Journal Articles

Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire Spotlight 

(1) Cheloni G (2) Karagkouni D (3) Pita-Juarez Y (4) Torres D (5) Kanata E (6) Liegel J (7) Avigan Z (8) Saldarriaga I (9) Chedid G (10) Rallis K (11) Miles B (12) Tiwari G (13) Kim J (14) Mattie M (15) Rosenblatt J (16) Vlachos IS (17) Avigan D

Nature communications | Free PMC Article

Cheloni and Karagkouni et al. characterized endogenous (non-CAR) T cells in patients with LBCL treated with anti-CD19 CAR T cells, who experienced either long-term response (LtR) or relapse (R). T cells from LtR patients (cf. R patients) were less differentiated at leukapheresis, had higher expression of cytotoxic and pro-inflammatory genes (which increased after CAR T infusion), and showed expansion of cytotoxic TCR clonotypes. R patient T cells, NK cells, and monocytes expressed genes associated with immune regulation and dampened responses. Clonotypic T cell expansion 4 weeks after CAR T treatment predicted patient response better than CAR T peak expansion.

Contributed by Alex Najibi

(1) Cheloni G (2) Karagkouni D (3) Pita-Juarez Y (4) Torres D (5) Kanata E (6) Liegel J (7) Avigan Z (8) Saldarriaga I (9) Chedid G (10) Rallis K (11) Miles B (12) Tiwari G (13) Kim J (14) Mattie M (15) Rosenblatt J (16) Vlachos IS (17) Avigan D

Nature communications | Free PMC Article

Cheloni and Karagkouni et al. characterized endogenous (non-CAR) T cells in patients with LBCL treated with anti-CD19 CAR T cells, who experienced either long-term response (LtR) or relapse (R). T cells from LtR patients (cf. R patients) were less differentiated at leukapheresis, had higher expression of cytotoxic and pro-inflammatory genes (which increased after CAR T infusion), and showed expansion of cytotoxic TCR clonotypes. R patient T cells, NK cells, and monocytes expressed genes associated with immune regulation and dampened responses. Clonotypic T cell expansion 4 weeks after CAR T treatment predicted patient response better than CAR T peak expansion.

Contributed by Alex Najibi

ABSTRACT: While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Bos

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (5) Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. (6) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (7) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (8) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (9) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Kite, a Gilead Company, Santa Monica, CA, USA. (12) Kite, a Gilead Company, Santa Monica, CA, USA. (13) Kite, a Gilead Company, Santa Monica, CA, USA. (14) Kite, a Gilead Company, Santa Monica, CA, USA. (15) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (16) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Spatial Technologies Unit, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. (17) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Harvard Medical School, Boston, MA, USA. davigan@bidmc.harvard.edu.

Citation: Nat Commun 2025 May 23 16:4819 Epub05/23/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40410132

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Adoptively transferred macrophages for cancer immunotherapy Spotlight 

(1) Park KS (2) Gottlieb AP (3) Janes ME (4) Prakash S (5) Kapate N (6) Suja VC (7) Wang LL (8) Guerriero JL (9) Mitragotri S

Journal for immunotherapy of cancer | Free PMC Article

Park et al. demonstrated that adoptively transferred, ex vivo-activated, antigen-pulsed macrophages (M_ther) elicited robust systemic and local antitumor immune responses in both subcutaneous and lung metastasis melanoma models. M_ther treatment activated antigen-specific CD8+ T cells, CD4+ T cells, and NK cells, and promoted antitumor cytokine production. M_ther activation also facilitated splenic DC and NK cell activation, while antigen-presenting functions triggered CD8+ T cell responses. The antitumor immune effects of M_ther were dependent on NK and CD8+ T cells, but not on CD4+ T cells.

