213 results on '"Salih HR"'
Search Results
2. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL
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Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, and Lo-Coco, F
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Hematology - Published
- 2019
3. Sustained complete remission of recurrent acute myeloid leukaemia with a single dose of gemtuzumab ozogamicin and low-dose interleukin-2 maintenance
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Radsak, MP, Salih, HR, Sökler, M, Kanz, L, and Denzlinger, C
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- 2002
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4. Differentielle Induktion von Apotose und Therapie-induzierter Seneszenz (TIS) durch die beiden DNA-Methyltransferase Inhibitoren 5-Azacytidin und 5-Aza-2'-deoxycytidin
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Venturelli, S, primary, Berger, A, additional, Weiland, T, additional, Essmann, F, additional, Waibel, M, additional, Nübling, T, additional, Häcker, S, additional, Schulze-Osthoff, K, additional, Salih, HR, additional, Fulda, S, additional, Sipos, B, additional, Johnstone, RW, additional, Lauer, UM, additional, and Bitzer, M, additional
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- 2014
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5. Differentielle Induktion von Apotose und Therapie-induzierter Seneszenz (TIS) durch die beiden DNA-Methyltransferase Inhibitoren 5-Azacytidin und 5-Aza-2′-deoxycytidin
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Venturelli, S, primary, Berger, A, additional, Weiland, T, additional, Essmann, F, additional, Waibel, M, additional, Nübling, T, additional, Häcker, S, additional, Schulze-Osthoff, K, additional, Salih, HR, additional, Fulda, S, additional, Sipos, B, additional, Johnstone, RW, additional, Lauer, UM, additional, and Bitzer, M, additional
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- 2013
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6. Differentielle molekulare Wirkmechanismen der beiden DNA-Methyltransferase Inhibitoren 5-Azacytidin und 5-Aza-2'-deoxycytidin für die Therapie von soliden Tumoren
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Venturelli, S, primary, Berger, A, additional, Weiland, T, additional, Essmann, F, additional, Waibel, M, additional, Nübling, T, additional, Häcker, S, additional, Schenk, M, additional, Schulze-Osthoff, K, additional, Salih, HR, additional, Fulda, S, additional, Sipos, B, additional, Johnstone, RW, additional, Lauer, UM, additional, and Bitzer, M, additional
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- 2013
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7. TNFSF18 (tumor necrosis factor (ligand) superfamily, member 18)
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Placke, T, primary, Kopp, HG, additional, Schmiedel, BJ, additional, and Salih, HR, additional
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- 2011
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8. Planning a sustainable neurosurgery mentorship program in a war-torn country: experience from Iraq.
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Al-Ageely TA, Ismail M, Alaraji ZA, Abdulwahid J, Ayad F, Jaafar H, Aktham A, Salih HR, and Hoz S
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The importance of mentorships in medical education and neurosurgery is highly attributed to the support and encouragement of the advances and learning opportunities for medical students and junior neurosurgeons. Planning a mentorship program according to the target audience offers to satisfy different interests and enhance education. One of the main issues with most of the already implemented programs is the sustainability and inability to maintain continuous cycles of mentorship, which have a negative impact and have led to an interrupted pattern of learning which eventually leads to a decline in the engagement of participants and loss of interest. This problem is most pronounced in war-torn countries, with Iraq as an example, where external circumstances lead to an arrest in the educational process and a depletion of the resources useful for such programs and training courses. This paper aims to address the main pathways essential in planning a sustainable mentorship program in a war-torn country by highlighting our experience in maintaining an ongoing mentorship with nine consecutive courses over the last 6 years in Iraq., (© 2024. The Author(s).)
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- 2024
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9. The bispecific B7H3xCD3 antibody CC-3 induces T cell immunity against bone and soft tissue sarcomas.
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Holzmayer SJ, Liebel K, Hagelstein I, Salih HR, and Märklin M
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- Humans, T-Lymphocytes immunology, T-Lymphocytes metabolism, Cell Line, Tumor, Bone Neoplasms immunology, Bone Neoplasms pathology, Female, Male, Animals, Lymphocyte Activation immunology, Middle Aged, CD3 Complex immunology, Aged, Cell Proliferation, Adult, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Sarcoma immunology, Sarcoma drug therapy, B7 Antigens immunology, B7 Antigens metabolism
- Abstract
Sarcomas are rare and heterogeneous malignancies that are difficult to treat. Approximately 50% of patients diagnosed with sarcoma develop metastatic disease with so far very limited treatment options. The transmembrane protein B7-H3 reportedly is expressed in various malignancies, including different sarcoma subtypes. In several cancer entities B7-H3 expression is associated with poor prognosis. In turn, B7-H3 is considered a promising target for immunotherapeutic approaches. We here report on the preclinical characterization of a B7-H3xCD3 bispecific antibody in an IgG-based format, termed CC-3, for treatment of different sarcoma subtypes. We found B7-H3 to be expressed on all sarcoma cells tested and expression on sarcoma patients correlated with decreased progression-free and overall survival. CC-3 was found to elicit robust T cell responses against multiple sarcoma subtypes, resulting in significant activation, release of cytokines and effector molecules. In addition, CC-3 promoted T cell proliferation and differentiation, resulting in the generation of memory T cell subsets. Finally, CC-3 induced potent target cell lysis in a target cell restricted manner. Based on these results, a clinical trial evaluating CC-3 in soft tissue sarcoma is currently in preparation., Competing Interests: HS is listed as inventor on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant is German Cancer Research Center, Heidelberg, and Medical Faculty University of Tübingen, Germany. The remaining authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Holzmayer, Liebel, Hagelstein, Salih and Märklin.)
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- 2024
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10. Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody.
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Stefańczyk SA, Hagelstein I, Lutz MS, Müller S, Holzmayer SJ, Jarjour G, Zekri L, Heitmann JS, Salih HR, and Märklin M
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- Humans, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, B7 Antigens metabolism, B7 Antigens pharmacology, Killer Cells, Natural, Leukemia, Myeloid, Acute drug therapy
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Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML., (© 2024. The Author(s).)
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- 2024
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11. Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome.
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Seller A, Tegeler CM, Mauermann J, Schreiber T, Hagelstein I, Liebel K, Koch A, Heitmann JS, Greiner SM, Hayn C, Dannehl D, Engler T, Hartkopf AD, Hahn M, Brucker SY, Salih HR, and Märklin M
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- Humans, Female, Research Personnel, Enzyme-Linked Immunosorbent Assay, Health Status, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating
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Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.
