Journal Articles

Immune checkpoint inhibitors unleash pathogenic immune responses against the microbiota

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To address mechanisms underlying immune-related adverse events (irAEs) commonly seen with immune checkpoint inhibitors (ICIs), Hu et al. established a mouse model of skin commensal bacteria-driven irAEs that recapitulated human cutaneous disease pathology. Combination of anti-CTLA-4 and skin neo-colonization with a commensal S. epidermidis caused a commensal-specific inflammatory CD4+ and CD8+ T cell response dependent on IL-17 production in skin. Initial CTLA-4 blockade also primed aberrant memory T cell responses against S. epidermidis, perpetuating inflammatory memory responses following cessation of ICI treatment.

Contributed by Katherine Turner

To address mechanisms underlying immune-related adverse events (irAEs) commonly seen with immune checkpoint inhibitors (ICIs), Hu et al. established a mouse model of skin commensal bacteria-driven irAEs that recapitulated human cutaneous disease pathology. Combination of anti-CTLA-4 and skin neo-colonization with a commensal S. epidermidis caused a commensal-specific inflammatory CD4+ and CD8+ T cell response dependent on IL-17 production in skin. Initial CTLA-4 blockade also primed aberrant memory T cell responses against S. epidermidis, perpetuating inflammatory memory responses following cessation of ICI treatment.

Contributed by Katherine Turner

ABSTRACT: Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.

Author Info: (1) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. National Cancer Insti

Author Info: (1) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. National Cancer Institute, Medical Oncology Fellowship Program, NIH, Bethesda, MD (2) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (3) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (4) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (5) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (6) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (7) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (8) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.

Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma

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To determine the predictive biomarkers and mechanisms of response or resistance to anti-PD-L1 and anti-VEGF combination therapy, Zhu et al. performed an integrated molecular analysis of 358 baseline tumors of HCC. High expression of CD274 (PD-L1), a Teff signature, and intratumoral CD8+ T cell density were associated with better prognosis with the combination, but high TMB or neoantigen load were not. A high Treg/Teff ratio and high GPC3 and AFP expression were associated with reduced clinical benefit. Anti-VEGF therapy inhibited VEGF-mediated angiogenesis, myeloid cell presence, and Treg proliferation to enhance anti-PD-L1 in vivo.

Contributed by Shishir Pant

To determine the predictive biomarkers and mechanisms of response or resistance to anti-PD-L1 and anti-VEGF combination therapy, Zhu et al. performed an integrated molecular analysis of 358 baseline tumors of HCC. High expression of CD274 (PD-L1), a Teff signature, and intratumoral CD8+ T cell density were associated with better prognosis with the combination, but high TMB or neoantigen load were not. A high Treg/Teff ratio and high GPC3 and AFP expression were associated with reduced clinical benefit. Anti-VEGF therapy inhibited VEGF-mediated angiogenesis, myeloid cell presence, and Treg proliferation to enhance anti-PD-L1 in vivo.

Contributed by Shishir Pant

ABSTRACT: Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358_patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase_1b or IMbrave150 phase_3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8(+)_T_cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T_cell (Treg) to effector T_cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.

Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Jiahui International Cancer Center, Jiahui Health, Shanghai, China. (2) Department of Onc

Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Jiahui International Cancer Center, Jiahui Health, Shanghai, China. (2) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (3) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (5) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (6) Department of Research Pathology, Genentech, Inc., South San Francisco, CA, USA. (7) Roche Tissue Diagnostics, Tucson, AZ, USA. (8) Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. (9) Division of Hematology and Oncology, Georgetown University Medical Center, Washington, DC, USA. (10) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. (11) Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. (12) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Division of Hematology-Oncology, UC San Diego Moores Cancer Center, La Jolla, CA, USA. (14) Department of Medicine, Division of Hematology-Oncology, UC Irvine Health, Orange, CA, USA. (15) Product Development, Genentech, Inc., South San Francisco, CA, USA. (16) Product Development, Genentech, Inc., South San Francisco, CA, USA. (17) The Jonsson Comprehensive Cancer Center, Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (18) Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. (19) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. wang.yulei@gene.com.

PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer

Preclinical experimentation revealed that established cancers treated with the immunogenic cell death (ICD) inducer oxaliplatin are sensitized to immune checkpoint inhibitors targeting PD-1. In contrast, no such sensitizing effect is observed when cisplatin, a non-immunogenic cell death inducer is used. Two randomized phase III clinical trials targeting unresectable gastric and gastro-esophageal junction carcinomas apparently validate this observation. Thus, oxaliplatin-based chemotherapy (together with capecitabine or 5-fluorouracil plus leucovorin) favorably interacted with nivolumab, yielding improved outcome. In contrast, the outcome of cisplatin-based chemotherapy (together with capecitabine or 5-fluorouracil) failed to be improved by concomitant treatment with pembrolizumab. These clinical findings underscore the importance of choosing appropriate ICD-inducing cytotoxicants for the development of chemoimmunotherapeutic regimens. Unfortunately, the FDA and EMA have approved PD-1 blockade in combination with "platinum-based chemotherapy" without specifying the precise nature of the platinum-containing drug. This is a non sequitur. Based on the available clinical data, such approvals should be restricted to the use of oxaliplatin.

Author Info: (1) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, UniversitŽ Paris Saclay, Villejuif, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la

Author Info: (1) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, UniversitŽ Paris Saclay, Villejuif, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, UniversitŽ de Paris, Sorbonne UniversitŽ, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. (2) INSERM U1015, Equipe LabellisŽe - Ligue Nationale contre le Cancer, Villejuif, France. (3) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, UniversitŽ Paris Saclay, Villejuif, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, UniversitŽ de Paris, Sorbonne UniversitŽ, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. (4) Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. (5) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, UniversitŽ Paris Saclay, Villejuif, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, UniversitŽ de Paris, Sorbonne UniversitŽ, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. (6) INSERM U1015, Equipe LabellisŽe - Ligue Nationale contre le Cancer, Villejuif, France. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. Gustave Roussy, ClinicObiome, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. (7) Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, UniversitŽ Paris Saclay, Villejuif, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, UniversitŽ de Paris, Sorbonne UniversitŽ, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France. Institut du Cancer Paris CARPEM, Department of Biology, APHP, H™pital EuropŽen Georges Pompidou, Paris, France.

Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing

Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCR__- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications.

Author Info: (1) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (2) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (3) Cellectis, Inc., 430 East 29th Street,

Author Info: (1) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (2) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (3) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (4) Institut Paoli-Calmettes; Aix-Marseille UniversitŽ UM105, CNRS UMR 7258, 13009, Marseille, France. (5) Institut Paoli-Calmettes; Aix-Marseille UniversitŽ UM105, CNRS UMR 7258, 13009, Marseille, France. (6) Institut Paoli-Calmettes; Aix-Marseille UniversitŽ UM105, CNRS UMR 7258, 13009, Marseille, France. (7) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (8) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (9) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. (10) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (11) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (12) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (13) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (14) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (15) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (16) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (17) Department of Experimental Medicine, University of Genova, Genova, Italy. (18) Institut Paoli-Calmettes; Aix-Marseille UniversitŽ UM105, CNRS UMR 7258, 13009, Marseille, France. (19) Institut Paoli-Calmettes; Aix-Marseille UniversitŽ UM105, CNRS UMR 7258, 13009, Marseille, France. daniel.olive@inserm.fr. (20) Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (21) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. Cellectis, 8 rue de la Croix Jarry, 75013, Paris, France. (22) Cellectis, Inc., 430 East 29th Street, New York, NY, 10016, USA. julien.valton@cellectis.com.

Annexin-1 is an oncogene in glioblastoma and causes tumour immune escape through the indirect upregulation of interleukin-8

Annexin-1 (ANXA1) is widely reported to be deregulated in various cancers and is involved in tumorigenesis. However, its effects on glioblastoma (GBM) remain unclear. Using immunohistochemistry with tissue microarrays, we showed that ANXA1 was overexpressed in GBM, positively correlated with higher World Health Organization (WHO) grades of glioma, and negatively associated with poor survival. To further explore its role and the underlying molecular mechanism in GBM, we constructed ANXA1shRNA U87 and U251 cell lines for further experiments. ANXA1 downregulation suppressed GBM cell proliferation, migration, and invasion and enhanced their radiosensitivity. Furthermore, we determined that ANXA1 was involved in dendritic cell (DC) maturation in patients with GBM and that DC infiltration was inversely proportional to GBM prognosis. Considering that previous reports have shown that Interleukin-8 (IL-8) is associated with DC migration and maturation and is correlated with NF-_B transcriptional regulation, we examined IL-8 and p65 subunit expressions and p65 phosphorylation levels in GBM cells under an ANXA1 knockdown. These results suggest that ANXA1 significantly promotes IL-8 production and p65 phosphorylation levels. We inferred that ANXA1 is a potential biomarker and a candidate therapeutic target for GBM treatment and may mediate tumour immune escape through NF-kB (p65) activation and IL-8 upregulation.

