Recent Articles

Molecular patterns of resistance to immune checkpoint blockade in melanoma

(1) Lauss M (2) Phung B (3) Borch TH (4) Harbst K (5) Kaminska K (6) Ebbesson A (7) Hedenfalk I (8) Yuan J (9) Nielsen K (10) Ingvar C (11) Carneiro A (12) Isaksson K (13) Pietras K (14) Svane IM (15) Donia M (16) Jnsson G

Nature communications - Open Access | Free PMC Article

Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1(+) CD8(+) T cells as compared to ICB nave metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Divisio

Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (3) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (4) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (5) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (6) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (7) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (8) Division of Molecular Hematology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (9) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Dermatology, Skne University Hospital and Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (10) Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (11) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, Skne University Hospital Comprehensive Cancer Center, 22185, Lund, Sweden. (12) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Surgery, Kristianstad Hospital, 29133, Kristianstad, Sweden. (13) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (14) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (15) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (16) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. goran_b.jonsson@med.lu.se. Lund University Cancer Center, LUCC, Lund, Sweden. goran_b.jonsson@med.lu.se.

Citation: Nat Commun 2024 Apr 9 15:3075 Epub04/09/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38594286

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Identification of Enhanced Vaccine Mimotopes for the p15E Murine Cancer Antigen

(1) Zhou S (2) Song Y (3) Luo Y (4) Quinn B (5) Jiao Y (6) Long MD (7) Abrams SI (8) Lovell JF

Cancer research communications - Open Access | Free PMC Article

(1) Zhou S (2) Song Y (3) Luo Y (4) Quinn B (5) Jiao Y (6) Long MD (7) Abrams SI (8) Lovell JF

Cancer research communications - Open Access | Free PMC Article

Mimotopes of short CD8+ T-cell epitopes generally comprise one or more mutated residues, and can increase the immunogenicity and function of peptide cancer vaccines. We recently developed a two-step approach to generate enhanced mimotopes using positional peptide microlibraries and herein applied this strategy to the broadly used H-2Kb-restricted murine leukemia p15E tumor rejection epitope. The wild-type p15E epitope (sequence: KSPWFTTL) was poorly immunogenic in mice, even when combined with a potent peptide nanoparticle vaccine system and did not delay p15E-expressing MC38 tumor growth. Following positional microlibrary functional screening of over 150 mimotope candidates, two were identified, both with mutations at residue 3 (p15E-P3C; "3C," and p15E-P3M; "3M") that better induced p15E-specific CD8+ T cells and led to tumor rejection. Although 3M was more immunogenic, 3C effectively delayed tumor growth in a therapeutic setting relative to the wild-type p15E. As 3C had less H-2Kb affinity relative to both p15E and 3M, 15 additional mimotope candidates (all that incorporated the 3C mutation) were assessed that maintained or improved predicted MHC-I affinity. Valine substitution at position 2 (3C2V, sequence: KVCWFTTL) led to improved p15E-specific immunogenicity, tumor rejection, and subsequent long-term antitumor immunity. 3C, 3M, and 3C2V mimotopes were more effective than p15E in controlling MC38 and B16-F10 tumors. T-cell receptor (TCR) sequencing revealed unique TCR transcripts for mimotopes, but there were no major differences in clonality. These results provide new p15E mimotopes for further vaccine use and illustrate considerations for MHC-I affinity, immunogenicity, and functional efficacy in mimotope design. SIGNIFICANCE: The MHC-I-restricted p15E tumor rejection epitope is expressed in multiple murine cancer lines and is used as a marker of antitumor cellular immunity, but has seen limited success as a vaccine immunogen. An in vivo screening approach based on a positional peptide microlibraries is used to identify enhanced p15E mimotopes bearing amino acid mutations that induce significantly improved functional immunogenicity relative to vaccination with the wild-type epitope.

Author Info: (1) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (2) Department of Biomedical Engineering, State University of New York at Buff

Author Info: (1) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (2) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (3) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (4) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (5) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York. (6) Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York. (7) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York. (8) Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York.

Citation: Cancer Res Commun 2024 Apr 2 4:958-969 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38506662

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Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma

(1) Schlenker R (2) Schwalie PC (3) Dettling S (4) Huesser T (5) Irmisch A (6) Mariani M (7) Martnez Gmez JM (8) Ribeiro A (9) Limani F (10) Herter S (11) Yngez E (12) Hoves S (13) Somandin J (14) Siebourg-Polster J (15) Kam-Thong T (16) de Matos IG (17) Umana P (18) Dummer R (19) Levesque MP (20) Bacac M

Med - Open Access

BACKGROUND: The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms. METHODS: We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed. FINDINGS: CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8(+) T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function. CONCLUSIONS: Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response. FUNDING: This research was funded by Roche Pharma Research and Early Development.

Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Cent

Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Center Basel, pRED, Basel, Switzerland. Electronic address: petra.schwalie@roche.com. (3) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (4) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (5) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (6) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (7) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (8) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (9) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (10) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (11) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (12) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (13) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (14) Roche Innovation Center Basel, pRED, Basel, Switzerland. (15) Roche Innovation Center Basel, pRED, Basel, Switzerland. (16) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (17) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (18) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (19) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (20) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland.

Citation: Med 2024 Apr 4 Epub04/04/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38593812

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A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results

(1) Rappaport AR (2) Kyi C (3) Lane M (4) Hart MG (5) Johnson ML (6) Henick BS (7) Liao CY (8) Mahipal A (9) Shergill A (10) Spira AI (11) Goldman JW (12) Scallan CD (13) Schenk D (14) Palmer CD (15) Davis MJ (16) Kounlavouth S (17) Kemp L (18) Yang A (19) Li YJ (20) Likes M (21) Shen A (22) Boucher GR (23) Egorova M (24) Veres RL (25) Espinosa JA (26) Jaroslavsky JR (27) Kraemer Tardif LD (28) Acrebuche L (29) Puccia C (30) Sousa L (31) Zhou R (32) Bae K (33) Hecht JR (34) Carbone DP (35) Johnson B (36) Allen A (37) Ferguson AR (38) Jooss K

Nature medicine

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9_months and 7.9_months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Author Info: (1) Gritstone bio, Emeryville, CA, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Gritstone bio, Emeryville, CA, USA. (4) Gritstone bio, Emeryville, CA, US

Author Info: (1) Gritstone bio, Emeryville, CA, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Gritstone bio, Emeryville, CA, USA. (4) Gritstone bio, Emeryville, CA, USA. (5) Sarah Cannon Research Institute, Nashville, TN, USA. (6) Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA. (7) University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA. (8) Mayo Clinic, Rochester, MN, USA. (9) University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA. (10) Virginia Cancer Specialists, Fairfax, VA, USA. (11) University of California, Los Angeles, Los Angeles, CA, USA. (12) Gritstone bio, Emeryville, CA, USA. (13) Gritstone bio, Emeryville, CA, USA. (14) Gritstone bio, Emeryville, CA, USA. (15) Gritstone bio, Emeryville, CA, USA. (16) Gritstone bio, Emeryville, CA, USA. (17) Gritstone bio, Emeryville, CA, USA. (18) Gritstone bio, Emeryville, CA, USA. (19) Gritstone bio, Emeryville, CA, USA. (20) Gritstone bio, Emeryville, CA, USA. (21) Gritstone bio, Emeryville, CA, USA. (22) Gritstone bio, Emeryville, CA, USA. (23) Gritstone bio, Emeryville, CA, USA. (24) Gritstone bio, Emeryville, CA, USA. (25) Gritstone bio, Emeryville, CA, USA. (26) Gritstone bio, Emeryville, CA, USA. (27) Gritstone bio, Emeryville, CA, USA. (28) Gritstone bio, Emeryville, CA, USA. (29) Gritstone bio, Emeryville, CA, USA. (30) Gritstone bio, Emeryville, CA, USA. (31) Gritstone bio, Emeryville, CA, USA. (32) Gritstone bio, Emeryville, CA, USA. (33) University of California, Los Angeles, Los Angeles, CA, USA. (34) The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. (35) MD Anderson Cancer Center, Houston, TX, USA. (36) Gritstone bio, Emeryville, CA, USA. (37) Gritstone bio, Emeryville, CA, USA. (38) Gritstone bio, Emeryville, CA, USA. kjooss@gritstone.com.

Citation: Nat Med 2024 Apr 30:1013-1022 Epub03/27/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38538867

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Neoantigen-targeted dendritic cell vaccination in lung cancer patients induces long-lived T cells exhibiting the full differentiation spectrum

(1) Ingels J (2) De Cock L (3) Stevens D (4) Mayer RL (5) Thry F (6) Sanchez GS (7) Vermijlen D (8) Weening K (9) De Smet S (10) Lootens N (11) Brusseel M (12) Verstraete T (13) Buyle J (14) Van Houtte E (15) Devreker P (16) Heyns K (17) De Munter S (18) Van Lint S (19) Goetgeluk G (20) Bonte S (21) Billiet L (22) Pille M (23) Jansen H (24) Pascal E (25) Deseins L (26) Vantomme L (27) Verdonckt M (28) Roelandt R (29) Eekhout T (30) Vandamme N (31) Leclercq G (32) Taghon T (33) Kerre T (34) Vanommeslaeghe F (35) Dhondt A (36) Ferdinande L (37) Van Dorpe J (38) Desender L (39) De Ryck F (40) Vermassen F (41) Surmont V (42) Impens F (43) Menten B (44) Vermaelen K (45) Vandekerckhove B