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- 2024
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12. FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
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Hackenbruch C, Bauer J, Heitmann JS, Maringer Y, Nelde A, Denk M, Zieschang L, Kammer C, Federmann B, Jung S, Martus P, Malek NP, Nikolaou K, Salih HR, Bitzer M, and Walz JS
- Abstract
The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals., Trial Registration Numbers: EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295)., Competing Interests: JB, YM and JW are listed as inventors on a patent related to the DNAJB1-PRKACA T cell epitopes and TCRs Peptides and antigen binding proteins for use in immunotherapy against fibrolamellar HCC and other cancers, Application number: EP21214728.4. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BJ declared a past co-authorship with the author JW to the handling editor., (Copyright © 2024 Hackenbruch, Bauer, Heitmann, Maringer, Nelde, Denk, Zieschang, Kammer, Federmann, Jung, Martus, Malek, Nikolaou, Salih, Bitzer and Walz.)
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- 2024
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13. Immunocytokines with target cell-restricted IL-15 activity for treatment of B cell malignancies.
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Zekri L, Hagelstein I, Märklin M, Klimovich B, Christie M, Lindner C, Kämereit S, Prakash N, Müller S, Stotz S, Maurer A, Greve C, Schmied B, Atar D, Rammensee HG, Jung G, and Salih HR
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- Animals, Humans, Mice, Adaptor Proteins, Signal Transducing, Antibodies, Antigens, CD19, Cytokines, Immunoglobulin Fc Fragments, Interleukin-15, Lymphoma
- Abstract
Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short half-life, poor accumulation at the tumor site, and severe toxicity due to unspecific immune activation. We here report modified immunocytokines consisting of Fc-optimized CD19 and CD20 antibodies fused to an IL-15 moiety comprising an L45E-E46K double mutation (MIC
+ format). The E46K mutation abrogated binding to IL-15Rα, thereby enabling substitution of physiological trans-presentation by target binding and thus conditional IL-15Rβγ stimulation, whereas the L45E mutation optimized IL-15Rβγ agonism and producibility. In vitro analysis of NK activation, anti-leukemia reactivity, and toxicity using autologous and allogeneic B cells confirmed target-dependent function of MIC+ constructs. Compared with Fc-optimized CD19 and CD20 antibodies, MIC+ constructs mediated superior target cell killing and NK cell proliferation. Mouse models using luciferase-expressing human NALM-6 lymphoma cells, patient acute lymphoblastic leukemia (ALL) cells, and murine EL-4 lymphoma cells transduced with human CD19/CD20 as targets and human and murine NK cells as effectors, respectively, confirmed superior and target-dependent anti-leukemic activity. In summary, MIC+ constructs combine the benefits of Fc-optimized antibodies and IL-15 cytokine activity and mediate superior NK cell immunity with potentially reduced side effects. They thus constitute a promising new immunotherapeutic approach shown here for B cell malignancies.- Published
- 2024
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14. Protocol of a first-in-human clinical trial to evaluate the safety, tolerability, and preliminary efficacy of the bispecific CD276xCD3 antibody CC-3 in patients with colorectal cancer (CoRe_CC-3).
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Jung S, Schlenk RF, Hackenbruch C, Roldan Pinzon SSL, Bitzer M, Pflügler M, Walz JS, Jung G, Heitmann JS, and Salih HR
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Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide in men and women. In the metastasized stage, treatment options and prognosis are limited. To address the high medical need of this patient population, we generated a CD276xCD3 bispecific antibody termed CC-3. CD276 is expressed on CRC cells and on tumor vessels, thereby allowing for a "dual" anticancer effect., Methods and Analysis: This first-in-human clinical study is planned as a prospective multicenter trial, enrolling patients with metastatic CRC after three lines of therapy. During the dose-escalation part, initially, an accelerated titration design with single-patient cohorts is employed. Here, each patient will receive a fixed dose level (starting with 50 µg for the first patient); however, between patients, dose level may be increased by up to 100%, depending on the decision of a safety review committee. Upon occurrence of any adverse events (AEs) grade ≥2, dose-limiting toxicity (DLT), or reaching a dose level of ≥800 µg, the escalation will switch to a standard 3 + 3 dose design. After maximum tolerated dose (MTD) has been determined, defined as no more than one of the six patients experiencing DLT, an additional 14 patients receive CC-3 at the MTD level in the dose-expansion phase. Primary endpoints are incidence and severity of AEs, as well as the best objective response to the treatment according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints include overall safety, efficacy, survival, quality of life, and pharmacokinetic investigations., Ethics and Dissemination: The CD276xCD3 study was approved by the Ethics Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf and the Paul-Ehrlich-Institut (P00702). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: ClinicalTrials.cov Registry (NCT05999396) and EU ClinicalTrials Registry (EU trial number 2022-503084-15-00)., Competing Interests: GJ, HS, and MP are listed as inventors on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant is German Cancer Research Center, Heidelberg, and Medical Faculty University of Tübingen, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jung, Schlenk, Hackenbruch, Roldan Pinzon, Bitzer, Pflügler, Walz, Jung, Heitmann and Salih.)
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- 2024
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15. Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults.
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Tandler C, Heitmann JS, Michel TM, Marconato M, Jaeger SU, Tegeler CM, Denk M, Richter M, Oezbek MT, Maringer Y, Schroeder SM, Schneiderhan-Marra N, Wiesmüller KH, Bitzer M, Ruetalo N, Schindler M, Meisner C, Fischer I, Rammensee HG, Salih HR, and Walz JS
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- Adult, Humans, COVID-19 Vaccines, CD8-Positive T-Lymphocytes, SARS-CoV-2, Peptides, Antibodies, Viral, COVID-19 prevention & control
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Objectives: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants., Methods: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12., Results: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4
+ ) and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed., Conclusion: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects., Competing Interests: Declarations of Competing Interest JSH, HRS, H-GR, and JSW are listed as inventors on a patent (EP 20 169 047.6) related to the SARS-CoV-2 T cell epitopes included in CoVac-1. H-GR and K-HW are listed as inventors on a patent related to the adjuvant XS15 included in CoVac-1 (DE102016005550.2). The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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16. An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer.