Contributed by Shishir Pant

(1) Park KS (2) Gottlieb AP (3) Janes ME (4) Prakash S (5) Kapate N (6) Suja VC (7) Wang LL (8) Guerriero JL (9) Mitragotri S

Journal for immunotherapy of cancer | Free PMC Article

Park et al. demonstrated that adoptively transferred, ex vivo-activated, antigen-pulsed macrophages (M_ther) elicited robust systemic and local antitumor immune responses in both subcutaneous and lung metastasis melanoma models. M_ther treatment activated antigen-specific CD8+ T cells, CD4+ T cells, and NK cells, and promoted antitumor cytokine production. M_ther activation also facilitated splenic DC and NK cell activation, while antigen-presenting functions triggered CD8+ T cell responses. The antitumor immune effects of M_ther were dependent on NK and CD8+ T cells, but not on CD4+ T cells.

Contributed by Shishir Pant

Background: Macrophages have been classically associated with their innate immune functions of responding to acute injury or pathogenic insult, but they have been largely overlooked as primary initiators of adaptive immune responses. Here, we demonstrate that adoptively transferred macrophages, with optimal activation prior to administration, act as a potent cellular cancer therapeutic platform against a murine melanoma model.

Method: The macrophage therapy was prepared from bone marrow-derived macrophages, pretreated ex vivo with an activation cocktail containing interferon-γ, tumor necrosis factor-α, polyinosinic:polycytidylic acid, and anti-CD40 antibody. The therapy was administered to tumor-bearing mice via the tail vein. Tumor growth and survival of the treated mice were monitored to evaluate therapeutic efficacy. Tumors and spleens were processed to examine immune responses and underlying mechanisms.

Results: This immunotherapy platform elicits systemic immune responses while infiltrating the tumor to exert direct antitumor effects in support of the systemic adaptive response. The macrophage-based immunotherapy produced a strong CD8+T cell response along with robust natural killer and CD4+T cell activation, inducing a "hot" tumor transition and achieving effective tumor suppression.

Conclusions: Owing to their inherent ability to home to and infiltrate inflamed tissues, macrophage-based cancer immunotherapies exhibited a unique in vivo trafficking behavior, efficiently reaching and persisting within tumors. Macrophages orchestrated a multiarmed immune attack led by CD8+T cells, with the potential for local, intratumoral activation of effector cells, demonstrating a novel cancer immunotherapy platform with meaningfully different characteristics than clinically evaluated alternatives.

Author Info: (1) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massa

Author Info: (1) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. (2) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. (3) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (4) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. (5) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (6) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. (7) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (8) Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, Massachusetts, USA. Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USA. (9) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA mitragotri@seas.harvard.edu. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA.

Citation: J Immunother Cancer 2025 May 24 13: Epub05/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40413021

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TEIPP-vaccination in checkpoint-resistant non-small cell lung cancer: a first-in-human phase I/II dose-escalation study Spotlight 

(1) Emmers M (2) Welters MJP (3) Dietz MV (4) Santegoets SJ (5) Boekesteijn S (6) Stolk A (7) Loof NM (8) Dumoulin DW (9) Geel AL (10) Steinbusch LC (11) Valentijn ARPM (12) Cohen D (13) de Miranda NFCC (14) Smit EF (15) Gelderblom H (16) van Hall T (17) Aerts JG (18) van der Burg SH

Nature communications | Free PMC Article

TAP deficiency leads to poor cell surface expression of peptide–MHC-I complexes, but often reveals novel T cell epitopes associated with impaired peptide processing (TEIPP). Emmers, Welters and Dietz et al. developed a synthetic long-peptide vaccine from LRPAP1, and carried out a first-in-human dose escalation study in 26 HLA-A*02:01+ checkpoint-resistant patients with stage IV NSCLC. One cohort received the highest dose of TEIPP vaccine plus pembrolizumab. LRPAP1-specific CD8+ and CD4+ T cells were detected in 83% and 62% patients, respectively. The vaccine was well tolerated, and 1 PR, 8 SD, and 2 MR were observed in 24 vaccinated patients.

