Journal Articles

Immune suppression

Local and peripheral suppression of immune cell activity, immune escape and strategies to revert these pro-tumorigenic mechanisms; cell types with immunosuppressive function

The route of administration dictates the immunogenicity of peptide-based cancer vaccines in mice

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Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.

Author Info: (1) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Washington University School of

Author Info: (1) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Washington University School of Medicine, Saint Louis, MO, USA. (2) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan. Department of Innovative Head and Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa, Japan. (3) Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan. Department of Pathology, Asahikawa Medical University, Asahikawa, Japan. (4) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. (5) Oncovir, Inc., Washington, DC, USA. (6) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. ecelis@augusta.edu.

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The Urinary Microbiome: Implications in Bladder Cancer Pathogenesis and Therapeutics

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Recent investigation has proven that the bladder is not sterile. However, the implications of this finding in the pathophysiology and management of urothelial cell carcinoma have not been fully described. In this review, we summarize the literature relating to the urinary and gastrointestinal microbiomes in the context of urothelial cell carcinoma. The bladder microbiome may relate to urothelial cell carcinoma pathogenesis/progression, act as a non-invasive and modifiable urinary biomarker and have implications in treatment using immunotherapy agents such as intravesical Bacillus Calmette Guerin. Investigators should continue to optimize techniques to characterize this intriguing new area of human health.

Author Info: (1) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: pbajic@lumc.edu. (2) Department of Microbiology and Immunology, Stritch School

Author Info: (1) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: pbajic@lumc.edu. (2) Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: awolfe@luc.edu. (3) Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL USA. Electronic address: gogupta@lumc.edu.

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Natural modulators of the hallmarks of immunogenic cell death

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Natural compounds act as immunoadjuvants as their therapeutic effects trigger cancer stress response and release of damage-associated molecular patterns (DAMPs). These reactions occur through an increase in the immunogenicity of cancer cells that undergo stress followed by immunogenic cell death (ICD). These processes result in a chemotherapeutic response with a potent immune-mediating reaction. Natural compounds that induce ICD may function as an interesting approach in converting cancer into its own vaccine. However, multiple parameters determine whether a compound can act as an ICD inducer, including the nature of the inducer, the premortem stress pathways, the cell death pathways, the intrinsic antigenicity of the cell, and the potency and availability of an immune cell response. Thus, the identification of hallmarks of ICD is important in determining the prognostic biomarkers for new therapeutic approaches and combination treatments.

Author Info: (1) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (2) Laboratoire de Biologie Moleculaire et Cellulaire

Author Info: (1) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (2) Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. (3) College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.

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Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy

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Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-cis-retinoic acid) has a US Food and Drug Administration (FDA)-registered indication for treating high-risk NB patients who achieved at least a partial response to prior first-line multi-agent, multimodality therapy. The FDA registration resulted from a prospective randomized trial assessing the benefit of adding dinutuximab + cytokines to post-myeloablative maintenance therapy for high-risk NB. Dinutuximab has also shown promising antitumor activity when combined with temozolomide and irinotecan in treating NB progressive disease. Clinical activity of dinutuximab and other GD2-targeted therapies relies on the presence of the GD2 antigen on NB cells. Some NBs have been reported as GD2 low or negative, and such tumor cells could be nonresponsive to anti-GD2 therapy. As dinutuximab relies on complement and effector cells to mediate NB killing, factors affecting those components of patient response may also decrease dinutuximab effectiveness. This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB, and the potential mechanisms of resistance to dinutuximab.

Author Info: (1) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. (2) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. Department of Internal Medicine, Patrick.Reynolds@ttuhsc.edu. Department of Cell Biology

Author Info: (1) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. (2) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. Department of Internal Medicine, Patrick.Reynolds@ttuhsc.edu. Department of Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA, Patrick.Reynolds@ttuhsc.edu.