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Lutz MS, Wang K, Jung G, Salih HR, and Hagelstein I
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- Humans, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Killer Cells, Natural, B7 Antigens metabolism, Immunotherapy methods, Pancreatic Neoplasms metabolism
- Abstract
Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ability to stimulate antibody-dependent cellular cytotoxicity (ADCC), which plays a crucial role in their therapeutic efficacy. As a result, significant effort has been focused on improving this critical function by engineering mAbs with Fc regions that have increased affinity for the Fc receptor CD16 expressed on natural killer (NK) cells, the major cell population that mediates ADCC in humans. Here we report on the preclinical characterization of a mAb directed to the target antigen B7-H3 (CD276) containing an Fc part with the amino acid substitutions S239D/I332E to increase affinity for CD16 (B7-H3-SDIE) for the treatment of pancreatic cancer. B7-H3 (CD276) is highly expressed in many tumor entities, whereas expression on healthy tissues is more limited. Our findings confirm high expression of B7-H3 on pancreatic cancer cells. Furthermore, our study shows that B7-H3-SDIE effectively activates NK cells against pancreatic cancer cells in an antigen-dependent manner, as demonstrated by the analysis of NK cell activation, degranulation and cytokine release. The activation of NK cells resulted in significant tumor cell lysis in both short-term and long-term cytotoxicity assays. In conclusion, B7-H3-SDIE constitutes a promising agent for the treatment of pancreatic cancer., Competing Interests: GJ and HS are listed as inventors on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant is German Cancer Research Center, Heidelberg, and Medical Faculty University of Tuebingen, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lutz, Wang, Jung, Salih and Hagelstein.)
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- 2024
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17. Bilateral basal ganglia hemorrhage in a 2-year-old child.
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Alrawi MA, Abdulqader MN, Salih HR, Saleh SA, Al-Ghuraibawi MA, Altaweel MM, Ismail M, and Hoz SS
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Background: Basal ganglia hemorrhage (BGH) is an intracerebral subtype of hemorrhage located in the caudate nucleus, putamen, globus pallidus, or adjacent structures such as the thalamus or internal capsule. Bilateral involvement of both basal ganglia is exceedingly infrequent. Herein, we report a case of a 2-year-old female who was discovered to have spontaneous bilateral BGH with a unique hemorrhagic extension., Case Description: A 2-year-old female child who presented with a decreased level of consciousness, seizure, and fever was discovered to have bilateral BGH during imaging evaluation that extended from the head of the caudate to involve the putamen, globus pallidus, and anterior limb of the internal capsule., Conclusion: Bilateral BGH is extremely rare, and to the best of our knowledge, this is the first case report in pediatric age groups., Competing Interests: There are no conflicts of interest, (Copyright: © 2023 Surgical Neurology International.)
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- 2023
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18. TOF IMS mass spectrometry-based immunopeptidomics refines tumor antigen identification.
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Hoenisch Gravel N, Nelde A, Bauer J, Mühlenbruch L, Schroeder SM, Neidert MC, Scheid J, Lemke S, Dubbelaar ML, Wacker M, Dengler A, Klein R, Mauz PS, Löwenheim H, Hauri-Hohl M, Martin R, Hennenlotter J, Stenzl A, Heitmann JS, Salih HR, Rammensee HG, and Walz JS
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- Humans, Antigens, Neoplasm, Mass Spectrometry methods, HLA Antigens, Peptides chemistry, Histocompatibility Antigens Class II, Histocompatibility Antigens Class I, Neoplasms therapy
- Abstract
T cell recognition of human leukocyte antigen (HLA)-presented tumor-associated peptides is central for cancer immune surveillance. Mass spectrometry (MS)-based immunopeptidomics represents the only unbiased method for the direct identification and characterization of naturally presented tumor-associated peptides, a key prerequisite for the development of T cell-based immunotherapies. This study reports on the implementation of ion mobility separation-based time-of-flight (TOF
IMS ) MS for next-generation immunopeptidomics, enabling high-speed and sensitive detection of HLA-presented peptides. Applying TOFIMS -based immunopeptidomics, a novel extensive benignTOFIMS dataset was generated from 94 primary benign samples of solid tissue and hematological origin, which enabled the expansion of benign reference immunopeptidome databases with > 150,000 HLA-presented peptides, the refinement of previously described tumor antigens, as well as the identification of frequently presented self antigens and not yet described tumor antigens comprising low abundant mutation-derived neoepitopes that might serve as targets for future cancer immunotherapy development., (© 2023. The Author(s).)- Published
- 2023
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19. Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells.
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Nelde A, Schuster H, Heitmann JS, Bauer J, Maringer Y, Zwick M, Volkmer JP, Chen JY, Stanger AMP, Lehmann A, Appiah B, Märklin M, Rücker-Braun E, Salih HR, Roerden M, Schroeder SM, Häring MF, Schlosser A, Schetelig J, Schmitz M, Boerries M, Köhler N, Lengerke C, Majeti R, Weissman IL, Rammensee HG, and Walz JS
- Subjects
- Humans, Peptides, Stem Cells, HLA Antigens, Leukemia, Myeloid, Acute genetics
- Abstract
Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell-based therapies with potential of eliminating residual LSCs in patients with AML., Significance: The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II-presented antigens, paving the way to the development of LSC-directed T cell-based immunotherapeutic approaches for patients with AML. See related commentary by Ritz, p. 430 . This article is featured in Selected Articles from This Issue, p. 419., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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20. Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.
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Schlenk RF, Weber D, Krzykalla J, Kindler T, Wulf G, Hertenstein B, Salih HR, Südhoff T, Krauter J, Martens U, Wessendorf S, Runde V, Tischler HJ, Bentz M, Koller E, Heuser M, Thol F, Benner A, Ganser A, Döhner K, and Döhner H
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- Humans, Aged, Etoposide adverse effects, Cytarabine adverse effects, Tretinoin therapeutic use, Nuclear Proteins, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m
2 , days 8-28; the dose of ATRA was reduced to 45 mg/m2 , days 8-10 and 15 mg/m2 , days 11-28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1-7 and etoposide 100 mg/day, p.o. or i.v., days 1-3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64-92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010)., (© 2023. Springer Nature Limited.)- Published
- 2023
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21. Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer.
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Kaidun P, Holzmayer SJ, Greiner SM, Seller A, Tegeler CM, Hagelstein I, Mauermann J, Engler T, Koch A, Hartkopf AD, Salih HR, and Märklin M
- Subjects
- Humans, Administration, Cutaneous, Aggression, Ligands, NK Cell Lectin-Like Receptor Subfamily K genetics, Receptors, IgG, CD3 Complex, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Recombinant Fusion Proteins therapeutic use
- Abstract
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti-CD3 (NKG2D-CD3) or anti-CD16 (NKG2D-CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1-4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D-CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D-CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D-based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.
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- 2023
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22. Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency.
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Heitmann JS, Tandler C, Marconato M, Nelde A, Habibzada T, Rittig SM, Tegeler CM, Maringer Y, Jaeger SU, Denk M, Richter M, Oezbek MT, Wiesmüller KH, Bauer J, Rieth J, Wacker M, Schroeder SM, Hoenisch Gravel N, Scheid J, Märklin M, Henrich A, Klimovich B, Clar KL, Lutz M, Holzmayer S, Hörber S, Peter A, Meisner C, Fischer I, Löffler MW, Peuker CA, Habringer S, Goetze TO, Jäger E, Rammensee HG, Salih HR, and Walz JS
- Subjects
- Humans, SARS-CoV-2, T-Lymphocytes, Peptides therapeutic use, COVID-19, Agammaglobulinemia
- Abstract
T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4
+ T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469., (© 2023. Springer Nature Limited.)- Published
- 2023
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23. Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease.