Contributed by Katherine Turner

(1) Emmers M (2) Welters MJP (3) Dietz MV (4) Santegoets SJ (5) Boekesteijn S (6) Stolk A (7) Loof NM (8) Dumoulin DW (9) Geel AL (10) Steinbusch LC (11) Valentijn ARPM (12) Cohen D (13) de Miranda NFCC (14) Smit EF (15) Gelderblom H (16) van Hall T (17) Aerts JG (18) van der Burg SH

Nature communications | Free PMC Article

TAP deficiency leads to poor cell surface expression of peptide–MHC-I complexes, but often reveals novel T cell epitopes associated with impaired peptide processing (TEIPP). Emmers, Welters and Dietz et al. developed a synthetic long-peptide vaccine from LRPAP1, and carried out a first-in-human dose escalation study in 26 HLA-A*02:01+ checkpoint-resistant patients with stage IV NSCLC. One cohort received the highest dose of TEIPP vaccine plus pembrolizumab. LRPAP1-specific CD8+ and CD4+ T cells were detected in 83% and 62% patients, respectively. The vaccine was well tolerated, and 1 PR, 8 SD, and 2 MR were observed in 24 vaccinated patients.

Contributed by Katherine Turner

ABSTRACT: Functional loss of the intracellular peptide Transporter associated with Antigen Processing (TAP) fosters resistance to T-cell based immunotherapy. We discovered the presentation of an alternative set of shared tumor antigens on such escaped cancers and developed a LRPAP1 synthetic long peptide vaccine (TEIPP24) to stimulate T-cell immunity. In this first-in-human multicenter dose-escalation study with extension cohort, HLA-A*0201-positive patients with non-small cell lung cancer progressive after checkpoint blockade were treated with TEIPP24 (NCT05898763). Dose escalation followed an adapted 3 + 3 scheme where in each cohort six patients received the TEIPP24 peptide emulsified in Montanide ISA-51 at either 20, 40, 100 µg of peptide, subcutaneously injected three times every three weeks in alternating limbs. The extension cohort of six patients received the highest safe dose of TEIPP24 combined with the PD-1 checkpoint blocker pembrolizumab. The primary objectives of the study were safety, tolerability and immunogenicity of the TEIPP24 vaccine. Secondary objectives included the evaluation of specificity and immune modulatory effects of the vaccine, antigen and immune status of the patients, progression free (PFS) and overall survival (OS) and radiological tumor response rate and duration. A total of 26 patients were enrolled across 2 institutions. Treatment was well tolerated, and vaccine-induced LRPAP1-specific CD8+ T cells were detected in 20 of 24 evaluable patients (83%). In 13 of 21 tested cases (62%) vaccine-specific CD4+ T cells were also detected. The increase in activated polyfunctional CD8+ effector T cells was influenced by vaccine dose, number of vaccines administered, induction of a CD4+ T-cell response, and the pre-existing frequency of monocytic cells. Co-administration of pembrolizumab resulted in the ex-vivo detection of activated (HLA-DR+ , PD-1+ , ICOS+ ) LRPAP1-specific CD8+ T cells. The observation of one PR, 8 stable diseases and 2 mixed responses in 24 evaluable patients after vaccination, correlated with a stronger vaccine-induced CD8+ T-cell response to this single epitope from this new class of cancer antigens.

Author Info: (1) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical

Author Info: (1) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (3) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (4) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (5) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (6) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (7) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (8) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (9) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (10) Department of Pulmonary Disease, Leiden University Medical Center, Leiden, The Netherlands. (11) Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. (12) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (13) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (14) Department of Pulmonary Disease, Leiden University Medical Center, Leiden, The Netherlands. (15) Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (17) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (18) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. shvdburg@lumc.nl.

Citation: Nat Commun 2025 May 28 16:4958 Epub05/28/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40436854

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INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering Spotlight 

(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL

Journal for immunotherapy of cancer | Free PMC Article

Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.

Contributed by Morgan Janes

(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL

Journal for immunotherapy of cancer | Free PMC Article

Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.

