scholarly journals Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 150
Author(s):  
Siddesh V. Hartimath ◽  
Boominathan Ramasamy ◽  
Tan Yun Xuan ◽  
Tang Jun Rong ◽  
Shivashankar Khanapur ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Granzyme B ◽  
Vaccine Therapy ◽  
Imaging Biomarker ◽  
Cpg Odn ◽  
Durable Response ◽  
Tumour Uptake ◽  
Cpg Oligodeoxynucleotides ◽  
In Situ Vaccine

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.

scholarly journals Extranodal NK/T-cell lymphoma in Tunisia: clinicopathological features, immunophenotype and EBV infection

2019 ◽  
Vol 31 (1) ◽  
Author(s):  
Nabiha Missaoui ◽  
Sarra Mestiri ◽  
Aida Bouriga ◽  
Nihed Abdessayed ◽  
Mouna Belakhdher ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
T Cell ◽  
Granzyme B ◽  
Clinicopathological Features ◽  
Histopathological Diagnosis ◽  
Ebv Infection ◽  
Nk T Cell ◽  
Epstein Barr ◽  
Hodgkin's Lymphomas

Abstract Background Extranodal NK/T-cell lymphomas (ENKTL) are rare non-Hodgkin’s lymphomas with aggressive clinical behavior. ENKTL are frequently associated with the Epstein-Barr virus (EBV). Data on ENKTL in Africa and Arab world are extremely limited. The study investigated the clinicopathological characteristics, EBV infection, and immunophenotype of ENKTL in Tunisia. We conducted a retrospective study of ENKTL. Main clinicopathological features were reported. The expression of CD3, CD4, CD5, CD8, CD20, CD56, CD57, and Granzyme B were analyzed by immunohistochemistry. EBV infection was detected by IHC (LMP-1) and Epstein-Barr encoding region (EBER1/2) in situ hybridization. Results A total of nine ENKTL were identified (mean age of 48 years and male-to-female ratio of 8:1). There were five nasal ENKTL, and the remaining four cases had extranasal involvement (palate, sub-mandibular gland, skin, and soft tissues of the ankle). The histopathology showed a lymphoid and pleomorphic proliferation characterized by images of angiocentrism. Strong and diffuse CD3 expression was observed in all cases. Tumor cells exhibited an expression of CD5 (two cases), CD8 (three cases), CD56 (six cases), CD57 (three cases), and Granzyme B (eight cases). All ENKTL cases were EBV-associated. Overall 5-year survival rate was 57%. Although six ENKTL were diagnosed at early clinical stages, the prognosis was unfavorable and associated with patient death in three cases. Conclusions ENKTL are exceptional in Tunisia with unfavorable outcome. Histopathological diagnosis remains challenging in clinical practice. However, a careful histopathological examination combined with a correct interpretation of immunohistochemistry and in situ hybridization results refines the ENKTL diagnosis.

scholarly journals Enhancement of Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus

2003 ◽  
Vol 77 (6) ◽  
pp. 3615-3623 ◽  
Author(s):  
Sang-Moo Kang ◽  
Richard W. Compans
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 4 ◽  
Cpg Odn ◽  
Virus Like Particles ◽  
Cpg Oligodeoxynucleotides ◽  
Immunodeficiency Virus ◽  
Helper Cell Type ◽  
Spleen And Lymph Nodes

ABSTRACT Cholera toxin (CT) is the most potent known mucosal adjuvant, but its toxicity precludes its use in humans. Here, in an attempt to develop safe and effective mucosal adjuvants, we compared immune responses to simian immunodeficiency virus (SIV) virus-like particles (VLPs) after intranasal coimmunization with RANTES, CpG oligodeoxynucleotides (ODN), or CT. Antibody analysis demonstrated that RANTES and CpG ODN had capacities for mucosal adjuvanticity, i.e., for enhancing serum and vaginal antibodies specific to SIV Env, similar to those for CT. RANTES and CpG ODN skewed serum antibodies predominantly to the immunoglobulin G2a isotype. Most importantly, RANTES and CpG ODN were more effective than CT in increasing neutralizing titers of both serum and vaginal antibodies. After intranasal coadministration with VLPs, RANTES or CpG ODN also induced increased levels of gamma interferon (IFN-γ)-producing lymphocyte and cytotoxic T-lymphocyte activities in both spleen and lymph nodes but did not increase the levels of interleukin-4-producing lymphocytes. The results suggest that RANTES and CpG ODN enhance immune responses in a T-helper-cell-type-1 (Th1)-oriented manner and that they can be used as effective mucosal adjuvants for enhancing both humoral and cellular immune responses in the context of VLPs, which are particulate antigens.

