Journal Articles

FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight 

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC. METHODS: Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing. RESULTS: Combination therapy induced dense intratumoral clusters of CD4(+) and CD8(+) T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4(+) and CD8(+) T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4(+) T cells toward a T helper cell 1 phenotype in combination-treated tumors. CONCLUSION: The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Ba

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (5) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (6) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Institute of Experimental Immunology, UniversitŠt ZŸrich, ZŸrich, Switzerland. Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany. (12) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (13) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland leo.kunz@roche.com.

Citation: J Immunother Cancer 2026 May 28 14: Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42208978

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Targeting CCR1 remodels the tumor microenvironment and relieves immune suppression in pancreatic cancer Featured  

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8+ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8+ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

ABSTRACT: A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid-cell driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS based genetically engineered mouse models of pancreatic cancer, with or without addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect formation of early lesions, but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker Arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (4) University of Michigan Medical Schooligan United States. (5) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (6) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (7) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (8) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (9) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (10) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (11) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (12) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (13) University of Maryland, Baltimore Baltimore United States. ROR: https://ror.org/04rq5mt64 (14) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (15) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (16) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (17) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (18) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (19) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (20) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (21) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (22) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (23) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (24) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (25) Cornell University Ithaca United States. ROR: https://ror.org/05bnh6r87 (26) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (27) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (28) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (29) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (30) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (31) Cedars-Sinai Medical Center Los Angeles, CA United States. ROR: https://ror.org/02pammg90 (32) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (33) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291

Citation: Cancer Immunol Res 2026 May 28 Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42207977

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Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial Spotlight 

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

ABSTRACT: Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (5) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (6) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (7) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (8) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (9) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (10) Department of Genitourinary Oncology, Weill Cornell Medicine, New York, NY, USA. (11) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (12) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (13) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (14) Immune Monitoring Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (15) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (16) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (17) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (18) Department of Pharmacy, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (19) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (20) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (21) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (22) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (23) USF Health Morsani College of Medicine, Tampa, FL, USA. Tampa General Hospital Cancer Institute, Tampa, FL, USA. (24) Department of Genitourinary Oncology, Orlando Health Cancer Institute, Orlando, FL, USA. Jad.Chahoud@orlandohealth.com.

Citation: Nat Commun 2026 May 25 Epub05/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42185255

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Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase 1 trial Spotlight 

(1) Garfinkle EAR (2) Perales-Linares R (3) Gimple RC (4) Livingstone AJ (5) Roberts KF (6) Butt OH (7) Goedegebuure SP (8) McLellan MD (9) Chang GS (10) Hundal J (11) Yan J (12) Navarro JB (13) Paxton SA (14) Chattopadhyay S (15) Cooch N (16) Perales-Puchalt A (17) Stavroulaki K (18) Rochestie S (19) Peters J (20) Junker B (21) Campian JL (22) Chheda MG (23) Chicoine MR (24) Kim AH (25) Willie JT (26) Zipfel GJ (27) Dowling JL (28) Miller CA (29) Griffith OL (30) Griffith M (31) Gillanders WE (32) Miller KE (33) Mardis ER (34) Sardesai NY (35) Dunn GP (36) Johanns TM

Nature cancer

In a phase 1 study, Garfinkle et al. vaccinated 9 patients with MGMT unmethylated glioblastoma with a personalized DNA-based vaccine following surgical resection and radiation. GNOS-PVO1 encoded up to 40 neoantigens identified from 3–4 distinct tumor regions per patient, and was well tolerated. The median 24-month survival rate was 33%, including a patient who remained disease-free over 4 years after diagnosis. Survival correlated with increases in peripheral CD8+CD69+ and CD8+IFNγ+ T cells. Increased tumor-infiltrating CD8+ T cells, with expanded de novo and pre-existing TCR clonotypes in the tumor and blood, were observed upon vaccination.

