Journal Articles

Endogenous Glucocorticoid Signaling Regulates Effector Differentiation and Development of Dysfunction in CD8+ T Cells in the Tumor Microenvironment

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Acharya and Madi et al. describe how glucocorticoid signaling in the tumor microenvironment is associated with dysfunctional tumor-infiltrating CD8+ T cells. By deleting the gene expression of the glucocorticoid receptor in T cells, they show improved tumor control and decreased immune checkpoint expression. The primary source of glucocorticoid production in the tumor environment was found to be tumor-associated myeloid cells. Glucocorticoid production resulted in increased checkpoint expression on CD8+ T cells and reduced their capacity to produce pro-inflammatory cytokines, leaving these cells in a dysfunctional state and inhibiting checkpoint inhibition therapy efficacy.

To read our interview with the researchers, click here: https://bit.ly/3cmrxGB 

Acharya and Madi et al. describe how glucocorticoid signaling in the tumor microenvironment is associated with dysfunctional tumor-infiltrating CD8+ T cells. By deleting the gene expression of the glucocorticoid receptor in T cells, they show improved tumor control and decreased immune checkpoint expression. The primary source of glucocorticoid production in the tumor environment was found to be tumor-associated myeloid cells. Glucocorticoid production resulted in increased checkpoint expression on CD8+ T cells and reduced their capacity to produce pro-inflammatory cytokines, leaving these cells in a dysfunctional state and inhibiting checkpoint inhibition therapy efficacy.

To read our interview with the researchers, click here: https://bit.ly/3cmrxGB 

ABSTRACT: Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. (2) Ev

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. (2) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (3) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (4) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (5) Departments of Dermatology, Pathology, and Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA. (6) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 01225, USA. (7) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Immunology, Harvard Medical School, Boston, MA02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (8) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: aregev@broadinstitute.org. (10) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu. (11) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: acanderson@bwh.harvard.edu.

Emerging roles of class I PI3K inhibitors in modulating tumor microenvironment and immunity

Immune system-mediated tumor killing has revolutionized anti-tumor therapies, providing long-term and durable responses in some patients. The phosphoinositide 3-kinase (PI3K) pathway controls multiple biological processes and is frequently dysregulated in malignancies. Enormous efforts have been made to develop inhibitors against class I PI3K. Notably, with the increasing understanding of PI3K, it has been widely accepted that PI3K inhibition not only restrains tumor progression, but also reshapes the immunosuppressive tumor microenvironment. In this review, we focus on the pivotal roles of class I PI3Ks in adaptive and innate immune cells, as well as other stromal components. We discuss the modulation by PI3K inhibitors of the tumor-supportive microenvironment, including eliminating the regulatory immune cells, restoring cytotoxic cells or regulating angiogenesis. The potential combinations of PI3K inhibitors with other therapies to enhance the anti-tumor immunity are also described.

Author Info: (1) Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. University of Chinese Academy o

Author Info: (1) Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. University of Chinese Academy of Sciences, Beijing, 100049, China. (2) Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. lhmeng@simm.ac.cn. University of Chinese Academy of Sciences, Beijing, 100049, China. lhmeng@simm.ac.cn.

Thymosin alpha-1 blocks the accumulation of myeloid suppressor cells in NSCLC by inhibiting VEGF production

BACKGROUND: Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC). METHODS: The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs. RESULTS: TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1_ in tumor cells. CONCLUSIONS: TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.

Author Info: (1) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Hen

Author Info: (1) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China. (2) Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China; Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. (3) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. (4) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. (5) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. (6) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China. (7) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China. (8) Center for Precision Medicine of Zhengzhou University, Zhengzhou, Henan, 450052, China; Departments of Otolaryngology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China. (9) Center for Precision Medicine of Zhengzhou University, Zhengzhou, Henan, 450052, China; Departments of Otolaryngology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China. (10) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. (11) Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, China. (12) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address: zonghong522@126.com. (13) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address: fccjinsl@zzu.edu.cn. (14) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address: doctormawang@126.com.

An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint that maintains peripheral T cell quiescence and inhibits anti-tumor immune responses. VISTA functions by dampening the interaction between myeloid cells and T cells, orthogonal to PD-1 and other checkpoints of the tumor-T cell signaling axis. Here, we report the use of yeast surface display to engineer an anti-VISTA antibody that binds with high affinity to mouse, human, and cynomolgus monkey VISTA. Our anti-VISTA antibody (SG7) inhibits VISTA function and blocks purported interactions with both PSGL-1 and VSIG3 proteins. SG7 binds a unique epitope on the surface of VISTA, which partially overlaps with other clinically relevant antibodies. As a monotherapy, and to a greater extent as a combination with anti-PD1, SG7 slows tumor growth in multiple syngeneic mouse models. SG7 is a promising clinical candidate that can be tested in fully immunocompetent mouse models and its binding epitope can be used for future campaigns to develop species cross-reactive inhibitors of VISTA.

