa8g751 (35) New York University New York City, NY United States. ROR: https://ror.org/0190ak572 (36) NYU Langone Medical Center New York, NY United States. (37) Simons Foundation. ROR: https://ror.org/01cmst727 (38) New York University New York, New York United States. ROR: https://ror.org/0190ak572 (39) National Institutes of Health Bethsada, MD United States. ROR: https://ror.org/01cwqze88 (40) NYU Langone Medical Center New York, New York United States.

    Citation: Cancer Immunol Res 2026 Oct 21 Epub10/21/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42905123

    Tags:
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