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Heitmann JS, Schlenk RF, Dörfel D, Kayser S, Döhner K, Heuser M, Thol F, Kapp-Schwoerer S, Labrenz J, Edelmann D, Märklin M, Vogel W, Bethge W, Walz JS, Große-Hovest L, Steiner M, Jung G, and Salih HR
- Subjects
- Humans, Antibodies, Monoclonal, Immunoglobulin Fc Fragments, Neoplasm, Residual, fms-Like Tyrosine Kinase 3, Antineoplastic Agents, Drug-Related Side Effects and Adverse Reactions, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells., Methods: This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1-5: single dose of 0.5 mg/m
2 , 1.5 mg/m2 , 5 mg/m2 , 15 mg/m2 , 45 mg/m2 ; cohort 6: 15 mg/m2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow., Results: Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses., Conclusions: FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254)., (© 2023. BioMed Central Ltd., part of Springer Nature.)- Published
- 2023
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24. Activity of decitabine combined with all- trans retinoic acid in oligoblastic acute myeloid leukemia: results from a randomized 2x2 phase II trial (DECIDER).
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Rummelt C, Grishina O, Schmoor C, Crysandt M, Heuser M, Götze KS, Schlenk RF, Döhner K, Salih HR, Heil G, Müller-Tidow C, Brugger W, Kündgen A, De Wit M, Giagounidis A, Scholl S, Neubauer A, Krauter J, Bug G, Al-Ali HK, Wäsch R, Becker H, May AM, Duyster J, Hackanson B, Ganser A, Döhner H, and Lübbert M
- Subjects
- Humans, Decitabine therapeutic use, Tretinoin therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Published
- 2023
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25. Societal challenges facing neurosurgeons in low- and middle-income countries: Iraq as an example.
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Ismail M, Ayad F, Al-Ageely TA, Elamin O, Salih HR, Aljuboori Z, and Hoz SS
- Abstract
Competing Interests: There are no conflicts of interest.
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- 2023
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26. In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts.
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Greve G, Andrieux G, Schlosser P, Blagitko-Dorfs N, Rehman UU, Ma T, Pfeifer D, Heil G, Neubauer A, Krauter J, Heuser M, Salih HR, Döhner K, Döhner H, Hackanson B, Boerries M, and Lübbert M
- Subjects
- Humans, Decitabine pharmacology, Transcriptome, DNA Methylation, DNA metabolism, Epigenome, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism
- Abstract
Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m
2 day 1-5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment., (© 2023. The Author(s).)- Published
- 2023
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27. Neurosurgery theater-based learning: Etiquette and preparation tips for medical students.
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Ismail M, AbdulWahid J, Al-Zaidy MF, Al-Khafaji AO, Albairmani SS, Abdulsada AM, Salih HR, and Hoz SS
- Abstract
Competing Interests: There are no conflicts of interest.
- Published
- 2023
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28. IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer.
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Lutz MS, Zekri L, Weßling L, Berchtold S, Heitmann JS, Lauer UM, Jung G, and Salih HR
- Subjects
- Humans, Immunoglobulin G, Neoplasm Recurrence, Local, T-Lymphocytes, Immunotherapy methods, B7 Antigens metabolism, Stomach Neoplasms therapy
- Abstract
T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer., Competing Interests: GJ, HS and LZ are listed as inventors on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant is German Cancer Research Center, Heidelberg, and Medical Faculty University of Tuebingen, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Lutz, Zekri, Weßling, Berchtold, Heitmann, Lauer, Jung and Salih.)
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- 2023
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29. An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers.
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Zekri L, Lutz M, Prakash N, Manz T, Klimovich B, Mueller S, Hoerner S, Hagelstein I, Engel M, Chashchina A, Pfluegler M, Heitmann JS, Jung G, and Salih HR
- Subjects
- Humans, Mice, Animals, Immunoglobulin G, T-Lymphocytes, Immunotherapy, Cell Line, Tumor, Gastrointestinal Neoplasms therapy, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use
- Abstract
T cell-based immunotherapy has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions remain rare, particularly in gastrointestinal cancers like colorectal cancer (CRC). B7-H3 is overexpressed in multiple cancer entities including CRC on both tumor cells and tumor vasculature, the latter facilitating influx of effector cells into the tumor site upon therapeutic targeting. We generated a panel of T cell-recruiting B7-H3xCD3 bispecific antibodies (bsAbs) and show that targeting a membrane-proximal B7-H3 epitope allows for a 100-fold reduction of CD3 affinity. In vitro, our lead compound CC-3 showed superior tumor cell killing, T cell activation, proliferation, and memory formation, whereas undesired cytokine release was reduced. In vivo, CC-3 mediated potent antitumor activity in three independent models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors. Thus, fine-tuning of both target and CD3 affinities as well as binding epitopes allowed for the generation of a B7-H3xCD3 bsAbs with promising therapeutic activity. CC-3 is presently undergoing good manufacturing practice (GMP) production to enable evaluation in a clinical "first-in-human" study in CRC., Competing Interests: Declaration of interests G.J., H.R.S., L.Z., T.M., S.H., and M.P. are listed as inventors on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant is German Cancer Research Center, Heidelberg, and Medical Faculty University of Tuebingen, Germany., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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30. Novel ACE2 fusion protein with adapting activity against SARS-CoV-2 variants in vitro .
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Zekri L, Ruetalo N, Christie M, Walker C, Manz T, Rammensee HG, Salih HR, Schindler M, and Jung G
- Subjects
- Humans, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus genetics, Protein Engineering, Recombinant Fusion Proteins, Angiotensin-Converting Enzyme 2 genetics, COVID-19, SARS-CoV-2 genetics
- Abstract
Despite the successful development of vaccines and neutralizing antibodies to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging variants prolong the pandemic and emphasize the persistent need to develop effective antiviral treatment regimens. Recombinant antibodies directed to the original SARS-CoV-2 have been successfully used to treat established viral disease. However, emerging viral variants escape the recognition by those antibodies. Here we report the engineering of an optimized ACE2 fusion protein, designated ACE2-M, which comprises a human IgG1 Fc domain with abrogated Fc-receptor binding linked to a catalytically-inactive ACE2 extracellular domain that displays increased apparent affinity to the B.1 spike protein. The affinity and neutralization capacity of ACE2-M is unaffected or even enhanced by mutations present in the spike protein of viral variants. In contrast, a recombinant neutralizing reference antibody, as well as antibodies present in the sera of vaccinated individuals, lose activity against such variants. With its potential to resist viral immune escape ACE2-M appears to be particularly valuable in the context of pandemic preparedness towards newly emerging coronaviruses., Competing Interests: GJ, LZ, HS, MS, NR and MC are listed as inventors on the patent application “Modified ACE2 proteins with improved activity against SARS-CoV-2”, EP22198499, applicant German Cancer Research Center, Heidelberg and University of Tuebingen, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zekri, Ruetalo, Christie, Walker, Manz, Rammensee, Salih, Schindler and Jung.)