scholarly journals Protection of BALB/c Mice against Brucella abortus 544 Challenge by Vaccination with Bacterioferritin or P39 Recombinant Proteins with CpG Oligodeoxynucleotides as Adjuvant

2001 ◽  
Vol 69 (8) ◽  
pp. 4816-4822 ◽  
Author(s):  
Ayman Al-Mariri ◽  
Anne Tibor ◽  
Pascal Mertens ◽  
Xavier De Bolle ◽  
Patrick Michel ◽  
...  
Keyword(s):  
Recombinant Proteins ◽  
Brucella Abortus ◽  
Mononuclear Cells ◽  
Brucella Melitensis ◽  
Cpg Odn ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Antigens ◽  
Cpg Oligodeoxynucleotides ◽  
Ifn Γ

ABSTRACT The P39 and the bacterioferrin (BFR) antigens of Brucella melitensis 16M were previously identified as T dominant antigens able to induce both delayed-type hypersensivity in sensitized guinea pigs and in vitro gamma interferon (IFN-γ) production by peripheral blood mononuclear cells from infected cattle. Here, we analyzed the potential for these antigens to function as a subunitary vaccine against Brucella abortus infection in BALB/c mice, and we characterized the humoral and cellular immune responses induced. Mice were injected with each of the recombinant proteins alone or adjuvanted with either CpG oligodeoxynucleotides (CpG ODN) or non-CpG ODN. Mice immunized with the recombinant antigens with CpG ODN were the only group demonstrating both significant IFN-γ production and T-cell proliferation in response to either Brucella extract or to the respective antigen. The same conclusion holds true for the antibody response, which was only demonstrated in mice immunized with recombinant antigens mixed with CpG ODN. The antibody titers (both immunoglobulin G1 [IgG1] and IgG2a) induced by P39 immunization were higher than the titers induced by BFR (only IgG2a). Using a B. abortus 544 challenge, the level of protection was analyzed and compared to the protection conferred by one immunization with the vaccine strain B19. Immunization with P39 and CpG ODN gave a level of protection comparable to the one conferred by B19 at 4 weeks postchallenge, and the mice were still significantly protected at 8 weeks postchallenge, although to a lesser extent than the B19-vaccinated group. Intriguingly, no protection was detected after BFR vaccination. All other groups did not demonstrate any protection.

scholarly journals The Radio-mitigative Effect of CpG-Oligodeoxynucleotides on Mice After Exposure to Carbon Ions Radiation.

2021 ◽  
Author(s):  
Chao Zhang ◽  
Hua Fu ◽  
Xiang-hui Zhu ◽  
Sha Li ◽  
Zhong-ze Tian ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Heavy Ion ◽  
Double Strand Breaks ◽  
Tunel Staining ◽  
Cpg Odn ◽  
Carbon Ions ◽  
Strand Breaks ◽  
Cpg Oligodeoxynucleotides ◽  
Tnf Α ◽  
Immune Tissues

Abstract Background: Heavy ion radiation constitutes a major health risk for astronaut in space flight, potential damage to healthy tissues surrounding the tumor target along its penetrating path should still be considered in hydrotherapy. Therefore, there is a demand for reliable countermeasure against heavy ions radiation. In this study, we will estimate the radiomitigative effect of CpG-ODN on immune tissues after carbon ions radiation (CIR). Methods: Firstly, the 30 days’ survival of mice was observed, peripheral blood cell was counted, the injury of three principal immune tissues (including bone marrow, thymus and spleen) was evaluated by histological examination, apoptosis and double strand breaks (DSB) were detected by TUNEL staining and γ-H2AX immunohistochemistry respectively, and cytokine (G-CSF, IL-6 and TNF-α) was measured by ELISA assay. Results: the 30 days’ survival improved, the injury of three principal immune tissues were obviously ameliorated, the number of γ-H2AX foci and TUNEL-positive nuclei decreased, and G-CSF, IL-6 and TNF-α expression increased by CpG-ODN treatment after CIR. Conclusion: CpG-ODN could enhanced mice survival, and ameliorate immune tissues injury, the mechanism may be that CpG-ODN induced cytokines production and inhibited the double strand breaks (DSB) and apoptosis in order to stimulate the generation and mobilization of the immune cells and reestablish immune system to combat bacterial infections.