Contributed by Morgan Janes

BACKGROUND: Immunotherapies targeting immune checkpoint inhibitors have revolutionized cancer treatment but are limited by incomplete patient responses. Costimulatory agonists like OX40 (CD134), a tumor necrosis factor receptor family member critical for T-cell survival and differentiation, have shown preclinical promise but limited clinical success due to suboptimal receptor activation. Conventional bivalent OX40 agonists fail to induce the trimeric engagement required for optimal downstream signaling. To address this, we developed INBRX-106, a hexavalent OX40 agonist designed to enhance receptor clustering independently of Fc-mediated crosslinking and boost antitumor T-cell responses. METHODS: We assessed INBRX-106's effects on receptor clustering, signal transduction, and T-cell activation using NF-k§ reporter assays, confocal microscopy, flow cytometry, and single-cell RNA sequencing. Therapeutic efficacy was evaluated in murine tumor models and ex vivo human samples. Clinical samples from a phase I/II trial (NCT04198766) were also analyzed for immune activation. RESULTS: INBRX-106 demonstrated superior receptor clustering and downstream signaling compared with bivalent agonists, leading to robust T-cell activation and proliferation. In murine models, hexavalent OX40 agonism resulted in significant tumor regression, enhanced survival, and increased CD8(+) T-cell effector function. Clinical pharmacodynamic analysis in blood samples from patients treated with INBRX-106 showed heightened T-cell activation and proliferation, particularly in central and effector memory subsets, validating our preclinical findings. CONCLUSIONS: Our data establish hexavalent INBRX-106 as a differentiated and more potent OX40 agonist, showcasing its ability to overcome the limitations of conventional bivalent therapies by inducing superior receptor clustering and multimeric engagement. This unique clustering mechanism amplifies OX40 signaling, driving robust T-cell activation, proliferation, and effector function in preclinical and clinical settings. These findings highlight the therapeutic potential of INBRX-106 and its capacity to redefine OX40-targeted immunotherapy, providing a compelling rationale for its further clinical development in combination with checkpoint inhibitors.

Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA

Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (3) Inhibrx Biosciences Inc, La Jolla, California, USA. (4) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (5) Inhibrx Biosciences Inc, La Jolla, California, USA. (6) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (7) Inhibrx Biosciences Inc, La Jolla, California, USA. (8) Inhibrx Biosciences Inc, La Jolla, California, USA. (9) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (10) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. The Ohio State University, Columbus, Ohio, USA. (11) Inhibrx Biosciences Inc, La Jolla, California, USA. (12) Inhibrx Biosciences Inc, La Jolla, California, USA william.redmond@providence.org yaiza@inhibrx.com. (13) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA william.redmond@providence.org yaiza@inhibrx.com.

Citation: J Immunother Cancer 2025 May 21 13: Epub05/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40404202

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Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy Spotlight 

(1) Benton A (2) Liu J (3) Poussin MA (4) Lang Goldgewicht A (5) Udawela M (6) Bear AS (7) Wellhausen N (8) Carreno BM (9) Smith PM (10) Beasley MD (11) Kiefel BR (12) Powell DJ Jr

Cancer cell

Benton and Liu et al. utilized the Retained Display library to identify high-affinity KRAS G12V binders, and incorporated them into CAR T cells to create mKRAS NeoCARs. mKRAS NeoCARs demonstrated robust antitumor responses against cancer cells expressing mutant KRAS peptides, but failed to achieve full tumor control in vivo due to low sensitivity or potency. Armoring mKRAS NeoCAR T cells with NFAT-inducible IL-12 enhanced their efficacy, but introduced low-level TCR-mediated xeno- or alloreactivity. Combining iIL-12 NeoCARs with TCR KO prevented T cell xenoreactivity and resulted in robust tumor clearance and enhanced survival in the NSCLC xenograft model.