- Published
- 2023
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31. Performance of phase-I dose finding designs with and without a run-in intra-patient dose escalation stage.
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Labrenz J, Edelmann D, Heitmann JS, Salih HR, Kopp-Schneider A, and Schlenk RF
- Subjects
- Humans, Bayes Theorem, Computer Simulation, Dose-Response Relationship, Drug, Maximum Tolerated Dose, Sample Size, Neoplasms, Research Design
- Abstract
Dose-finding designs for phase-I trials aim to determine the recommended phase-II dose (RP2D) for further phase-II drug development. If the trial includes patients for whom several lines of standard therapy failed or if the toxicity of the investigated agent does not necessarily increase with dose, optimal dose-finding designs should limit the frequency of treatment with suboptimal doses. We propose a two-stage design strategy with a run-in intra-patient dose escalation part followed by a more traditional dose-finding design. We conduct simulation studies to compare the 3 + 3 design, the Bayesian Optimal Interval Design (BOIN) and the Continual Reassessment Method (CRM) with and without intra-patient dose escalation. The endpoints are accuracy, sample size, safety, and therapeutic efficiency. For scenarios where the correct RP2D is the highest dose, inclusion of an intra-patient dose escalation stage generally increases accuracy and therapeutic efficiency. However, for scenarios where the correct RP2D is below the highest dose, intra-patient dose escalation designs lead to increased risk of overdosing and an overestimation of RP2D. The magnitude of the change in operating characteristics after including an intra-patient stage is largest for the 3 + 3 design, decreases for the BOIN and is smallest for the CRM., (© 2022 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)
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- 2023
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32. Extensive tension pneumocephalus presented in the setting of a challenging etiology.
- Author
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Salih HR, Jaafer H, Ismail M, Khallaf AK, Mohammed AJ, Al-Mosawy MSMJ, Naser HS, Maulood ZT, Hafedh AN, and Hoz SS
- Abstract
Background: Pneumocephalus (PNC) is a well-described consequence in postoperative settings and skull fractures that is usually self-limiting. It can get complicated into tension PNC on some rare occasions, leading to an intracranial mass effect. PNC was also reported after unintentional dural puncture throughout the epidural anesthesia process. However, tension PNC resulting from epidural anesthesia procedures is an extremely rare outcome that implies urgent intervention to relieve the tension within the brain. Here, we report a case of an extensive tension intraventricular PNC 2 days following an epidural anesthesia procedure for a femur fixation surgery., Case Description: A 23-year-old male presented to the emergency department with basal skull fractures and a femur fracture due to a motorcycle accident. His skull base fracture was managed conservatively then he underwent a femur fixation procedure under epidural anesthesia. Two days after, he developed a severe headache with a disturbed level of consciousness. Computed tomography of the brain revealed an extensive PNC that involved all the subarachnoid spaces down to the cervical region and compressing the cerebellum, which was not found in the initial imaging. The patient's status improved after the twist-drill burr-hole evacuation of air under the water seal., Conclusion: Extensive tension PNC can occur after traumatic brain injury, especially after epidural anesthesia. Such cases should gain high focus because they may differ from simple PNC regarding diagnosis, treatment, and follow-up., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)
- Published
- 2022
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33. Atypical slow-flow paramedian AVM with venous varix.
- Author
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Ismail M, Al-Ageely TA, Talib SH, Hadi RT, Al-Taie RH, Aktham AA, Alrawi MA, Salih HR, Al-Jehani H, and Hoz SS
- Abstract
Background: Cerebral arteriovenous malformations (CAVMs) are either clinically silent or symptomatic. The most common presentation in more than half of all CAVMs presenting patients is hemorrhage which is accompanied by long-standing neurological morbidity and mortality. This report presents a case of an atypical large, slow-flow paramedian AVM with a dilated venous varix managed with surgery. The impact of the intraoperative findings on the diagnosis and the operative technique will be discussed., Case Description: In otherwise, healthy 26-year-old male complained of repeated episodes of generalized seizures and loss of consciousness. Brain magnetic resonance imaging (MRI) revealed a right parietal paramedian arteriovenous malformation (AVM) with signs of an old hemorrhagic cavity beneath it. Digital subtraction angiography demonstrated a slow-filling AVM with dilated venous varix drains into the superior sagittal sinus. However, the exact point of drainage cannot be appreciated. The filling of the AVM occurred precisely with the beginning of the venous phase. Intraoperatively, we noticed a whitish spherical mass, thick hemosiderin tissue, and a large cavity below the nidus; then, a complication-free complete microsurgical resection of this high-grade AVM was performed. Postoperatively, the patient suffered two attacks of seizures in the first few hours after the surgery, for which he received antiepileptics. MRI was clear during follow-up, and the patient was seizure-free and neurologically intact., Conclusion: Parietal convexity AVMs are challenging lesions to tackle. However, the chronicity and the slow-filling of the AVM, in this case, can render the surgical pathway more direct and accessible., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)
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- 2022
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34. Extracranial carotid localized fibromuscular dysplasia: A case report and literature review.
- Author
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Ismail M, Al-Ageely TA, Alzerkani MAA, Al-Khazaali YM, Salih HA, Al-Khafaji AO, Kareem ZM, Abdulsada AM, Salih HR, and Hoz SS
- Abstract
Background: Fibromuscular dysplasia (FMD) is a noninflammatory and nonatherosclerotic arteriopathy that is characterized by irregular cellular proliferation and deformed construction of the arterial wall that causes segmentation, constriction, or aneurysm in the intermediate-sized arteries. The incidence of FMD is 0.42-3.4%, and the unilateral occurrence is even rarer. Herein, we report a rare case of a localized extracranial carotid unilateral FMD associated with recurrent transient ischemic attacks (TIAs) treated by extracranial-intracranial bypass for indirect revascularization. The specific localization of the disease rendered our case unique., Methods: We conducted a review of the PubMed Medline database search using the following combined formula: ((FMD [Title/Abstract]) AND ((isolated [Title/Abstract]) OR (localized [Title/Abstract]))) AND Internal carotid artery (ICA) (Title/Abstract). Additional resources were included by screening the reference list of the selected papers., Results: A total of six cases were found, and all accounted for localized FMD affecting the ICA. The age range was between 19 and 52, the male-to-female ratio was (2:4), and all of the cases consisted of unilateral carotid FMD, mainly on the left side with a left-to-right ratio of 5:1. The management and outcome of these cases varied according to the case and associated complications., Conclusion: Extracranial localized FMD of the ICA is a rare subtype of FMD that has little documentation in the literature. In our case, it was a localized extracranial carotid unilateral FMD associated with recurrent TIAs. The appropriate treatment was using the intracranial-extracranial bypass., Competing Interests: There are no conflicts of interest, (Copyright: © 2022 Surgical Neurology International.)
