DC vaccine loaded with Bacteroides fragilis elicits functional cross-reactivity and enhances anti-PD-1 immunotherapy
(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
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
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
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
Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic cancer: the randomized phase 2 AMPLIFY-7P trial Spotlight
(1) George B (2) Singh H (3) Devoe CE (4) Chung V (5) Hosein PJ (6) Hendifar A (7) Kim DW (8) Valerin JB (9) Bekaii-Saab T (10) Cardin DB (11) Hidalgo M (12) Kasi PM (13) Leal AD (14) Pelster M (15) Fei N (16) Weekes CD (17) O'Hara MH (18) George TJ (19) Kazmi SM (20) Mizrahi JD (21) Nair S (22) Maiers M (23) Kheoh T (24) Amato G (25) Xavier J (26) Snyder JP (27) Milaszewski MH (28) Cabana-Puig X (29) Perry JR (30) McNeil LK (31) Welkowsky E (32) DeMuth PC (33) Haqq CM (34) Pant S (35) Wainberg ZA (36) O'Reilly EM
In a phase 2 clinical trial, patients with stage I-III KRAS-mutated PDAC recently (<6 months) cleared by standard therapy were treated with either camupepimut (a lymph-node targeting, CpG-adjuvanted vaccine targeting KRAS G12D and G12R neoantigens; n=96) or standard-of-care/observation (n=48). DFS lasted a median of 23.8 versus 21.2 months, which did not meet the primary endpoint, but an improved 6-month DFS rate of 75.7% vs. 61.7% was significantly associated with treatment. In camupepimut-treated patients, mKRAS-specific T cell responses above 9.17-fold over baseline correlated with improved DFS (NR vs. 6.08 months), with evidence of epitope spreading.
Contributed by Lauren Hitchings
(1) George B (2) Singh H (3) Devoe CE (4) Chung V (5) Hosein PJ (6) Hendifar A (7) Kim DW (8) Valerin JB (9) Bekaii-Saab T (10) Cardin DB (11) Hidalgo M (12) Kasi PM (13) Leal AD (14) Pelster M (15) Fei N (16) Weekes CD (17) O'Hara MH (18) George TJ (19) Kazmi SM (20) Mizrahi JD (21) Nair S (22) Maiers M (23) Kheoh T (24) Amato G (25) Xavier J (26) Snyder JP (27) Milaszewski MH (28) Cabana-Puig X (29) Perry JR (30) McNeil LK (31) Welkowsky E (32) DeMuth PC (33) Haqq CM (34) Pant S (35) Wainberg ZA (36) O'Reilly EM
In a phase 2 clinical trial, patients with stage I-III KRAS-mutated PDAC recently (<6 months) cleared by standard therapy were treated with either camupepimut (a lymph-node targeting, CpG-adjuvanted vaccine targeting KRAS G12D and G12R neoantigens; n=96) or standard-of-care/observation (n=48). DFS lasted a median of 23.8 versus 21.2 months, which did not meet the primary endpoint, but an improved 6-month DFS rate of 75.7% vs. 61.7% was significantly associated with treatment. In camupepimut-treated patients, mKRAS-specific T cell responses above 9.17-fold over baseline correlated with improved DFS (NR vs. 6.08 months), with evidence of epitope spreading.
Contributed by Lauren Hitchings
ABSTRACT: Camupepimut (ELI-002 7P) drives mutated KRAS (mKRAS)-specific T cell responses that correlated with disease-free survival (DFS) and overall survival (OS) in patients with mKRAS pancreatic adenocarcinoma (PDAC) in the phase 1 AMPLIFY-201 trial. In the phase 2 AMPLIFY-7P trial, patients with stage I-III KRAS-mutated PDAC without recurrence within 6 months of standard therapy were randomized 2:1 to camupepimut (n = 96) or standard-of-care/observation (n = 48). Stratification balanced nodal status. The primary DFS endpoint was not met (median 23.8 versus 21.2 months; HR 0.85, P = 0.5329). However, prespecified and exploratory analyses were informative. A numerical DFS advantage at 6 months of 14.0% (75.7% versus 61.7%; HR 0.55, P = 0.0557) corresponded to camupepimut dosing. Post hoc multivariate Cox regression analysis of DFS indicated an improved outcome for camupepimut (adjusted HR 0.47, P = 0.0086), a worse outcome for stage III disease (adjusted HR 2.29, P = 0.0127), an elevated baseline CA19-9 (adjusted HR 3.16, P < 0.0001) and baseline circulating tumor DNA (ctDNA) positivity (adjusted HR 5.99, P < 0.0001). Prespecified subgroup analyses addressing prognostic and predictive factors suggested DFS benefit for camupepimut (ctDNA negative: HR 0.51, P = 0.0280; no prior radiation: HR 0.59, P = 0.0221). Exploratory analysis demonstrated that ex vivo mKRAS-specific T cell responses were robust (98.9%, 89/90) and associated with antigen spreading (86.7%, 13/15). In camupepimut-treated patients, mKRAS-specific T cell response >9.17-fold over baseline (82.2%, 74/90) correlated with improved DFS (HR 0.22, P < 0.0001), with the median DFS not reached versus 6.08 months for above and below 9.17-fold, respectively. Camupepimut safety was similar to observation, with grade ≥3 adverse events in 10.4% (10/96) versus 14.6% (7/48), and few serious AEs (6.3%, 6/96 versus 8.3%, 4/48; reflecting progression/surgical complication). These efficacy and immunogenicity signals will inform a refined strategy for a confirmatory phase 3 trial. ClinicalTrials.gov identifier: NCT05726864 .
Author Info: (1) Medical College of Wisconsin, Milwaukee, WI, USA. george.ben@mayo.edu. Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. george.ben@mayo.edu. (2) Dana Farber Cancer