Contributed by Shishir Pant

(1) Benton A (2) Liu J (3) Poussin MA (4) Lang Goldgewicht A (5) Udawela M (6) Bear AS (7) Wellhausen N (8) Carreno BM (9) Smith PM (10) Beasley MD (11) Kiefel BR (12) Powell DJ Jr

Cancer cell

Benton and Liu et al. utilized the Retained Display library to identify high-affinity KRAS G12V binders, and incorporated them into CAR T cells to create mKRAS NeoCARs. mKRAS NeoCARs demonstrated robust antitumor responses against cancer cells expressing mutant KRAS peptides, but failed to achieve full tumor control in vivo due to low sensitivity or potency. Armoring mKRAS NeoCAR T cells with NFAT-inducible IL-12 enhanced their efficacy, but introduced low-level TCR-mediated xeno- or alloreactivity. Combining iIL-12 NeoCARs with TCR KO prevented T cell xenoreactivity and resulted in robust tumor clearance and enhanced survival in the NSCLC xenograft model.

Contributed by Shishir Pant

ABSTRACT: Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.

Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of

Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Bioengineering Graduate Group, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (5) Myrio Tx, Melbourne, VIC, Australia. (6) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA. (7) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Myrio Tx, Melbourne, VIC, Australia. (10) Myrio Tx, Melbourne, VIC, Australia. (11) Myrio Tx, Melbourne, VIC, Australia. (12) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: poda@pennmedicine.upenn.edu.

Citation: Cancer Cell 2025 Jun 4 Epub06/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40480232

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Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade

Spotlight 

Lucas Blanchard (1,2,5,*); Estefania Vina (1,2,5); Jerko Ljubetic (1,2); Cécile Meneur (1,2); Dorian Tarroux (1,2); Maria Baez (3); Alessandra Marino (3); Nathalie Ortega (1,2); David A. Knorr (3,4); Jeffrey V. Ravetch (3); and Jean-Philippe Girard (1,2,6,*)

Cell Reports Medicine

Blanchard and Vina et al. investigated mechanisms by which anti-CTLA-4 mAbs modulate tumor-associated high endothelial venules (TA-HEVs), which are important for supporting lymphocyte entry into tumors. In mouse models, anti-CTLA-4 Fc-derived effector function was required to increase TA-HEVs. CD4+ T cells and IFNγ were also found to be important during anti-CTLA-4 therapy. Consequently, Fc engineering of ipilimumab was necessary to increase TA-HEVs in humanized mice. Combination with anti-PD-1 increased TA-HEVs, promoted CD4+ and CD8+ T cell infiltration into tumors, and sensitized cold, refractory tumors to PD-1 blockade.

Contributed by Katherine Turner

Lucas Blanchard (1,2,5,*); Estefania Vina (1,2,5); Jerko Ljubetic (1,2); Cécile Meneur (1,2); Dorian Tarroux (1,2); Maria Baez (3); Alessandra Marino (3); Nathalie Ortega (1,2); David A. Knorr (3,4); Jeffrey V. Ravetch (3); and Jean-Philippe Girard (1,2,6,*)

Cell Reports Medicine

Blanchard and Vina et al. investigated mechanisms by which anti-CTLA-4 mAbs modulate tumor-associated high endothelial venules (TA-HEVs), which are important for supporting lymphocyte entry into tumors. In mouse models, anti-CTLA-4 Fc-derived effector function was required to increase TA-HEVs. CD4+ T cells and IFNγ were also found to be important during anti-CTLA-4 therapy. Consequently, Fc engineering of ipilimumab was necessary to increase TA-HEVs in humanized mice. Combination with anti-PD-1 increased TA-HEVs, promoted CD4+ and CD8+ T cell infiltration into tumors, and sensitized cold, refractory tumors to PD-1 blockade.