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Endoplasmic Reticulum Stress Responses in Intratumoral Immune Cells: Implications for Cancer Immunotherapy

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Protective anti-tumor immune responses are mediated by effector molecules that enable successful elimination of malignant cells. As the site where transmembrane and secreted proteins are generated, the endoplasmic reticulum (ER) of immune cells plays a key role in this process. Recent studies have indicated that adverse conditions within tumors perturb ER homeostasis in infiltrating immune cells, which can impede the development of effective anti-cancer immunity. Here, we describe how the tumor microenvironment induces ER stress in immune cells, and discuss the detrimental consequences of persistent ER stress responses in intratumoral immune populations. We also explore the concept of targeting ER stress responses to reinvigorate endogenous anti-tumor immunity and enhance the efficacy of various forms of cancer immunotherapy.

Author Info: (1) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York

Author Info: (1) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. (2) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: jur2016@med.cornell.edu.

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Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial

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BACKGROUND: Sintilimab (Innovent Biologics, Suzhou, China), a highly selective, fully humanised, monoclonal antibody, blocks the interaction between PD-1 and its ligands. We aimed to assess the activity and safety profile of sintilimab in Chinese patients with relapsed or refractory classical Hodgkin lymphoma. METHODS: In this ongoing, single-arm, phase 2 study, we recruited patients with histopathologically diagnosed classical Hodgkin lymphoma that was relapsed or refractory after two or more lines of therapy from 18 hospitals in China. Patients were given intravenous sintilimab (200 mg, once every 3 weeks) until progression, death, unacceptable toxicity, or withdrawal of consent. The primary outcome was the proportion of patients in the full analysis set (ie, those with classical Hodgkin lymphoma confirmed by the central pathology laboratory) who had an objective response, as assessed by an independent radiological review committee (IRRC), by 24 weeks after enrolment of the last patient. Tumour response was assessed by enhanced CT scan or MRI at baseline, at weeks 6, 15, and 24, every 12 weeks from weeks 24 to 48, and every 16 weeks beyond week 48. Safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03114683, and is ongoing. FINDINGS: Between April 19, 2017, and Nov 1, 2017, 96 patients were enrolled and commenced treatment. Four patients, whose diagnosis was not subsequently confirmed by the central pathology laboratory, were excluded from the full analysis set. Ten patients discontinued treatment. Median duration of follow-up was 10.5 months. In the full analysis set (n=92), 74 patients (80.4%; 95% CI 70.9-88.0) had an IRRC-assessed objective response before the analysis cutoff date of April 16, 2018. 89 (93%) of 96 patients had treatment-related adverse events, and 17 patients (18%) had grade 3 or 4 treatment-related adverse events, the most common being pyrexia (three [3%] patients). 14 (15%) patients had serious adverse events of any cause. No patient died during the study. INTERPRETATION: Sintilimab could be a new treatment option for patients with relapsed or refractory classical Hodgkin lymphoma in China. FUNDING: Innovent Biologics, Eli Lilly and Company, National New Drug Innovation Programme, and the National Key Scientific Programme Precision Medicine Research Fund of China.

Author Info: (1) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: syuankai@cicams.ac.cn

Author Info: (1) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: syuankai@cicams.ac.cn. (2) Department of Lymphoma, 307th Hospital of Chinese People's Liberation Army, Beijing, China. (3) Department of Haematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China. (4) Sun Yat-Sen University Cancer Centre, Guangzhou, Guangdong, China. (5) Department of Oncology, Second Hospital of Dalian Medical University, Dalian, Liaoning, China. (6) Department of Haematology, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China. (7) Department of Haematology, Peking Union Medical College Hospital, Beijing, China. (8) Department of Haematology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. (9) Department of Haematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. (10) Department of Haematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (11) Department of Oncology, Cancer Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong, China. (12) Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. (13) Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. (14) Department of Oncology, First Hospital of Jilin University, Changchun, Jilin, China. (15) Department of Haematology, Changhai Hospital, Shanghai, China. (16) Department of Haematology, Qilu Hospital of Shandong University, Jinan, Shandong, China. (17) Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China. (18) Department of Oncology, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, China. (19) Department of Haematology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China. (20) Innovent Biologics (Suzhou) Co, Suzhou, Jiangsu, China. (21) Innovent Biologics (Suzhou) Co, Suzhou, Jiangsu, China. (22) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