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

Citation: Nat Med 2026 Oct 23 Epub10/23/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42919966
The human gut microbiome primes fever after vaccination Spotlight
(1) Huus KE (2) Abo H (3) Tan YH (4) Atay E (5) Rytter H (6) Keller R (7) Dauser S (8) Vu DL (9) Azad MB (10) Knight R (11) Ke A (12) Lotoski L (13) Langlois MA (14) Liu R (15) Tyakht AV (16) Youngblut N (17) Kang SM (18) Parsonnet J (19) Maier L (20) Chassaing B (21) Kremsner PG (22) Gewirtz AT (23) Esen M (24) Ley RE
Huus et al. studied the impact of the SARS-CoV-2 mRNA vaccine on the gut microbiome–immune axis in 171 healthy volunteers. Participants with temperatures ≥ 0.8ºC above personal baseline upon vaccination demonstrated chronic low-grade intestinal inflammation, high expression of flagellin, and abundance of flagellated bacteria. In mice, the microbiome from these participants drove innate immune detection of flagellin by TLR5 and NLRC4, and vaccine-induced adverse reactions. Western diet and common food additives boosted the abundance of flagellated bacteria and microbial flagellin production in vitro and in vivo.
Contributed by Ute Burkhardt
(1) Huus KE (2) Abo H (3) Tan YH (4) Atay E (5) Rytter H (6) Keller R (7) Dauser S (8) Vu DL (9) Azad MB (10) Knight R (11) Ke A (12) Lotoski L (13) Langlois MA (14) Liu R (15) Tyakht AV (16) Youngblut N (17) Kang SM (18) Parsonnet J (19) Maier L (20) Chassaing B (21) Kremsner PG (22) Gewirtz AT (23) Esen M (24) Ley RE
Huus et al. studied the impact of the SARS-CoV-2 mRNA vaccine on the gut microbiome–immune axis in 171 healthy volunteers. Participants with temperatures ≥ 0.8ºC above personal baseline upon vaccination demonstrated chronic low-grade intestinal inflammation, high expression of flagellin, and abundance of flagellated bacteria. In mice, the microbiome from these participants drove innate immune detection of flagellin by TLR5 and NLRC4, and vaccine-induced adverse reactions. Western diet and common food additives boosted the abundance of flagellated bacteria and microbial flagellin production in vitro and in vivo.
Contributed by Ute Burkhardt
ABSTRACT: Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. To understand variation in fever risk, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving Severe acute respiratory syndrome coronavirus 2 mRNA vaccines. Fever risk correlated with low-grade intestinal inflammation, increased abundance of flagellated Lachnospiraceae bacteria, and increased flagellin expression prevaccine. Microbiomes from fever-high donors triggered stronger inflammation in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mice. Moreover, microbiome flagellin phenotypes and murine vaccine reactions were modifiable by diet. Consistent with this, human fever risk was associated with self-reported diet and metabolic markers. These findings identify the gut microbiome as a driver of vaccine-induced fever, suggesting that microbiome-targeting strategies could modulate immune tone and improve vaccine side effects.
Author Info: (1) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany.