Contributed by Katherine Turner

ABSTRACT: The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent re-modelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4+ T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4+ and CD8+ T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Mo

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, USA 4-Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5-These authors contributed equally 6-Lead contact *Correspondence: lblanchard@rockefeller.edu, jean-philippe.girard@ipbs.fr

Citation: Cell rep med 2025

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Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer

Spotlight 

(1) Li H (2) Zhang MJ (3) Zhang B (4) Lin WP (5) Li SJ (6) Xiong D (7) Wang Q (8) Wang WD (9) Yang QC (10) Huang CF (11) Deng WW (12) Sun ZJ

Nature communications | Free PMC Article

Li and Zhang et al. reported the presence of stem-like T cells and B cells at various stages of tertiary lymphoid structure (TLS) maturation in patient HNSCC tumors. Mature TLS (mTLS) were enriched for stem-like and functional CD8+ T cells, CD4+ Texprog/Tfh cells, and diverse subtypes of B cells and plasma cells. Immature TLS displayed an enrichment of B cells without concurrent plasma cells. Spatial transcriptomics confirmed the presence of triads of CD4+ Texprog/Tfh cells with DCs and B cells, suggesting mTLSs have a role in B cell maturation and effector memory CD8+ T cell generation. The presence of mTLSs was associated with response to ICB therapy in HNSCC.

Contributed by Shishir Pant

(1) Li H (2) Zhang MJ (3) Zhang B (4) Lin WP (5) Li SJ (6) Xiong D (7) Wang Q (8) Wang WD (9) Yang QC (10) Huang CF (11) Deng WW (12) Sun ZJ

Nature communications | Free PMC Article

Li and Zhang et al. reported the presence of stem-like T cells and B cells at various stages of tertiary lymphoid structure (TLS) maturation in patient HNSCC tumors. Mature TLS (mTLS) were enriched for stem-like and functional CD8+ T cells, CD4+ Texprog/Tfh cells, and diverse subtypes of B cells and plasma cells. Immature TLS displayed an enrichment of B cells without concurrent plasma cells. Spatial transcriptomics confirmed the presence of triads of CD4+ Texprog/Tfh cells with DCs and B cells, suggesting mTLSs have a role in B cell maturation and effector memory CD8+ T cell generation. The presence of mTLSs was associated with response to ICB therapy in HNSCC.

Contributed by Shishir Pant

ABSTRACT: Tumor tertiary lymphoid structures (TLS), especially mature TLS (mTLS), have been associated with better prognosis and improved responses to immune checkpoint blockade (ICB), but the underlying mechanisms remain incompletely understood. Here, by performing single-cell RNA, antigen receptor sequencing and spatial transcriptomics on tumor tissue from head and neck squamous cell carcinoma (HNSCC) patients with different statuses of TLS, we observe that mTLS are enriched with stem-like T cells, and B cells at various maturation stages. Notably, progenitor exhausted CD4(+) T cells, with features resembling follicular helper T cells, support these responses, by activating B cells to produce plasma cells in the germinal center, and interacting with DC-LAMP(+) dendritic cells to support CD8(+) T cell activation. Conversely, non-mTLS tumors do not promote local anti-tumor immunity which is abundant of immunosuppressive cells or a lack of stem-like B and T cells. Furthermore, patients with mTLS manifest improved overall survival and response to ICB compared to those with non-mTLS. Overall, our study provides insights into mechanisms underlying mTLS-mediated intra-tumoral immunity events against cancer.

Author Info: (1) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, Sch

Author Info: (1) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. (2) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (3) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (4) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (5) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (6) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (7) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (8) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (9) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (10) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (11) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. dww@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. dww@whu.edu.cn. (12) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. sunzj@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. sunzj@whu.edu.cn.

Citation: Nat Commun 2025 May 7 16:4228 Epub05/07/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40335494

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Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens Spotlight 

(1) Gamboa L (2) Zamat AH (3) Thiveaud CA (4) Lee HJ (5) Kulaksizoglu E (6) Zha Z (7) Campbell NS (8) Chan CS (9) F‡brega S (10) Oliver SA (11) Su FY (12) Phuengkham H (13) Vanover D (14) Peck HE (15) Sivakumar A (16) Dahotre SN (17) Harris AM (18) Santangelo PJ (19) Kwong GA

Nature cancer

Gamboa and Zamat et al. optimized LNPs to deliver a synthetic antigen (the camelid VHH) to tumors, enabling recognition by anti-VHH CAR T cells. Anti-VHH CAR T cells responded to VHH+ tumor cell lines, but not VHH- human PBMCs, and were well tolerated in naive mice. Intratumoral VHH-LNP injection led to tumor cell VHH expression, and subsequent adoptive transfer of anti-VHH CAR T cells controlled tumor growth and prompted antigen spreading, restricting growth of even VHH- parental tumor cells. This treatment strategy had superior efficacy to standard CAR T cells (anti-HER2 CAR T) in mixed antigen (e.g., HER2+/-) models.