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Current status of immune checkpoint inhibitors in treatment of non-small cell lung cancer

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Lung cancer remains a leading cause of cancer mortality worldwide, including in Korea. Systemic therapy including platinum-based chemotherapy and targeted therapy should be provided to patients with stage IV non-small cell lung cancer (NSCLC). Applications of targeted therapy, such as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors, in patients with NSCLC and an EGFR mutation or ALK gene rearrangement has enabled dramatic improvements in efficacy and tolerability. Despite advances in research and a better understanding of the molecular pathways of NSCLC, few effective therapeutic options are available for most patients with NSCLC without druggable targets, especially for patients with squamous cell NSCLC. Immune checkpoint inhibitors such as anti-cytotoxic T lymphocyte antigen-4 or anti-programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have demonstrated durable response rates across a broad range of solid tumors, including NSCLC, which has revolutionized the treatment of solid tumors. Here, we review the current status and future approaches of immune checkpoint inhibitors that are being investigated for NSCLC with a focus on pembrolizumab, nivolumab, atezolizumab, durvalumab, and ipilimumab.

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (2) Division of Hematology-Oncology, Department of Medicine, Samsung

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (2) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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Follicular regulatory T cells infiltrated the ovarian carcinoma and resulted in CD8 T cell dysfunction dependent on IL-10 pathway

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A high Treg/CD8 T cell ratio in ovarian carcinoma was negatively associated with the prognosis of the patients. The human follicular regulatory T (Tfr) cells are a newly characterized subset of Treg cells with features of both follicular helper T (Tfh) cells (CXCR5(+)) and canonical Treg cells (CD25(+)Foxp3(+)). The role of Tfr cells in ovarian cancer is yet unclear. We found that in peripheral blood, the ovarian cancer patients presented significantly higher levels of both CD4(+)CD25(+)CD127(-)CXCR5(+) T cells and CD4(+)CD25(+)CD127(-)CXCR5(+)Foxp3(+) T cells than the healthy controls. In resected tumor samples, Tfr cells represented a much greater percentage of lymphocytes than in peripheral blood. Interestingly, the circulating Tfr cells from ovarian cancer patients presented significantly higher TGFB1 and IL10 expression than their counterparts in healthy controls directly ex vivo, and significantly higher IL10 after stimulation. The tumor-infiltrating Tfr cells presented further upregulated expression of TGFB1 and IL10. In addition, the levels of TGFB1 and IL10 expression by Tfr cells negatively associated with the expression of IFNG in tumor-infiltrating CD8 T cells. In an in vitro CD8 T cell/Tfr cell coculture system, we found that Tfr cells could significantly suppress the activation of CD8 T cells, in a manner that was dependent on IL-10 and probably on TGF-beta. Overall, our study found that Tfr cells could suppress CD8 T cells, and in ovarian cancer patients, the Tfr cells were increased in both frequency and function.

Author Info: (1) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. Electronic address: lili_ulmq@sina.com. (2) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical

Author Info: (1) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. Electronic address: lili_ulmq@sina.com. (2) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China. (3) Department of Gynecology, Third Affiliated Hospital, Xinjiang Medical University, Urumqi 830011, China.

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Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression

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Macrophages orchestrate inflammation and control the promotion or inhibition of tumors and metastasis. Ferumoxytol (FMT), a clinically approved iron oxide nanoparticle, possesses anti-tumor therapeutic potential by inducing pro-inflammatory macrophage polarization. Toll-like receptor 3 (TLR3) activation also potently enhances the anti-tumor response of immune cells. Herein, the anti-tumor potential of macrophages harnessed by FMT combined with the TLR3 agonist, poly (I:C) (PIC), and FP-NPs (nanoparticles composed of amino-modified FMT (FMT-NH2) surface functionalized with PIC) was explored. Methods: Proliferation of B16F10 cells co-cultured with macrophages was measured using immunofluorescence or flow cytometry (FCM). Phagocytosis was analyzed using FCM and fluorescence imaging. FP-NPs were prepared through electrostatic interactions and their properties were characterized using dynamic light scattering, transmission electron microscopy, and gel retardation assay. Anti-tumor and anti-metastasis effects were evaluated in B16F10 tumor-bearing mice, and tumor-infiltrating immunocytes were detected by immunofluorescence staining and FCM. Results: FMT, PIC, or the combination of both hardly impaired B16F10 cell viability. However, FMT combined with PIC synergistically inhibited their proliferation by shifting macrophages to a tumoricidal phenotype with upregulated TNF-alpha and iNOS, increased NO secretion and augmented phagocytosis induced by NOX2-derived ROS in vitro. Combined treatment with FMT/PIC and FMT-NH2/PIC respectively resulted in primary melanoma regression and alleviated pulmonary metastasis with elevated pro-inflammatory macrophage infiltration and upregulation of pro-inflammatory genes in vivo. In comparison, FP-NPs with properties of internalization by macrophages and accumulation in the lung produced a more pronounced anti-metastatic effect accompanied with decreased myeloid-derived suppressor cells, and tumor-associated macrophages shifted to M1 phenotype. In vitro mechanistic studies revealed that FP-NPs nanoparticles barely affected B16F10 cell viability, but specifically retarded their growth by steering macrophages to M1 phenotype through NF-kappaB signaling. Conclusion: FMT synergized with the TLR3 agonist PIC either in combination or as a nano-composition to induce macrophage activation for primary and metastatic melanoma regression, and the nano-composition of FP-NPs exhibited a more superior anti-metastatic efficacy.

Author Info: (1) The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China. (2) MOE Key Laboratory of High

Author Info: (1) The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China. (2) MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University , Nanjing, 210093, PR China. (3) The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China. (4) Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing 211166, PR China. (5) Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing, Jiangsu 210093, PR China. (6) The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China. (7) General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China. (8) The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, PR China.

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T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target

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Cancer immunotherapy has proven high efficacy in treating diverse cancer entities by immune checkpoint modulation and adoptive T-cell transfer. However, patterns of treatment response differ substantially from conventional therapies, and reliable surrogate markers are missing for early detection of responders versus non-responders. Current imaging techniques using (18)F-fluorodeoxyglucose-positron-emmission-tomograpy ((18)F-FDG-PET) cannot discriminate, at early treatment times, between tumor progression and inflammation. Therefore, direct imaging of T cells at the tumor site represents a highly attractive tool to evaluate effective tumor rejection or evasion. Moreover, such markers may be suitable for theranostic imaging. Methods: We mainly investigated the potential of two novel pan T-cell markers, CD2 and CD7, for T-cell tracking by immuno-PET imaging. Respective antibody- and F(ab )2 fragment-based tracers were produced and characterized, focusing on functional in vitro and in vivo T-cell analyses to exclude any impact of T-cell targeting on cell survival and antitumor efficacy. Results: T cells incubated with anti-CD2 and anti-CD7 F(ab )2 showed no major modulation of functionality in vitro, and PET imaging provided a distinct and strong signal at the tumor site using the respective zirconium-89-labeled radiotracers. However, while T-cell tracking by anti-CD7 F(ab )2 had no long-term impact on T-cell functionality in vivo, anti-CD2 F(ab )2 caused severe T-cell depletion and failure of tumor rejection. Conclusion: This study stresses the importance of extended functional T-cell assays for T-cell tracer development in cancer immunotherapy imaging and proposes CD7 as a highly suitable target for T-cell immuno-PET imaging.

Author Info: (1) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (2) Clinic and Policlinic for Internal Medicine

Author Info: (1) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (2) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (4) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (5) German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (6) Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (7) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (8) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (9) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (10) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (11) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (12) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. (13) German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (14) German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (15) German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (16) Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (17) Clinic and Policlinic for Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany.

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