Cell reports. Medicine - Open Access

Non-small cell lung cancer (NSCLC) is known for high relapse rates despite resection in early stages. Here, we present the results of a phase I clinical trial in which a dendritic cell (DC) vaccine targeting patient-individual neoantigens is evaluated in patients with resected NSCLC. Vaccine manufacturing is feasible in six of 10 enrolled patients. Toxicity is limited to grade 1-2 adverse events. Systemic T cell responses are observed in five out of six vaccinated patients, with T cell responses remaining detectable up to 19 months post vaccination. Single-cell analysis indicates that the responsive T cell population is polyclonal and exhibits the near-entire spectrum of T cell differentiation states, including a naive-like state, but excluding exhausted cell states. Three of six vaccinated patients experience disease recurrence during the follow-up period of 2 years. Collectively, these data support the feasibility, safety, and immunogenicity of this treatment in resected NSCLC.

Author Info: (1) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (2) Cancer

Author Info: (1) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (2) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium. (3) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (4) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium; VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, East-Flanders, Belgium. (5) Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium; VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, East-Flanders, Belgium. (6) Department of Pharmacotherapy and Pharmaceutics, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; Institute for Medical Immunology, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; Universit Libre de Bruxelles Center for Research in Immunology, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; WELBIO Department, WEL Research Institute, 1300 Wavre, Walloon Brabant, Belgium. (7) Department of Pharmacotherapy and Pharmaceutics, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; Institute for Medical Immunology, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; Universit Libre de Bruxelles Center for Research in Immunology, Universit Libre de Bruxelles, 1050 Brussels, Brussels, Belgium; WELBIO Department, WEL Research Institute, 1300 Wavre, Walloon Brabant, Belgium. (8) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (9) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (10) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (11) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (12) Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (13) Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (14) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (15) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (16) GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (17) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (18) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (19) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (20) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, East-Flanders, Belgium. (21) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (22) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (23) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (24) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (25) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium. (26) Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium. (27) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (28) VIB Single Cell Core, VIB, 9000/3000 Ghent/Leuven, East-Flanders/Flemish Brabant, Belgium. (29) VIB Single Cell Core, VIB, 9000/3000 Ghent/Leuven, East-Flanders/Flemish Brabant, Belgium. (30) VIB Single Cell Core, VIB, 9000/3000 Ghent/Leuven, East-Flanders/Flemish Brabant, Belgium. (31) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (32) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium. (33) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, East-Flanders, Belgium; Hematology, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (34) Nephrology, Ghent University Hospital, Ghent University, 9000 Ghent, East-Flanders, Belgium. (35) Nephrology, Ghent University Hospital, Ghent University, 9000 Ghent, East-Flanders, Belgium. (36) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Pathology, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (37) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Pathology, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (38) Thoracic and Vascular Surgery, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (39) Thoracic and Vascular Surgery, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (40) Thoracic and Vascular Surgery, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (41) Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. (42) Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium; VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, East-Flanders, Belgium. (43) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, East-Flanders, Belgium. (44) Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; Respiratory Medicine, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. Electronic address: karim.vermaelen@ugent.be. (45) Department of Diagnostic Sciences, Ghent University, 9000 Ghent, East-Flanders, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Easy-Flanders, Belgium; GMP Unit Cell Therapy, Ghent University Hospital, 9000 Ghent, East-Flanders, Belgium. Electronic address: bart.vandekerckhove@ugent.be.

Citation: Cell Rep Med 2024 Apr 9 101516 Epub04/09/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38626769

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Control of adaptive immunity by pattern recognition receptors

(1) Carroll SL (2) Pasare C (3) Barton GM

Immunity

(1) Carroll SL (2) Pasare C (3) Barton GM

Immunity

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.

Author Info: (1) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA. (2) Division of Immunobiology and C

Author Info: (1) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA. (2) Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH USA. (3) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720 USA. Electronic address: barton@berkeley.edu.

Citation: Immunity 2024 Apr 9 57:632-648 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599163

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Pembrolizumab plus chemotherapy for first-line treatment of advanced triple-negative breast cancer

(1) Haiderali A (2) Huang M (3) Pan W (4) Akers KG (5) Maciel D (6) Frederickson AM

Future oncology - Open Access

(1) Haiderali A (2) Huang M (3) Pan W (4) Akers KG (5) Maciel D (6) Frederickson AM

Future oncology - Open Access

Aim: A systematic review and network meta-analysis (NMA) was performed to evaluate the efficacy of first-line treatments for locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) patients. Materials & methods: Databases were searched for randomized controlled trials evaluating first-line treatments for locally recurrent unresectable or metastatic TNBC patients. NMA was performed to estimate relative treatment effects on overall and progression-free survival between pembrolizumab + chemotherapy and other interventions. Results: NMA including eight trials showed that the relative efficacy of pembrolizumab + chemotherapy was statistically superior to that of other immunotherapy- or chemotherapy-based treatment regimens. Conclusion: Pembrolizumab + chemotherapy confers benefits in survival outcomes versus alternative interventions for the first-line treatment of locally recurrent unresectable or metastatic TNBC patients.