Author Info: (1) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (2) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (3) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (4) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (5) Microbiome-Host Interactions, Institut Pasteur, Universit Paris Cit, Paris, France. (6) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (7) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (8) Mass Spectrometry Facility, Max Planck Institute for Biology Tbingen, Tbingen, Germany. (9) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (10) Department of Pediatrics; Center for Microbiome Innovation; Department of Computer Science and Engineering; Shu Chien-Gene Lay Department of Bioengineering; Halõcõo_lu Data Science Institute, University of California San Diego, La Jolla, CA, USA. Hong Kong University of Science and Technology Jockey Club Institute for Advanced Study, Hong Kong University of Science and Technology, Hong Kong SAR, China. (11) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (12) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (13) Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, OT, Canada. (14) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (15) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (16) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. (17) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (18) Departments of Medicine and of Epidemiology and Population Health, Stanford University, Stanford, CA, USA. (19) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. Institute for Tropical Medicine, University of Tbingen, Tbingen, Germany. (20) Microbiome-Host Interactions, Institut Pasteur, Universit Paris Cit, Paris, France. (21) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. Interfaculty Institute of Microbiology and Infection Medicine, University of Tbingen, Tbingen, Germany. Centre de Recherches Medicales de Lambarn, Lambarn, Gabon. German Center for Infection Research (DZIF), partner site Tbingen, Tbingen, Germany. (22) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (23) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany. Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Centre de Recherches Medicales de Lambarn, Lambarn, Gabon. (24) Department of Microbiome Science, Max Planck Institute for Biology, Tbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, Tbingen, Germany.

Citation: Science 2026 Oct 8 394:eaea7733 Epub10/08/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42848888
Metastasis enables immunogenicity through migrasome-mediated antigen release Spotlight
(1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L
Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.
Contributed by Shishir Pant
(1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L
Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.
Contributed by Shishir Pant
ABSTRACT: Antigen release is a critical step in initiating antitumor immune responses, yet its regulation during metastasis is not well understood. Here we show that circulating tumor cells undergoing vascular migration produce migrasomes that serve as a metastasis-specific mechanism of antigen release. These migrasomes are enriched in tumor-associated antigens, including cancer-testis and mutated antigens, and are captured efficiently by antigen-presenting cells in secondary lymphoid organs, where they undergo cross-presentation to elicit CD8(+) T cell-mediated immune responses that constrain metastatic progression. Genetic inhibition of migrasome formation enhances metastasis, while administration of purified cancer-derived migrasomes restores immune-mediated suppression of metastatic growth. These findings show paradoxically that metastasis can enhance tumor immunogenicity through migrasome-mediated antigen release, highlighting a link between cancer dissemination and immune activation and establishing migrasomes as a distinct and potent platform for endogenous tumor antigen delivery.
Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantat

Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. jiang-dong@zju.edu.cn. (2) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (3) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (4) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (5) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (6) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (7) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (10) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (11) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (12) Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. (13) Beijing Stomatological Hospital, Capital Medical University, Beijing, China. (14) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. liyulab@mail.tsinghua.edu.cn.