Contributed by Ute Burkhardt

(1) Garfinkle EAR (2) Perales-Linares R (3) Gimple RC (4) Livingstone AJ (5) Roberts KF (6) Butt OH (7) Goedegebuure SP (8) McLellan MD (9) Chang GS (10) Hundal J (11) Yan J (12) Navarro JB (13) Paxton SA (14) Chattopadhyay S (15) Cooch N (16) Perales-Puchalt A (17) Stavroulaki K (18) Rochestie S (19) Peters J (20) Junker B (21) Campian JL (22) Chheda MG (23) Chicoine MR (24) Kim AH (25) Willie JT (26) Zipfel GJ (27) Dowling JL (28) Miller CA (29) Griffith OL (30) Griffith M (31) Gillanders WE (32) Miller KE (33) Mardis ER (34) Sardesai NY (35) Dunn GP (36) Johanns TM

Nature cancer

In a phase 1 study, Garfinkle et al. vaccinated 9 patients with MGMT unmethylated glioblastoma with a personalized DNA-based vaccine following surgical resection and radiation. GNOS-PVO1 encoded up to 40 neoantigens identified from 3–4 distinct tumor regions per patient, and was well tolerated. The median 24-month survival rate was 33%, including a patient who remained disease-free over 4 years after diagnosis. Survival correlated with increases in peripheral CD8+CD69+ and CD8+IFNγ+ T cells. Increased tumor-infiltrating CD8+ T cells, with expanded de novo and pre-existing TCR clonotypes in the tumor and blood, were observed upon vaccination.

Contributed by Ute Burkhardt

ABSTRACT: Glioblastoma is a fatal disease with a median prognosis of 12-18_months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of an open-label, single-arm, phase 1 clinical trial (GT-20) to evaluate the safety and feasibility (primary endpoints) as well as immunogenicity and preliminary clinical activity (secondary endpoints) of GNOS-PV01 monotherapy, a DNA-based personalized therapeutic cancer vaccine administered following surgical resection and radiation for patients with MGMT unmethylated glioblastoma. The GT-20 study vaccinated nine patients, using up to 40 neoantigens per patient (range, 17-40) without causing any serious adverse events, unexpected toxicities or dose-limiting toxicities. The vaccine induced activation and expansion of circulating peripheral T_cells in all evaluated patients, except one who was being treated with dexamethasone. The secondary endpoint was to evaluate 6_month progression-free survival and 12_month overall survival; each observed in 66.7% of patients. Median progression-free survival was 8.5_months, median overall survival was 16.3_months and survival at 24_months was 33%, including one long-term survivor still alive 4_years from the time of initial surgery. This study met the pre-specified endpoints and supports the use of GNOS-PV01 as a potentially impactful component of glioblastoma immunotherapy. ClinicalTrials.gov: NCT04015700 .

Author Info: (1) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. (2) Geneos Therapeutics, Philadelphia, PA, USA. (3) Department

Author Info: (1) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. (2) Geneos Therapeutics, Philadelphia, PA, USA. (3) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (4) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. (7) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA. (8) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (9) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (10) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (11) Geneos Therapeutics, Philadelphia, PA, USA. (12) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. (13) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH, USA. (14) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. The Ohio State University, Columbus, OH, USA. (15) Geneos Therapeutics, Philadelphia, PA, USA. (16) Geneos Therapeutics, Philadelphia, PA, USA. (17) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. (18) Geneos Therapeutics, Philadelphia, PA, USA. (19) Geneos Therapeutics, Philadelphia, PA, USA. (20) BioProcess Advantage LLC, Westfield, NJ, USA. (21) Department of Neurology, Mayo Clinic, Rochester, MN, USA. (22) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. (23) Department of Neurosurgery, University of Missouri, Columbia, MO, USA. (24) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (25) Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (26) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (27) The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (28) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (29) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (30) Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (31) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. (32) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. (33) The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. (34) Geneos Therapeutics, Philadelphia, PA, USA. (35) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (36) Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. tannerjohanns@wustl.edu. The Brain Tumor Center at Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. tannerjohanns@wustl.edu. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Program, Washington University School of Medicine, St. Louis, MO, USA. tannerjohanns@wustl.edu.

Citation: Nat Cancer 2026 May 12 Epub05/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42120910

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

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

Cancer immunology research

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

Contributed by Katherine Turner

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

Cancer immunology research

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

Contributed by Katherine Turner

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

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

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

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

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

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Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery Featured  

(1) Wang N (2) Yeh H (3) Lai B (4) Perera J (5) Jude KM (6) Risch I (7) Um J (8) Chen X (9) Xiang X (10) Wang C (11) Liu LD (12) Yang X (13) Paley MA (14) Khan AA (15) Garcia KC

Nature biotechnology

Using high-throughput yeast display and protein language models (pLMs), Wang, Yeh, et al. developed a new approach to determine TCR recognition that goes beyond the TCR sequence. This method generates deep peptide recognition profiles (PRPs), with PRP functional distance predicting the specificity of a new TCR, thereby enabling the discovery of novel candidate autoantigens in autoimmune disease.