Author Info: (1) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (2) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 0706

Author Info: (1) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (2) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (3) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (4) PRECISIONheor; New York, NY 11203, USA. (5) PRECISIONheor; New York, NY 11203, USA. (6) PRECISIONheor; New York, NY 11203, USA.

Citation: Future Oncol 2024 Apr 10 Epub04/10/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38597713

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Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

(1) Elez E (2) Cubillo A (3) Alfonso PG (4) Middleton MR (5) Chau I (6) Alkuzweny B (7) Alcasid A (8) Zhang X (9) Van Cutsem E

BMC cancer - Open Access

(1) Elez E (2) Cubillo A (3) Alfonso PG (4) Middleton MR (5) Chau I (6) Alkuzweny B (7) Alcasid A (8) Zhang X (9) Van Cutsem E

BMC cancer - Open Access

BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. TRIAL REGISTRATION: NCT03271047 (09/01/2017).

Author Info: (1) Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autnoma de Barcelona, Barcelona, Spain. meelez@vhio.net. (2

Author Info: (1) Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autnoma de Barcelona, Barcelona, Spain. meelez@vhio.net. (2) Centro Integral, Oncolgico Clara Campal, HM CIOCC, Madrid, Spain. Facultad HM Hospitales de Ciencias de La Salud UCJC, 28050, Madrid, Spain. (3) Medical Oncology Service, Hospital General Universitario Gregorio Maran, Instituto de Investigacin Sanitaria Gregorio Maran (IiSGM), Universidad Complutense, Madrid, Spain. (4) Department of Oncology, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. (5) Gastrointestinal Unit, Royal Marsden Hospital, London & Surrey, UK. (6) Formerly Pfizer, Inc, San Diego, CA, USA. (7) Pfizer Inc, Collegeville, PA, USA. (8) Pfizer, Inc, New York, NY, USA. (9) University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.

Citation: BMC Cancer 2024 Apr 11 24:446 Epub04/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38600471

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(1) Salminen A

Journal of molecular medicine

(1) Salminen A

Journal of molecular medicine

The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8(+) T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8(+) T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. KEY MESSAGES: Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

Author Info: (1) Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. antero.salminen@uef.fi.

Citation: J Mol Med (Berl) 2024 Apr 11 Epub04/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38600305

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A pan-cancer analysis of the microbiome in metastatic cancer

(1) Battaglia TW (2) Mimpen IL (3) Traets JJH (4) van Hoeck A (5) Zeverijn LJ (6) Geurts BS (7) de Wit GF (8) No M (9) Hofland I (10) Vos JL (11) Cornelissen S (12) Alkemade M (13) Broeks A (14) Zuur CL (15) Cuppen E (16) Wessels L (17) van de Haar J (18) Voest E

Cell - Open Access

Microbial communities are resident to multiple niches of the human body and are important modulators of the host immune system and responses to anticancer therapies. Recent studies have shown that complex microbial communities are present within primary tumors. To investigate the presence and relevance of the microbiome in metastases, we integrated mapping and assembly-based metagenomics, genomics, transcriptomics, and clinical data of 4,160 metastatic tumor biopsies. We identified organ-specific tropisms of microbes, enrichments of anaerobic bacteria in hypoxic tumors, associations between microbial diversity and tumor-infiltrating neutrophils, and the association of Fusobacterium with resistance to immune checkpoint blockade (ICB) in lung cancer. Furthermore, longitudinal tumor sampling revealed temporal evolution of the microbial communities and identified bacteria depleted upon ICB. Together, we generated a pan-cancer resource of the metastatic tumor microbiome that may contribute to advancing treatment strategies.

Author Info: (1) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer

Author Info: (1) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (2) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (3) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (4) Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Head and Neck Surgery and Oncology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. (5) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (6) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (7) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (8) Department of Pathology, Antoni van Leeuwenhoek/the Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (10) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Head and Neck Service and Immunogenomic Oncology Platform, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (12) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (13) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (14) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Head and Neck Surgery and Oncology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Otorhinolaryngology Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands. (15) Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht 3584CX, the Netherlands; Hartwig Medical Foundation, Science Park, Amsterdam 1098XH, the Netherlands. (16) Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Faculty of EEMCS, Delft University of Technology, Delft 2628 CD, the Netherlands. (17) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (18) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. Electronic address: e.voest@nki.nl.

Citation: Cell 2024 Apr 5 Epub04/05/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599211

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