Citation: Nat Immunol 2026 Oct 27:2088-2101 Epub09/22/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42773266
Tags:
Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells
Spotlight(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK
Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.
Contributed by Katherine Turner
(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK
Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.
Contributed by Katherine Turner
ABSTRACT: Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy, yet whether chemotherapy synergizes with cancer vaccines remains unclear. Here, we tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens. Both carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide improve vaccine efficacy and enhance antigen-specific CD8(+) T cell responses. These chemotherapies act as immunological adjuvants independently of tumor presence. Mechanistically, CarboTaxol induces an early, antigen-independent expansion of stem-like T cell factor 1 (TCF1)(+)CD8(+) T cells, an effect also observed in patients with different cancer types. Genetic or pharmacological disruption of TCF1 impairs the immunological adjuvant effect of CarboTaxol. Adding programmed cell death 1 (PD-1) blockade to viral vector vaccines and CarboTaxol further improves tumor control and survival. Together, these findings identify a TCF1-dependent mechanism underlying the immune adjuvant effect of chemotherapy and provide a rationale for clinical evaluation of this triple combination therapy.
Author Info: (1) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Ludwig Institute for Cancer Research, Nuffield Department of Medici

Author Info: (1) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (4) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (5) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (6) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (7) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (8) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (9) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (10) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (11) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (13) Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (14) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (15) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (17) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (18) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, de Duve Institute, UCLouvain, Brussels, Belgium; WEL Research Institute, Brussels, Belgium. Electronic address: benoit.vandeneynde@ludwig.ox.ac.uk. (19) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: carol.leung@immonc.ox.ac.uk.

Citation: Cancer Cell 2026 Oct 2 Epub10/02/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42826713
Antigen presentation requirements for effective cDC1-based cancer immunotherapy Spotlight
(1) Pineda JE (2) Minowa T (3) Shen L (4) Zhou Y (5) Dyevoich A (6) Patel B (7) Schneider SM (8) Keshari S (9) Saha A (10) Riba MN (11) Wang J (12) Watowich SS (13) Gubin MM
Ex vivo-differentiated cDC1s offer superior tumor protection compared to monocyte-derived DCs used in DC vaccine trials. Pinesa and Minowa et al. found that vaccine-delivered cDC1s closely resembled tumor-infiltrating endogenous cDC1s transcriptionally. Robust tumor control upon cDC1 vaccination required both MHC-I and MHC-II antigen presentation on the same cDC1, and transient CD40 stimulation was insufficient to compensate for MHC-II KO on cDC1s vaccines, suggesting direct in cis coordination of CD4+ and CD8+ T cell responses. Lack of host cDC1s in Irf8+32-/- mice with poorly immunogenic B16 tumors reduced the efficacy of cDC1 vaccination.
Contributed by Ute Burkhardt
(1) Pineda JE (2) Minowa T (3) Shen L (4) Zhou Y (5) Dyevoich A (6) Patel B (7) Schneider SM (8) Keshari S (9) Saha A (10) Riba MN (11) Wang J (12) Watowich SS (13) Gubin MM
Ex vivo-differentiated cDC1s offer superior tumor protection compared to monocyte-derived DCs used in DC vaccine trials. Pinesa and Minowa et al. found that vaccine-delivered cDC1s closely resembled tumor-infiltrating endogenous cDC1s transcriptionally. Robust tumor control upon cDC1 vaccination required both MHC-I and MHC-II antigen presentation on the same cDC1, and transient CD40 stimulation was insufficient to compensate for MHC-II KO on cDC1s vaccines, suggesting direct in cis coordination of CD4+ and CD8+ T cell responses. Lack of host cDC1s in Irf8+32-/- mice with poorly immunogenic B16 tumors reduced the efficacy of cDC1 vaccination.
Contributed by Ute Burkhardt
ABSTRACT: Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with murine cDC1s, generated in culture from bone marrow cells (termed here "in vitro-derived cDC1s"), elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro-derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma. As expected, MHC-I or MHC-II deficiency had minimal impact on the transcriptional state of cDC1s in homeostasis or following stimulation with the adjuvant poly dI:dC. Moreover, in vitro-derived cDC1s cultured under steady-state conditions closely resembled tumor-infiltrating cDC1s, whereas their poly dI:dC-stimulated counterparts resembled CCR7+ tumor-infiltrating DC populations, also referred to as mregDCs or LAMP3+ DCs. Our data further show that both MHC-I and MHC-II contribute to tumor control upon cDC1 vaccination and that coexpression of MHC-I and MHC-II on the same cDC1 is necessary for a robust vaccine response. We also identified an important function for host cDC1s in supporting the efficacy of vaccination with in vitro-derived cDC1s, as judged by impaired tumor control in Irf8+32-/- mice, which lack endogenous cDC1s. Overall, these results indicate that effective antitumor responses depend on MHC-I and MHC-II antigen presentation by vaccine-delivered cDC1s, with additional contributions from host cDC1s.
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The Univer