Contributed by Alex Najibi

(1) Gamboa L (2) Zamat AH (3) Thiveaud CA (4) Lee HJ (5) Kulaksizoglu E (6) Zha Z (7) Campbell NS (8) Chan CS (9) F‡brega S (10) Oliver SA (11) Su FY (12) Phuengkham H (13) Vanover D (14) Peck HE (15) Sivakumar A (16) Dahotre SN (17) Harris AM (18) Santangelo PJ (19) Kwong GA

Nature cancer

Gamboa and Zamat et al. optimized LNPs to deliver a synthetic antigen (the camelid VHH) to tumors, enabling recognition by anti-VHH CAR T cells. Anti-VHH CAR T cells responded to VHH+ tumor cell lines, but not VHH- human PBMCs, and were well tolerated in naive mice. Intratumoral VHH-LNP injection led to tumor cell VHH expression, and subsequent adoptive transfer of anti-VHH CAR T cells controlled tumor growth and prompted antigen spreading, restricting growth of even VHH- parental tumor cells. This treatment strategy had superior efficacy to standard CAR T cells (anti-HER2 CAR T) in mixed antigen (e.g., HER2+/-) models.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells.

Author Info: (1) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (2) Wallace H. Coulter Department of Bi

Author Info: (1) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (2) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (3) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (4) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (5) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (6) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (7) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (8) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (9) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (10) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (11) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (12) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (13) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (14) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (15) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (16) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (17) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (18) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (19) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. gkwong@gatech.edu. Parker H. Petit Institute of Bioengineering and Bioscience, Atlanta, GA, USA. gkwong@gatech.edu. Institute for Matter and Systems, Georgia Institute of Technology, Atlanta, GA, USA. gkwong@gatech.edu. The Georgia Immunoengineering Consortium, Emory University and Georgia Tech, Atlanta, GA, USA. gkwong@gatech.edu. Winship Cancer Institute, Emory University, Atlanta, GA, USA. gkwong@gatech.edu.

Citation: Nat Cancer 2025 May 16 Epub05/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40379831

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Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer Featured  

(1) Apavaloaei A (2) Zhao Q (3) Hesnard L (4) Cahuzac M (5) Durette C (6) Larouche JD (7) Hardy MP (8) Vincent K (9) Brochu S (10) Laverdure JP (11) Lanoix J (12) Courcelles M (13) Gendron P (14) Lajoie M (15) Ruiz Cuevas MV (16) Kina E (17) Perrault J (18) Humeau J (19) Ehx G (20) Lemieux S (21) Watson IR (22) Speiser DE (23) Bassani-Sternberg M (24) Thibault P (25) Perreault C

Nature cancer

Apavaloaei et al. analyzed tumor cell surface expression of MHC-I-associated peptides (MAPs) derived from tumor antigens (TAs) in melanoma and non-small cell lung cancer. The vast majority of detected MAPs were from unmutated genomic regions. Mutated tumor-specific antigens were limited due to low RNA expression and being outside of MAP hotspots. High numbers of unmutated TAs were identified. Responders to anti-PD-1 treatment exhibited a decrease in aberrantly-expressed tumor-specific antigens (aeTSAs), which were found to be highly immunogenic, cancer-specific, and shared between patients.