(1) Wang N (2) Yeh H (3) Lai B (4) Perera J (5) Jude KM (6) Risch I (7) Um J (8) Chen X (9) Xiang X (10) Wang C (11) Liu LD (12) Yang X (13) Paley MA (14) Khan AA (15) Garcia KC

Nature biotechnology

Using high-throughput yeast display and protein language models (pLMs), Wang, Yeh, et al. developed a new approach to determine TCR recognition that goes beyond the TCR sequence. This method generates deep peptide recognition profiles (PRPs), with PRP functional distance predicting the specificity of a new TCR, thereby enabling the discovery of novel candidate autoantigens in autoimmune disease.

ABSTRACT: Predicting T cell receptor (TCR) specificity on the basis of sequence is challenging because TCRs of similar sequence can recognize entirely different antigens, whereas TCRs of different sequence can recognize the same antigens. Here we present a system that integrates high-throughput yeast display with fine-tuned protein language models (pLMs) to generate deep peptide recognition profiles (PRPs) for individual TCRs, each detailing binding against millions of peptides. We provide detailed PRPs for a panel of HLA-B*27:05-restricted TCRs from persons with ankylosing spondylitis and acute anterior uveitis that almost exclusively recognize peptides through CDR3β. pLMs trained on these PRPs outperform AlphaFold3 and tFold-TCR in predicting T cell activation. We discover and validate novel candidate autoantigens, demonstrate that model generalization to new TCRs correlates with functional distance (PRP divergence) rather than sequence similarity and introduce a model-intrinsic uncertainty metric to quantify prediction confidence. This system and its associated PRP datasets offer a scalable approach to mapping TCR recognition, accelerating antigen discovery and guiding TCR engineering.

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medic

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (2) Biohub, Chicago, IL, USA. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Medical Scientist Training Program, University of Chicago, Chicago, IL, USA. (3) Biohub, Chicago, IL, USA. (4) Biohub, Chicago, IL, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (6) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (7) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (8) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (14) Biohub, Chicago, IL, USA. aakhan@uchicago.edu. Departments of Pathology, and Family Medicine, University of Chicago, Chicago, IL, USA. aakhan@uchicago.edu. (15) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.

Citation: Nat Biotechnol 2026 May 13 Epub05/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42129507

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In vivo reprogramming of cytotoxic effector CD8+ T cells via fractalkine-conjugated mRNA-LNP

Spotlight 

Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

Science immunology

Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

Contributed by Lauren Hitchings

Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

Science immunology

Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

Contributed by Lauren Hitchings

ABSTRACT: Selective in vivo reprogramming of cytotoxic effector CD8 T (Teff) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1+ Teff cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic Teff cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse Teff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood Teff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood Teff cells and detection of human CD62L+ Teff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of Teff cells.

Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania

Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 4Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 6Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Division of Animal Resources, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 9Acuitas Therapeutics, Vancouver, Canada. 10Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, USA. 11Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. 12Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Citation: Epub 2026 May 8.

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/42102231/

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    Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer

    Spotlight 

    (1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

    Cancer cell

    Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

    Contributed by Shishir Pant

    (1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

    Cancer cell

    Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

    Contributed by Shishir Pant

    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8(+) T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8(+) T cells or tumor cell MHC expression but instead requires IFN_-producing CD4(+) T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4(+) T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4(+) T cell-IFN_ axis could be efficacious in PDAC.

    Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farbe

    Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (2) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School Program in Virology, Boston, MA, USA. (3) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (6) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (7) Brookline High School, Brookline, MA, USA. (8) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (9) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (10) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (11) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (12) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (13) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (14) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (16) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (17) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (18) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (20) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (21) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (22) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, MA, USA. (24) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (27) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (28) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (30) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (31) Bristol Myers Squibb, Princeton, NJ, USA. (32) Bristol Myers Squibb, Princeton, NJ, USA. (33) Bristol Myers Squibb, Princeton, NJ, USA. (34) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (35) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (36) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

    Citation: Cancer Cell 2026 May 7 Epub05/07/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102812

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    Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1 Featured  