Author Info: (1) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Department of Hepatobiliary Surgery, The First Aff

Author Info: (1) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. (2) Department of Oncology, The Second Clinical Medical College, Yangtze University, Jingzhou, China. (3) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (4) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (5) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (6) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (7) Department of Oncology, Zhongnan Hospital, Wuhan university, Wuhan, China. (8) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Dendritic peptide-conjugated polymeric nanovectors for non-toxic delivery of plasmid DNA and enhanced non-viral transfection of immune cells

Plasmid DNA (pDNA) transfection is advantageous for gene therapies requiring larger genetic elements, including "all-in-one" CRISPR/Cas9 plasmids, but is limited by toxicity as well as poor intracellular release and transfection efficiency in immune cell populations. Here, we developed a synthetic non-viral gene delivery platform composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers linked to a cationic dendritic peptide (DP) via a reduceable bond, PEG-b-PPS-ss-DP (PPDP). A library of self-assembling PPDP polymers was synthesized and screened to identify optimal constructs capable of transfecting macrophages with small (pCMV-DsRed, 4.6 kb) and large (pL-CRISPR.EFS.tRFP, 11.7 kb) plasmids. The optimized PPDP construct transfected macrophages, fibroblasts, dendritic cells, and T cells more efficiently and with less toxicity than a commercial Lipo2K reagent, regardless of pDNA size and under standard culture conditions in the presence of serum. The PPDP technology described herein is a stimuli-responsive polymeric nanovector that can be leveraged to meet diverse challenges in gene delivery.

Author Info: (1) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, U

Author Info: (1) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 16419, Republic of Korea. (3) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. (4) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. (5) Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26505, USA. (6) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. (7) Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611, USA.

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its "off-the-shelf" potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.

Author Info: (1) Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China. Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038

Author Info: (1) Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China. Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China. (2) Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China. Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China. (3) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. (4) Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China. ztlzy1971@163.com. (5) Department of Immunology, School of Basic Medical, Jiamusi University, 154007, Jiamusi, China. yandongmei@jmsu.edu.cn. (6) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. jiayu@coh.org. (7) Institute of Materia Medica, College of Pharmacy, Army Medical University, 400038, Chongqing, China. youcai.deng@tmmu.edu.cn. Department of Clinical Hematology, College of Pharmacy, Army Medical University, 400038, Chongqing, China. youcai.deng@tmmu.edu.cn.

Phase I Trial of a Novel Anti-HER2 Antibody-Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer

PURPOSE: ARX788 is a novel antibody-drug conjugate (ADC) comprised of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269 that is site-specifically conjugated to the antibody via a nonnatural amino acid incorporated into the antibody. Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, or 1.5 mg/kg every 3 weeks, or 0.88, 1.1, or 1.3 mg/kg every 4 weeks. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities. RESULTS: In total, 69 patients were enrolled. No DLT or drug-related deaths occurred. Most patients (67/69; 97.1%) experienced at least one treatment-related adverse event (TRAE). Common (³ 30%) TRAEs included an increase in aspartate aminotransferase, an increase in alanine aminotransferase, corneal epitheliopathy, alopecia, hypokalemia, interstitial lung disease (ILD)/pneumonitis, and an increase in aldosterone. While 34.8% of participants experienced ILD/pneumonitis, only 2 had a severity of grade 3. At 1.5 mg/kg every 3 weeks, the recommended phase II dose, the objective response rate was 65.5% [19/29, 95% confidence interval (CI), 45.7-82.1], the disease control rate was 100% (95% CI, 81.2-100), and the median progression-free survival was 17.02 months (95% CI, 10.09-not reached). CONCLUSIONS: ARX788 demonstrated a manageable safety profile with promising preliminary signs of activity in patients with HER2-positive MBC who progressed on prior anti-HER2 therapies.

Author Info: (1) Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. (2

Author Info: (1) Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. (2) Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Head, Neck and Neuroendocrine Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. (3) Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. (4) Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China. (5) Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China. (6) Baylor Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas. (7) Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Department of Breast and Urinary Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood_brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

Author Info: (1) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan Universi

Author Info: (1) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (2) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (3) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (4) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (5) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (6) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. (7) Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.

Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors

BACKGROUND: Both ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer. METHODS: Anti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models. RESULTS: The ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model. CONCLUSION: These findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.

Author Info: (1) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. (2) Dmitriy Rogachev National Medical Research C

Author Info: (1) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. (2) Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia. (3) Orekhovich Institute of Biomedical Chemistry, Moscow, Russia. (4) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. (5) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. Real Target LLC, Moscow, Russia. (6) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. (7) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. (8) Lomonosov Moscow State University, Moscow, Russia. (9) Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia. (10) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. Sechenov First Moscow State Medical University, Moscow, Russia. (11) Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia khol@mail.ru. Real Target LLC, Moscow, Russia.

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