(1) Apavaloaei A (2) Zhao Q (3) Hesnard L (4) Cahuzac M (5) Durette C (6) Larouche JD (7) Hardy MP (8) Vincent K (9) Brochu S (10) Laverdure JP (11) Lanoix J (12) Courcelles M (13) Gendron P (14) Lajoie M (15) Ruiz Cuevas MV (16) Kina E (17) Perrault J (18) Humeau J (19) Ehx G (20) Lemieux S (21) Watson IR (22) Speiser DE (23) Bassani-Sternberg M (24) Thibault P (25) Perreault C

Nature cancer

Apavaloaei et al. analyzed tumor cell surface expression of MHC-I-associated peptides (MAPs) derived from tumor antigens (TAs) in melanoma and non-small cell lung cancer. The vast majority of detected MAPs were from unmutated genomic regions. Mutated tumor-specific antigens were limited due to low RNA expression and being outside of MAP hotspots. High numbers of unmutated TAs were identified. Responders to anti-PD-1 treatment exhibited a decrease in aberrantly-expressed tumor-specific antigens (aeTSAs), which were found to be highly immunogenic, cancer-specific, and shared between patients.

ABSTRACT: Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.

Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Cana

Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (2) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (3) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (4) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (5) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (6) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (7) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (8) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (9) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (10) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (11) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (12) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (13) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (14) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (15) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (16) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (17) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (18) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (19) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. (20) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (21) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. (22) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (23) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (24) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. Department of Chemistry, University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. (25) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca.

Citation: Nat Cancer 2025 May 22 Epub05/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40405018

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Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial Spotlight 

(1) Saxena M (2) Anker JF (3) Kodysh J (4) O'Donnell T (5) Kaminska AM (6) Meseck M (7) Hapanowicz O (8) Niglio SA (9) Salazar AM (10) Shah HR (11) Kinoshita Y (12) Brody R (13) Rubinsteyn A (14) Sebra RP (15) Bhardwaj N (16) Galsky MD

Nature cancer

Saxena, Anker, Kodysh et al. demonstrated that the personalized long-peptide neoantigen vaccine PGV001, in combination with atezolizumab, was feasible, safe, and elicited durable neoantigen-specific T cell responses in patients with urothelial cancer (UC). Introduction of anti-PD-L1 during the priming cycle, after the first three PGV001 doses, produced neoantigen-specific T cell response in 100% of evaluable participants. Among 5 patients with metastatic UC, 2 achieved an objective response to treatment, and among 4 patients treated in the adjuvant setting, 3 remained recurrence-free at a median follow-up of 39 months.

Contributed by Shishir Pant

(1) Saxena M (2) Anker JF (3) Kodysh J (4) O'Donnell T (5) Kaminska AM (6) Meseck M (7) Hapanowicz O (8) Niglio SA (9) Salazar AM (10) Shah HR (11) Kinoshita Y (12) Brody R (13) Rubinsteyn A (14) Sebra RP (15) Bhardwaj N (16) Galsky MD

Nature cancer

Saxena, Anker, Kodysh et al. demonstrated that the personalized long-peptide neoantigen vaccine PGV001, in combination with atezolizumab, was feasible, safe, and elicited durable neoantigen-specific T cell responses in patients with urothelial cancer (UC). Introduction of anti-PD-L1 during the priming cycle, after the first three PGV001 doses, produced neoantigen-specific T cell response in 100% of evaluable participants. Among 5 patients with metastatic UC, 2 achieved an objective response to treatment, and among 4 patients treated in the adjuvant setting, 3 remained recurrence-free at a median follow-up of 39 months.

Contributed by Shishir Pant

ABSTRACT: Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3_weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39_months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 .

Author Info: (1) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Medicine, Division of Hematology Oncology

Author Info: (1) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) New York University Langone Laura and Isaac Perlmutter Cancer Center, New York, NY, USA. (9) Oncovir, Inc., Washington, D.C., USA. (10) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (14) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA. nina.bhardwaj@mssm.edu. (16) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. matthew.galsky@mssm.edu.

Citation: Nat Cancer 2025 May 9 Epub05/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40346292

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