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- 2022
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35. The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.
- Author
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Bauer J, Köhler N, Maringer Y, Bucher P, Bilich T, Zwick M, Dicks S, Nelde A, Dubbelaar M, Scheid J, Wacker M, Heitmann JS, Schroeder S, Rieth J, Denk M, Richter M, Klein R, Bonzheim I, Luibrand J, Holzer U, Ebinger M, Brecht IB, Bitzer M, Boerries M, Feucht J, Salih HR, Rammensee HG, Hailfinger S, and Walz JS
- Subjects
- Humans, Gene Expression Regulation, Neoplastic, Neoplasm Recurrence, Local genetics, Oncogene Proteins, Fusion genetics, Immunotherapy, Peptides genetics, HSP40 Heat-Shock Proteins genetics, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular therapy, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Liver Neoplasms therapy, Liver Neoplasms pathology
- Abstract
The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8
+ and T-helper 1 CD4+ T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4+ T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion., (© 2022. The Author(s).)- Published
- 2022
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36. B7-H3-targeting Fc-optimized antibody for induction of NK cell reactivity against sarcoma.
- Author
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Hagelstein I, Engel M, Hinterleitner C, Manz T, Märklin M, Jung G, Salih HR, and Zekri L
- Subjects
- Humans, Immunoglobulin Fc Fragments, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, B7 Antigens genetics, Killer Cells, Natural, Sarcoma therapy, Sarcoma drug therapy
- Abstract
Natural killer (NK) cells largely contribute to antibody-dependent cellular cytotoxicity (ADCC), a central factor for success of monoclonal antibodies (mAbs) treatment of cancer. The B7 family member B7-H3 (CD276) recently receives intense interest as a novel promising target antigen for immunotherapy. B7-H3 is highly expressed in many tumor entities, whereas expression on healthy tissues is rather limited. We here studied expression of B7-H3 in sarcoma, and found substantial levels to be expressed in various bone and soft-tissue sarcoma subtypes. To date, only few immunotherapeutic options for treatment of sarcomas that are limited to a minority of patients are available. We here used a B7-H3 mAb to generate chimeric mAbs containing either a wildtype Fc-part (8H8_WT) or a variant Fc part with amino-acid substitutions (S239D/I332E) to increase affinity for CD16 expressing NK cells (8H8_SDIE). In comparative studies we found that 8H8_SDIE triggers profound NK cell functions such as activation, degranulation, secretion of IFNγ and release of NK effector molecules, resulting in potent lysis of different sarcoma cells and primary sarcoma cells derived from patients. Our findings emphasize the potential of 8H8_SDIE as novel compound for treatment of sarcomas, particularly since B7-H3 is expressed in bone and soft-tissue sarcoma independent of their subtype., Competing Interests: GJ, HS, LZ, and TM are listed as inventors on the patent application “Antibodies targeting, and other modulators of, the CD276 antigen, and uses thereof,” EP3822288A1, applicant German Cancer Research Center, Heidelberg, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hagelstein, Engel, Hinterleitner, Manz, Märklin, Jung, Salih and Zekri.)
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- 2022
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37. BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro.
- Author
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Kauer J, Märklin M, Pflügler M, Hörner S, Hinterleitner C, Tandler C, Jung G, Salih HR, and Heitmann JS
- Subjects
- Antibodies, Bispecific, Cytokines, Dasatinib pharmacology, Drug Resistance, Neoplasm, Humans, Imatinib Mesylate therapeutic use, Protein Kinase Inhibitors therapeutic use, Fusion Proteins, bcr-abl metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose: Acute B-lymphoblastic leukemia (B-ALL) is a malignant disease characterized by accumulation of clonal immature lymphocytes in the bone marrow and peripheral blood. The approval of BCR::ABL1 tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib and ponatinib marked a milestone in targeted therapy only for a subset of patients carrying the translocation t(9;22)(q34;q11). Immunotherapy with the bispecific antibody (bsAb) blinatumomab targeting CD19xCD3 revolutionized treatment of all B-ALL cases. The combination of both TKI and bsAb, so-called "dual targeting", is currently under clinical investigation, although TKI might influence T cell effects., Methods: We here investigated the combination of different TKI and blinatumomab in BCR::ABL1
+ and BCR::ABL1- B-ALL cell lines and primary samples regarding T cell proliferation, differentiation, cytokine release and killing of tumor cells., Results: In vitro analysis revealed profound reduction of T cell proliferation, differentiation, cytokine release and killing of tumor cells upon application of BCR::ABL1 TKI with blinatumomab. Inhibition was more pronounced with dasatinib and ponatinib compared to nilotinib and imatinib. T cell signalling after CD3 stimulation was impaired by TKI mirrored by inhibition of LCK phosphorylation. This known off-target effect might influence the efficacy of bsAb therapy when combined with BCR::ABL1 TKI., Conclusion: In conclusion, we propose that nilotinib and imatinib might also be suitable substances for combination with blinatumomab and suggest evaluation in clinical trials., (© 2022. The Author(s).)- Published
- 2022
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38. Expression of the immune checkpoint modulator OX40 indicates poor survival in acute myeloid leukemia.