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (2) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (3) xCella Bioscie

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (2) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (3) xCella Biosciences, Menlo Park, CA, 94025, USA. (4) Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA. (5) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA. (6) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. Immunology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA. (7) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (8) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (9) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA. (10) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. (11) Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA. jennifer.cochran@stanford.edu. xCella Biosciences, Menlo Park, CA, 94025, USA. jennifer.cochran@stanford.edu. Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA. jennifer.cochran@stanford.edu. Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA. jennifer.cochran@stanford.edu. Immunology Program, Stanford University School of Medicine, Stanford, CA, 94305, USA. jennifer.cochran@stanford.edu.

Oncolytic HSV Vectors and Anti-Tumor Immunity

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses; and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic¨ for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment.

Author Info: (1) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (2) Department of Microbiology and Molecular Genetics, Uni

Author Info: (1) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (2) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (3) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (4) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (5) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA , USA. (6) Department of Neurological Surgery, Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (7) Department of Neurological Surgery, Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) Department of Neurosurgery, McGovern Medical School at UTHealth, Houston, TX, USA. (9) City of Hope Medical Center, Duarte, CA, USA. (10) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (11) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. (12) Oncorus Inc., Cambridge, MA, USA.

Neoantigen-specific CD4(+) T-cell response is critical for the therapeutic efficacy of cryo-thermal therapy

BACKGROUND: Traditional tumor thermal ablations, such as radiofrequency ablation (RFA) and cryoablation, can result in good local control of tumor, but traditional tumor thermal ablations are limited by poor long-term survival due to the failure of control of distal metastasis. Our previous studies developed a novel cryo-thermal therapy to treat the B16F10 melanoma mouse model. Long-term survival and T-cell-mediated durable antitumor immunity were achieved after cryo-thermal therapy, but whether tumor antigen-specific T-cells were augmented by cryo-thermal therapy was not determined. METHODS: The long-term antitumor therapeutic efficacy of cryo-thermal therapy was performed in B16F10 murine melanoma models. Splenocytes derived from mice treated with RFA or cryo-thermal therapy were coincubated with tumor antigen peptides to detect the frequency of antigen specific CD4(+) and CD8(+) T-cells by flow cytometry. Splenocytes were then stimulated and expanded by _CD3 or peptides and adoptive T-cell therapy experiments were performed to identify the antitumor efficacy of T-cells induced by RFA and cryo-thermal therapy. Na•ve mice and tumor-bearing mice were used as control groups. RESULTS: Local cryo-thermal therapy generated a stronger systematic antitumor immune response than RFA and a long-lasting antitumor immunity that protected against tumor rechallenge. In vitro studies showed that the antigen-specific CD8(+) T-cell response was induced by both cryo-thermal therapy and RFA, but the strong neoantigen-specific CD4(+) T-cell response was only induced by cryo-thermal therapy. Cryo-thermal therapy-induced strong antitumor immune response was mainly mediated by CD4(+) T-cells, particularly neoantigen-specific CD4(+) T-cells. CONCLUSION: Cryo-thermal therapy induced a stronger and broader antigen-specific memory T-cells. Specifically, cryo-thermal therapy, but not RFA, led to a strong neoantigen-specific CD4(+) T-cell response that mediated the resistance to tumor challenge.

Author Info: (1) School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. (2) Providence Portland Medical Center, Earle A Chiles Research Institute, Portland, Oregon, U

Author Info: (1) School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. (2) Providence Portland Medical Center, Earle A Chiles Research Institute, Portland, Oregon, USA. (3) School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China pingliu@sjtu.edu.cn. (4) School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

EZH2 inhibition: a promising strategy to prevent cancer immune editing

Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells' immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment.

Author Info: (1) Department of Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. (2) Belgian Volition SPRL, Parc Scientifique CrŽalys,

Author Info: (1) Department of Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. (2) Belgian Volition SPRL, Parc Scientifique CrŽalys, Rue Phocas Lejeune 22, BE-5032 Isnes, Belgium. (3) Faculty of Medicine, UniversitŽ Laval, 1050, avenue de la MŽdecine, QuŽbec, QC, G1V 0A6, Canada. (4) Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK. (5) Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK. (6) Department of Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. Department of Urologic Sciences, The Vancouver Prostate Centre, The University of British Columbia, 2660 Oak St, Vancouver, BC, V6H 3Z6, Canada. (7) Cancer Research Group, School of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.