    (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

    Nature

    Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

    (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

    Nature

    Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

    ABSTRACT: Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer(1). Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1_mg_kg(-1)) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3_mg_kg(-1)) or intravenous ipilimumab (3_mg_kg(-1)). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (T(reg)) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural T(reg) cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fc_ receptor (Fc_R) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated T(reg) cell and Fc_R(+) M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

    Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie I

    Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (2) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (3) Gustave Roussy, Service de Biostatistiques et d'EpidŽmiologie (SBE), UniversitŽ Paris Saclay, Villejuif, France. INSERM U1018, ONCOSTAT, Equipe LabellisŽe Ligue contre le Cancer, Villejuif, France. (4) INSERM U981, Gustave Roussy, Villejuif, France. (5) Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (6) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. (7) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (8) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (9) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (10) Gustave Roussy, DŽpartement d'Imagerie MŽdicale, Villejuif, France. (11) Gustave Roussy, Service de Promotion d'Etudes Cliniques, DRC, Villejuif, France. (12) INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (13) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (14) INSERM CIC 1428, BIOTHERIS, Villejuif, France. (15) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (16) Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (17) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (18) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (19) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U1015, Immunologie des tumeurs et immunothŽrapie contre le cancer, Villejuif, France. (20) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (21) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, Service de Pharmacologie, DŽpartement de Biologie et Pathologie mŽdicales, Villejuif, France. (22) INSERM CIC 1428, BIOTHERIS, Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (23) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (24) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (25) INSERM U981, Gustave Roussy, Villejuif, France. (26) CHU de Toulouse, Service d'Oncodermatologie, IUCT-O, Toulouse, France. INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France. UniversitŽ Toulouse III - Paul Sabatier, DŽpartement de Dermatologie, Toulouse, France. (27) UniversitŽ Paris CitŽ, AP-HP Dermato-oncologie et CIC, Institut du Cancer APHP nord, Paris, France. INSERM U1342-Equipe 1-CNRS EMR8000, H™pital Saint Louis, Paris, France. (28) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. INSERM U1052-CNRS UMR5286, PlasticitŽ Tumorale dans le MŽlanome, Centre de Recherche en CancŽrologie de Lyon, Centre LŽon BŽrard, Lyon, France. UniversitŽ Claude Bernard Lyon 1, Lyon, France. (29) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (30) INSERM CIC 1428, BIOTHERIS, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. aurelien.marabelle@gustaveroussy.fr. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. aurelien.marabelle@gustaveroussy.fr.

    Citation: Nature 2026 Apr 29 Epub04/29/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056527

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    Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer Spotlight 

    (1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

    Cell reports. Medicine

    Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

    Contributed by Katherine Turner

    (1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

    Cell reports. Medicine

    Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

    Contributed by Katherine Turner

    ABSTRACT: Colorectal cancer (CRC) accounts for 10% of cancer cases and is the second leading cause of cancer-related deaths. Although anti-PD-1 therapy improves outcomes, 50% of advanced mismatch repair-deficient (MMRd) and most mismatch repair-proficient (MMRp) CRC cases fail to respond. Using orthotopic and patient-derived CRC models with single-cell and spatial analyses, we show that tumor control during anti-PD-1 treatment associates with colocalization of MHC(+) C1Q(+) CXCL9(+) macrophages and TCF(+) PRF1(+) T cells. Resistance correlates with increased TIM3, LAG3, TIGIT, and PD-1 expression on T cells and enrichment of TREM2(+) macrophages in T cell-excluded regions. A combinatorial blockade targeting TREM2, LAG3, CTLA4, and PD-1 induces up to 100% tumor clearance in MMRd and >70% in MMRp models. This strategy promotes immune memory mediated by interactions among MHC(+) macrophages and CD4(+)/CD8(+)/TCF(+) T cells, while reducing immunosuppressive myeloid infiltration and T cell exhaustion, identifying key cellular programs that overcome immune escape in CRC.

    Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic ad

    Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: guillaume.mestrallet@mssm.edu. (2) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) Department of Radiation Oncology and the Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA 94143, USA. (5) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (6) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Department of Otolaryngology-Head and Neck Surgery and the Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143, USA. (8) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (9) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (10) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: robert.samstein@mountsinai.org. (11) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: nina.bhardwaj@mssm.edu.

    Citation: Cell Rep Med 2026 May 5 102786 Epub05/05/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42092363

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