- Author
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Marconato M, Kauer J, Salih HR, Märklin M, and Heitmann JS
- Subjects
- Genetic Markers, Humans, Immunologic Factors, Immunologic Surveillance, Ligands, OX40 Ligand metabolism, Survival Rate, Leukemia, Myeloid, Acute genetics, Receptors, OX40 metabolism
- Abstract
Despite therapeutic advances, mortality of Acute Myeloid Leukemia (AML) is still high. Currently, the determination of prognosis which guides treatment decisions mainly relies on genetic markers. Besides molecular mechanisms, the ability of malignant cells to evade immune surveillance influences the disease outcome and, among others, the expression of checkpoints modulators contributes to this. In AML, functional expression of the checkpoint molecule OX40 was reported, but the prognostic relevance of OX40 and its ligand OX40L axis has so far not been investigated. Here we described expression and prognostic relevance of the checkpoint modulators OX40 and OX40L, analyzed on primary AML cells obtained from 92 therapy naïve patients. Substantial expression of OX40 and OX40L on AML blasts was detected in 29% and 32% of the investigated subjects, respectively, without correlation between the expression of the receptor and its ligand. Whereas OX40L expression was not associated with different survival, patients with high expression levels of the receptor (OX40
high ) on AML blasts survived significantly shorter than OX40low patients (p = 0.009, HR 0.46, 95% CI 0.24-0.86), which identifies OX40 as novel prognostic marker and a potential therapeutic target in AML patients., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
39. IgG-Based Bispecific Anti-CD95 Antibodies for the Treatment of B Cell-Derived Malignancies and Autoimmune Diseases.
- Author
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Hörner S, Moustafa-Oglou M, Teppert K, Hagelstein I, Kauer J, Pflügler M, Neumann K, Rammensee HG, Metz T, Herrmann A, Salih HR, Jung G, and Zekri L
- Abstract
Antibodies against the B cell-specific antigens CD20 and CD19 have markedly improved the treatment of B cell-derived lymphoma and autoimmune diseases by depleting malignant and autoreactive B cells. However, since CD20 and CD19 are also expressed on healthy B cells, such antibodies lack disease specificity. Here, we optimize a previously developed concept that uses bispecific antibodies to induce apoptosis selectively in malignant and autoreactive B cells that express the death receptor CD95. We describe the development and characterization of bispecific antibodies with CD95xCD20 and CD95xCD19 specificity in a new IgG-based format. We could show that especially the CD95xCD20 antibody mediated a strong induction of apoptosis in malignant B cells in vitro. In vivo, the antibody was clearly superior to the previously used Fabsc format with identical specificities. In addition, both IgGsc antibodies depleted activated B cells in vitro, leading to a significant reduction in antibody production and cytokine secretion. The killing of resting B cells and hepatocytes that lack CD95 and CD20/CD19, respectively, was marginal. Thus, our results imply that bispecific anti-CD95 antibodies in the IgGsc format are an attractive tool for a more selective and efficient depletion of malignant as well as autoreactive B cells.
- Published
- 2022
- Full Text
- View/download PDF
40. Controversial Role of the Immune Checkpoint OX40L Expression on Platelets in Breast Cancer Progression.
- Author
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Rittig SM, Lutz MS, Clar KL, Zhou Y, Kropp KN, Koch A, Hartkopf AD, Hinterleitner M, Zender L, Salih HR, Maurer S, and Hinterleitner C
- Abstract
In conventional T cells, OX40 has been identified as a major costimulating receptor augmenting survival and clonal expansion of effector and memory T cell populations. In regulatory T cells, (Treg) OX40 signaling suppresses cellular activity and differentiation. However, clinical trials investigating OX40 agonists to enhance anti-tumor immunity, showed only limited success so far. Here we show that platelets from breast cancer patients express relevant levels of OX40L and platelet OX40L (pOX40L) inversely correlates with platelet-expressed immune checkpoint molecules GITRL (pGITRL) and TACI (pTACI). While high expression of pOX40L correlates with T and NK cell activation, elevated pOX40L levels identify patients with higher tumor grades, the occurrence of metastases, and shorter recurrence-free survival (RFS). Of note, OX40 mRNA levels in breast cancer correlate with enhanced expression of anti-apoptotic, immune-suppressive, and tumor-promoting mRNA gene signatures. Our data suggest that OX40L on platelets might play counteracting roles in cancer and anti-tumor immunity. Since pOX40L reflects disease relapse better than the routinely used predictive markers CA15-3, CEA, and LDH, it could serve as a novel biomarker for refractory disease in breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rittig, Lutz, Clar, Zhou, Kropp, Koch, Hartkopf, Hinterleitner, Zender, Salih, Maurer and Hinterleitner.)
- Published
- 2022
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41. A customized checklist for microsurgical clipping of intracranial aneurysms.
- Author
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Hoz SS, Arkawazi AH, Al-Sharshahi ZF, Al-Rawi MA, Al-Taweel MM, Sadik H, and Salih HR
- Published
- 2022
- Full Text
- View/download PDF
42. HLA-DR Presentation of the Tumor Antigen MSLN Associates with Clinical Outcome of Ovarian Cancer Patients.
- Author
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Tegeler CM, Scheid J, Rammensee HG, Salih HR, Walz JS, Heitmann JS, and Nelde A
- Abstract
T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line, in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4
+ T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery.- Published
- 2022
- Full Text
- View/download PDF
43. Identification of CD105 (endoglin) as novel risk marker in CLL.
- Author
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Greiner SM, Märklin M, Holzmayer S, Kaban K, Meyer S, Hinterleitner C, Tandler C, Hagelstein I, Jung G, Salih HR, Heitmann JS, and Kauer J
- Subjects
- Endoglin genetics, Endothelial Cells metabolism, Flow Cytometry, Humans, Prognosis, Endoglin analysis, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Myeloid, Acute genetics
- Abstract
Several genetic and clinical markers are established as prognostic factors in chronic lymphocytic leukemia (CLL). However, additional markers are needed for risk stratification. Flow cytometric analysis is a mainstay of CLL diagnostics, thus identification of novel prognostic surface markers can improve risk assessment without increasing burden for patients and physicians. Furthermore, surface molecules preferentially expressed in high-risk cases could serve as therapeutic targets for immunotherapy. CD105 (endoglin) is a TGF-beta coreceptor and activates endothelial cells in healthy tissues and cancer. In addition, it is expressed on healthy hematopoietic precursors as well as lymphoid and myeloid leukemias. In acute myeloid leukemia (AML), a CD105 antibody is successfully applied in clinical studies. In CLL, mRNA expression of the CD105 gene ENG reportedly correlates with other risk factors but failed to show significant correlation with overall survival. However, CD105 protein expression in CLL has never been studied. We here analyzed CD105 surface expression on CLL cells from 71 patients by flow cytometry and report for the first time that substantial levels of CD105 are detectable on CLL cells in 70.4% of patients. Using receiver operating characteristics, we established a cutoff of 5.99% positive cells to distinguish between low and high CD105 levels, the latter correlating with decreased time to first treatment and overall survival. High CD105 expression further correlates with CD38 expression. Our study identified membrane expression of CD105 as a potential risk marker and therapeutic target in high-risk CLL. However, multivariant analyses of large cohorts should be performed in confirmatory studies., (© 2022. The Author(s).)