A Novel In Situ Vaccine: Intratumoral Flt3L and Poly-ICLC with Low-Dose Radiotherapy

2016 ◽  
Vol 16 ◽  
pp. S97-S98
Author(s):  
Thomas Marron ◽  
Nina Bhardwaj ◽  
Linda Hammerich ◽  
Fiby George ◽  
Seunghee Kim-Schulze ◽  
...  
Keyword(s):  
Low Dose ◽  
Low Dose Radiotherapy ◽  
In Situ Vaccine

scholarly journals Granzyme B PET Imaging of the Innate Immune Response

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3102
Author(s):  
Kathleen M. Capaccione ◽  
Mikhail Doubrovin ◽  
Nikunj Bhatt ◽  
Akiva Mintz ◽  
Andrei Molotkov
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Pet Imaging ◽  
Granzyme B ◽  
Innate Immune ◽  
Human Immune System ◽  
Specific Staining ◽  
Cellular Activation ◽  
Human Immune ◽  
Time Point

The human immune system is a complex system which protects against invaders and maintains tissue homeostasis. It is broadly divided into the innate and adaptive branches. Granzyme B is serine protease that plays an important role in both and can serve as a biomarker for cellular activation. Because of this, a granzyme B PET agent (GZP) has recently been developed and has been shown to be able to monitor response to immunotherapy. Here, we evaluated the utility of granzyme B PET imaging to assess the innate immune response. We subcutaneously administered LPS to mice to induce inflammation and performed granzyme B PET imaging after 24 and 120 h. We dissected out tissue in the region of injection and performed granzyme B immunofluorescence (IF) to confirm specificity of the GZP radiotracer. Granzyme B PET imaging demonstrated increased uptake in the region of LPS injection after 24 h, which normalized at 120 h. Granzyme B immunofluorescence showed specific staining in tissue from the 24 h time point compared to the PBS-injected control. These findings support the use of granzyme B PET for imaging innate immunity. In certain clinical contexts, the use of GZP PET imaging may be superior to currently available agents, and we therefore suggest further preclinical studies with the ultimate goal of translation to clinical use.

scholarly journals Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor 64 Cu-Macrin in Mice, Rabbits, and Pigs

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Matthias Nahrendorf ◽  
Friedrich Felix Hoyer ◽  
Anu E. Meerwaldt ◽  
Mandy M.T. van Leent ◽  
Max L. Senders ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Flow Cytometry ◽  
Confocal Microscopy ◽  
Pet Imaging ◽  
Near Infrared ◽  
Emission Tomography ◽  
Imaging Biomarker ◽  
Positron Emission ◽  
Pulmonary Macrophages

Background: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases. Methods: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer 64 Cu-Macrin—a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose. Results: PET imaging using 64 Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle ( VT680 Macrin) primarily in tissue macrophages. In 5-day-old mice, 64 Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of 64 Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that 64 Cu-Macrin is safe for use in humans. Conclusions: Taken together, these results indicate 64 Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. 64 Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.

scholarly journals Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[11C]Methyl-AMD3465 PET

2019 ◽  
Vol 22 (4) ◽  
pp. 883-890
Author(s):  
SV Hartimath ◽  
O. Draghiciu ◽  
T Daemen ◽  
H.W. Nijman ◽  
A. van Waarde ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Viral Vector ◽  
Tracer Uptake ◽  
Imaging Biomarker ◽  
Cxcr4 Antagonist ◽  
Single Fraction ◽  
Vector Vaccine ◽  
Cxcr4 Signaling ◽  
Chemokine Cxcl12 ◽  
Induced Changes

Abstract Purpose Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[11C]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. Procedure TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[11C]methyl-AMD3465 PET. Results PET imaging showed N-[11C]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 ± 0.31 %ID/g vs. 0.42 ± 0.05 % ID/g, p < 0.01). The tumor uptake was further increased by 4-fold (1.73 ± 0.17 % ID/g vs 0.42 ± 0.05 % ID/g, p < 0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 ± 0.1 % ID/g, p < 0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. Conclusion This study demonstrates the feasibility of N-[11C]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.

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