The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

Breast cancer affects roughly one in eight women over their lifetime and is a leading cause of cancer-related death in women. While outcomes have improved in recent years, prognosis remains poor for patients who present with either disseminated disease or aggressive molecular subtypes. Cancer immunotherapy has revolutionized the treatment of several cancers, with therapeutic vaccines aiming to direct the cytotoxic immune program against tumor cells showing particular promise. However, these results have yet to translate to breast cancer, which remains largely refractory from such approaches. Recent evidence suggests that the breast tumor microenvironment (TME) is an important and long understudied barrier to the efficacy of therapeutic vaccines. Through an improved understanding of the complex and biologically diverse breast TME, it may be possible to advance new combination strategies to render breast carcinomas sensitive to the effects of therapeutic vaccines. Here, we discuss past and present efforts to advance therapeutic vaccines in the treatment of breast cancer, the molecular mechanisms through which the TME contributes to the failure of such approaches, as well as the potential means through which these can be overcome.

Author Info: (1) Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA. Medical Scientist Training Program, University of Illinois College

Author Info: (1) Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA. Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL 60612, USA. (2) Division of Hematology and Oncology, University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.

PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates

Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomarkers as well as a deeper mechanistic analysis of the cellular populations involved in clinical responses. With the aim to find predictive biomarkers for PD-1 checkpoint blockade, an in-depth immune monitoring study was conducted in 36 advanced melanoma patients receiving pembrolizumab or nivolumab treatment at Karolinska University Hospital. Blood samples were collected before treatment and before administration of the second and fourth doses. Peripheral blood mononuclear cells were isolated and stained for flow cytometric analysis within 2 h of sample collection. Overall survival and progression-free survival (PFS) were inversely correlated with CD69 expression NK cells. In the myeloid compartment, high frequencies of non-classical monocytes and low frequencies of monocytic myeloid derived suppressor cells (MoMDSCs) correlated with response rates and OS. A deeper characterization of monocytic subsets showed that PD-L1 expression in MDSCs, non-classical and intermediate monocytes was significantly increased in patients with shorter PFS in addition to correlating inversely with OS. Our results suggest that cellular populations other than T cells can be critical in the outcome of PD-1 blockade treatment. Specifically, the frequencies of activated NK cells and monocytic subsets are inversely correlated with survival and clinical benefit, suggesting that their role as predictive biomarkers should be further evaluated.

Author Info: (1) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (2) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Theme Cancer

Author Info: (1) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (2) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Theme Cancer, Patient Area Head and Neck, Lung, and Skin, Karolinska University Hospital Solna, Stockholm, Sweden. (3) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (4) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan. (5) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (6) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. (7) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Theme Cancer, Patient Area Head and Neck, Lung, and Skin, Karolinska University Hospital Solna, Stockholm, Sweden. (8) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Theme Cancer, Patient Area Head and Neck, Lung, and Skin, Karolinska University Hospital Solna, Stockholm, Sweden. (9) Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. Theme Cancer, Patient Area Head and Neck, Lung, and Skin, Karolinska University Hospital Solna, Stockholm, Sweden.

Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients

Purpose This was a phase I/II adoptive T cell trial in 7 locally advanced and metastatic pancreatic cancer patients using 3-8 infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (BATs) to determine safety, the maximum tolerated dose (MTD), immune responses, time to progression (TTP), and overall survival (OS). Study Design: T cells obtained by apheresis were expanded and armed with EGFRBi, cryopreserved for infusions. In a phase I dose escalation, five patients received three weekly infusions of 10-40 _ 10(9) BATs/infusion followed by a booster infusion 3 months later, and 2 patients received 8 infusions twice weekly for 4 weeks in a phase II. The trials were registered at http://www.clinicaltrials.gov, NCT01420874 and NCT02620865. Results: There were no dose-limiting toxicities (DLTs), and the targeted dose of 80 _ 10(9) BATs was met. The median TTP is 7 months, and the median OS is 31 months. Two patients had stable disease for 6.5 and 25+ months, and two patients developed complete responses (CRs) after restarting chemotherapy. Infusions of BATs induced anti-pancreatic cancer cytotoxicity, innate immune responses, cytokine responses (IL-12, IP-10), and shifts in CD4 and CD8 V_ repertoire with enhanced cytoplasmic IFN-_ staining in the V_ repertoire of the CD8 subset that suggest specific clonal TCR responses. Conclusions: Infusions of BATs are safe, induce endogenous adaptive anti-tumor responses, and may have a potential to improve overall survival.

Author Info: (1) Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA. (2) Stem Cell Transp

Author Info: (1) Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA. (2) Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA. (3) Department of Oncology, Stony Brook University, Stony Brook, NY, USA. (4) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (5) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (6) Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA. (7) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (8) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (9) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (10) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (11) Department of Radiology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. (12) Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA.

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