- Published
- 2022
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- View/download PDF
44. A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL.
- Author
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Mehta NK, Pfluegler M, Meetze K, Li B, Sindel I, Vogt F, Marklin M, Heitmann JS, Kauer J, Osburg L, Zekri L, Bühring HJ, Mueller S, Hörner S, Baeuerle PA, Michaelson JS, Jung G, and Salih HR
- Subjects
- Animals, Humans, Immunoglobulin G therapeutic use, Immunotherapy, Adoptive, Interleukin-3 Receptor alpha Subunit, Lectins, C-Type, Mice, Receptors, Mitogen, Leukemia, Myeloid, Acute drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Background: In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs., Methods: We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chain/scFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo., Results: CLN-049 induced target-restricted activation of CD4+ and CD8+ T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts., Conclusions: CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic., Competing Interests: Competing interests: NKM, KM, BL, PAB, JSM, GJ and HRS have ownership in Cullinan Florentine, which is seeking to commercialize CLN-049., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
- View/download PDF
45. Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies.
- Author
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Lutz MS, Klimovich B, Maurer S, Heitmann JS, Märklin M, Zekri L, Jung G, Salih HR, and Hinterleitner C
- Subjects
- Aged, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Male, Antibodies, Bispecific metabolism, Blood Platelets metabolism, Immune Checkpoint Inhibitors therapeutic use, T-Lymphocytes metabolism
- Abstract
T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4
+ and CD8+ T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-β)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-β axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
- Full Text
- View/download PDF
46. More Laboratory Simulations-Fewer Brain Complications: Prospects from the First Neurosurgery Laboratory in Iraq.
- Author
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Hoz SS, Al-Sharshahi ZF, Esene IN, Al-Awadi OM, Salih HR, Alrawi MA, Aktham A, and Al-Taweel M
- Subjects
- Brain pathology, Brain surgery, Clinical Competence, Computer Simulation, Humans, Internship and Residency, Iraq, Microsurgery economics, Microsurgery education, Neurosurgeons, Neurosurgery economics, Neurosurgery education, Neurosurgical Procedures methods, Vascular Surgical Procedures, Laboratories organization & administration, Neurosurgery organization & administration, Postoperative Complications prevention & control
- Abstract
Background: The intensive training requirements needed to achieve the requisiste microneurosurgical milestones makes proper training and skill acquisition a challenge to the novice neurosurgeon. This problem is compounded in low- and middle-income nations, where neurosurgery is subject to a myriad of human and financial resource constraints. A temporary solution may be provided by low-cost laboratories that are adaptive to local needs., Methods: The "HOZ NeuroSurgery LAB" is a nonprofit facility dedicated to microneurosurgery education and skills training. The laboratory, established in June 2015, is housed at the Neurosurgery Teaching Hospital in Baghdad, Iraq. It operates under the motto "More Laboratory Simulation-Fewer Brain Complications.". The fundamental infrastructure of the facility consists of a relatively inexpensive microscope, indigenous locally created training equipment, and animal-based models., Results: Since its inception, this lab has functioned as a hub for resident education and microneurosurgery service, in addition to contributing to the specialty's academic output in the nation. The lab is directly responsible for training 4 vascular neurosurgeons who are currently directing the nation's first organized neurovascular service. Also, it has delivered 53 microneurosurgery skills courses, coordinated 8 student neurosurgery elective cycles with a total of 532 participants, and published approximately 70 research articles., Conclusions: Our experience may serve as a model for other low- and middle-income countries interested in using the principle of "doing more with less" to overcome some of the challenges associated with microneurosurgery in these parts of the world., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
47. A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity.
- Author
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Heitmann JS, Bilich T, Tandler C, Nelde A, Maringer Y, Marconato M, Reusch J, Jäger S, Denk M, Richter M, Anton L, Weber LM, Roerden M, Bauer J, Rieth J, Wacker M, Hörber S, Peter A, Meisner C, Fischer I, Löffler MW, Karbach J, Jäger E, Klein R, Rammensee HG, Salih HR, and Walz JS
- Subjects
- Administration, Cutaneous, Adolescent, Adult, Aged, Aged, 80 and over, CD8-Positive T-Lymphocytes immunology, COVID-19 prevention & control, COVID-19 virology, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines adverse effects, Clinical Trials, Phase II as Topic, Female, Granuloma immunology, Humans, Immunogenicity, Vaccine, Interferon-gamma immunology, Male, Middle Aged, T-Lymphocytes, Helper-Inducer immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit adverse effects, Young Adult, COVID-19 immunology, COVID-19 Vaccines immunology, SARS-CoV-2 immunology, T-Lymphocytes immunology, Vaccines, Subunit immunology
- Abstract
T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins
1,2 , combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
48. Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course.
- Author
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Clar KL, Weber LM, Schmied BJ, Heitmann JS, Marconato M, Tandler C, Schneider P, and Salih HR
- Abstract
Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as "functional" prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.
- Published
- 2021
- Full Text
- View/download PDF
49. Immunoprofiling of 4-1BB Expression Predicts Outcome in Chronic Lymphocytic Leukemia (CLL).
- Author
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Kaban K, Greiner SM, Holzmayer S, Tandler C, Meyer S, Hinterleitner C, Salih HR, Märklin M, and Heitmann JS
- Abstract
Recent success of novel therapies has improved treatment of chronic lymphocytic leukemia (CLL) patients, but most of them still require several treatment regimes. To improve treatment choice, prognostic markers suitable for prediction of disease outcome are required. Several molecular/genetic markers have been established, but accessibility for the entirety of all patients is limited. We here evaluated the relevance of GITR/4-1BB as well as their ligands for the prognosis of CLL patients. Surface expression of GITR/GITRL and 4-1BB/4-1BBL was correlated with established prognostic markers. Next, we separated our patient population according to GITR/GITRL and 4-1BB/4-1BBL expression in groups with high/low expression levels and performed Kaplan-Meier analyses. Interestingly, no correlation was observed with the defined prognostic markers. Whereas no significant difference between high and low expression of GITR, GITRL and 4-1BBL was observed, high 4-1BB levels on leukemic cells were associated with significantly shorter survival. Thereby we identify 4-1BB as prognostic marker for CLL.
- Published
- 2021
- Full Text
- View/download PDF
50. The four-handed technique in microsurgery, a useful addition to the vascular neurosurgeon armamentarium.
- Author
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Hoz SS, Aljuboori Z, Al-Sharshahi ZF, Salih HR, and Alrawi MA
- Subjects
- Humans, Neurosurgeons, Intracranial Aneurysm surgery, Microsurgery methods
- Published
- 2021
- Full Text
- View/download PDF
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