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (6) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (13) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Citation: J Immunol 2026 Aug 4 215: Epub
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42592936
A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized Phase I trial
SpotlightChristian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau
Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.
Contributed by Shishir Pant
Christian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau
Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.
Contributed by Shishir Pant
ABSTRACT: In approximately one third of patients, resected head and neck squamous cell carcinoma will recur. We postulated that the induction of tumor neoantigen-specific T cell responses could prevent relapse. To this end, we developed TG4050, an individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens delivered by a Modified Vaccinia Ankara viral vector. We tested adjuvant TG4050 as single agent in a randomized phase I trial comparing treatment with TG4050 immediately after standard of care adjuvant therapy versus watchful waiting and treatment with TG4050 after recurrence (NCT04183166). The primary endpoint was safety, secondary endpoints included feasibility and efficacy, and immunogenicity was exploratory. TG4050 was well tolerated. Of 16 evaluable patients randomized the immediate treatment arm, none relapsed after a median follow-up of 30 months, while 3 of 16 relapsed in the control arm. T cell responses to vaccine neoantigens were detected in 73.3% of patients treated with TG4050 immediately, with a median of 3 neoantigens per responder. These responses were maintained throughout treatment and persisted for over one year after the last dose. Vaccine neoantigen-specific CD8+ T cells had an effector phenotype, displayed high expression of cytotoxic and tissue-resident markers, were polyclonal and comprised both de novo responses and amplification of pre-existing tumor-infiltrating T cell clones. Together, these translational data are consistent with the hypothesis in which single-agent delivery of TG4050 induces long-lasting tumor neoantigen-specific cytotoxic T cell responses that can prevent tumor recurrence.
Citation: Nat com 2026
Tags:
Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial Spotlight
(1) Wang HH (2) Huff AL (3) Haldar SD (4) Berg M (5) Thoburn C (6) Heumann TR (7) Anders RA (8) Barrett B (9) Bever KM (10) Pishvaian MJ (11) Lee V (12) Le DT (13) Christenson ES (14) Baretti M (15) Yarchoan M (16) Laheru D (17) Thomas A (18) Durham JN (19) Nauroth JM (20) Lu J (21) Wang H (22) Jaffee EM (23) Azad NS (24) Zaidi N
Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.
Contributed by Ute Burkhardt
(1) Wang HH (2) Huff AL (3) Haldar SD (4) Berg M (5) Thoburn C (6) Heumann TR (7) Anders RA (8) Barrett B (9) Bever KM (10) Pishvaian MJ (11) Lee V (12) Le DT (13) Christenson ES (14) Baretti M (15) Yarchoan M (16) Laheru D (17) Thomas A (18) Durham JN (19) Nauroth JM (20) Lu J (21) Wang H (22) Jaffee EM (23) Azad NS (24) Zaidi N
Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.
Contributed by Ute Burkhardt
ABSTRACT: Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFN_ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.
Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University S

Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (6) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (13) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (14) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (15) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (16) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (17) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (19) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (22) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (23) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nilo.azad@jhu.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (24) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.

Citation: Nat Commun 2026 Jun 23 Epub06/23/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42336869
A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle-based mRNA vaccines Spotlight
(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H
Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.
Contributed by Katherine Turner
(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H
Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.
Contributed by Katherine Turner
ABSTRACT: Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.
Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Bi

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (2) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (3) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (4) Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (5) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, United States. (6) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (7) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Immune Network Research Unit, Institute for Frontier Science Initiative InFiniti, Kanazawa University, Kanazawa, Japan. (8) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (9) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (10) Kyoto University Immunomonitoring Center, Liaison Office, Kyoto University, Kyoto, Japan. Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (11) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. (12) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (13) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Citation: Sci Adv 2026 Jul 17 12:eaec7827 Epub07/17/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42467780
