ImaginAb (United States)

ObjectiveThis study investigated the acute effects of cocoa flavanol (CF) supplementation onglucose homeostasis, aerobic performance, and lactate concentration in rats with type 1diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and normoglycemia (NORM).Materials and methodsThe study included 28 male Wistar rats (220-290 g). Induction of T1DM (n = 8) wasachieved through intraperitoneal injection of streptozotocin, while T2DM (n = 10) wasinduced using an ad libitum high-fat diet combined with a fructose-richbeverage. The rats in the NORM group (n = 10) received a standard diet for 30 days. Twoexperiments were conducted: (1) T1DM rats performed two successive 30-minutetreadmill runs below the anaerobic threshold and (2) T2DM and NORM ratsunderwent two incremental maximal treadmill running tests, both after CF or placebosupplementation. Blood glucose concentrations were measured from pre-exercise to 60minutes post-exercise.ResultsGlycemic reduction at 60 minutes post-exercise was significantly potentiated by CFcompared with placebo supplementation in T1DM, T2DM, and normoglycemic rats (p < 0.05for all). In T2DM rats, CF induced a glycemic response comparable to the NORMplacebo-supplemented condition. These effects of CF persisted despite variations inaerobic performance or lactate concentration after incremental exercise.ConclusionSupplementation with CF prior to physical exercise elicited a pronounced post-aerobicexercise glycemic reduction. This represents a promising strategy for mitigating theduration of hyperglycemia exposure after physical exercise.

BackgroundImmune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically “hot” tumors. However, immune dynamics in the low T-cell infiltrating “cold” tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response.Methods[89Zr]Zr-DFO-CD4 and [89Zr]Zr-DFO-CD8 radiotracers were used to quantify changes in intratumoral and splenic CD4 T cells and CD8 T cells in response to ICB treatment in 4T1 and MMTV-HER2 mouse models, which represent immunologically “cold” tumors. A correlation between PET quantification metrics and long-term anti-tumor response was observed. Further biological validation was obtained by autoradiography and immunofluorescence.ResultsFollowing ICB treatment, an increase in the CD8-specific PET signal was observed within 6 days, and an increase in the CD4-specific PET signal was observed within 2 days in tumors that eventually responded to immunotherapy, while no significant differences in CD4 or CD8 were found at the baseline of treatment that differentiated responders from nonresponders. Furthermore, mice whose tumors responded to ICB had a lower CD8 PET signal in the spleen and a higher CD4 PET signal in the spleen compared to non-responders. Intratumoral spatial heterogeneity of the CD8 and CD4-specific PET signals was lower in responders compared to non-responders. Finally, PET imaging, autoradiography, and immunofluorescence signals were correlated when comparing in vivo imaging to ex vivo validations.ConclusionsCD4- and CD8-specific immuno-PET imaging can be used to characterize the in vivo distribution of CD4 + and CD8 + T cells in response to immune checkpoint blockade. Imaging metrics that describe the overall levels and distribution of CD8 + T cells and CD4 + T cells can provide insight into immunological alterations, predict biomarkers of response to immunotherapy, and guide clinical decision-making in those tumors where the kinetics of the response differ.

TPS9601 Background: Immune checkpoint inhibitors (ICI) improved outcomes of patients (pts) with advanced melanoma. Nevertheless, a significant number have immune-mediated adverse event (iAE). Due to the impact on quality of life and other therapeutic options, early identification of pts with increased risk of iAE is needed. CD8 immuno-PET with [89Zr] crefmirlimab berdoxam (Zr-Df-IAB22M2C) has shown to be a specific tool to visualize CD8+ T cells mediating both anti-tumor immune response and inflammatory adverse effects rendering this an innovative evaluation method in the field of immuno-oncology. Methods: Trial design: Open-label, single-arm, single center study to determine if CD8+ T-cell infiltration evaluated by immune-PET provides diagnostic gain in early detection of severe iAE. Pts with irresectable stage III/IV melanoma receiving nivolumab + ipilimumab (NIVO+IPI) may be included. Primary objective: Feasibility of early detection of iAE by semiquantitative assessment of CD8+ T-cell infiltration using immune-PET. Secondary objectives: 1) Prediction of iAE using immuno-PET for semiquantitative assessment of CD8+ T-cell infiltration; 2) Correlation between CD8+ T-cell infiltration in metastasis and lymphoid organs and response. Baseline Imaging. To assess glucose metabolism in metastases, primary and secondary lymphatic organs [18F] FDG PET/CT (60 min p.i. 1.5 MBq/KG/BW) is performed on a high sensitivity PET/CT with large field of view (Siemens Vision Quadra). Immediately after PET/CT data acquisition, pts are injected with [89Zr] crefmirlimab berdoxam (37 MBq ±20%) and undergo immuno-PET/CT 24 hours p.i. to detect CD8+ T-cells in metastases and lymphoid organs. NIVO+IPI is administered immediately after completion of [89Zr] crefmirlimab berdoxam-PET/CT. Blood samples are taken for immune cell composition analysis, activation state, proteomic investigation (cytokine/chemokines) as well as metabolic profile. Therapy Phase Imaging: Three weeks after first ICI cycle and before second cycle, follow-up PET/CT are performed with both radiotracers [18F]FDG and [89Zr] crefmirlimab berdoxam following the identical protocol described above. Clinical trial information: EudraCT number - 2021-004328-13 .

Abstract Small cell lung cancer (SCLC) is the most aggressive subtype of lung carcinoma with a 5-year survival rate below 7%. While the addition of anti-PD-1 antibody treatment has improved SCLC patient outcomes, nearly all patients relapse, indicating an unmet need for more efficacious therapeutics. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is over-expressed on the surface of SCLC tumor cells. Due to this, DLL3 has become a target of interest for SCLC treatment and several agents are in preclinical and clinical evaluation using different strategies such as antibody-drug conjugates, bispecific T cell engagers, and DLL3-targeting CAR-T. Minibodies are antibody fragments that provide optimal pharmacokinetics for the delivery of radioactive payloads. Their molecular weight of 80 kDa allows for rapid tumor uptake and faster circulation clearance than full-length antibodies. These scaffolds also present deeper tumor penetration relative to full-length antibodies, and higher target specificity and retention at the tumor site, with respect to small molecules. We hypothesized that a minibody targeting DLL3 (IAB57) would be a valid approach for radiopharmaceutical therapy (RPT) of SCLC and tested its efficacy in a preclinical model of SCLC. We conjugated the IAB57 minibody with DOTAGA and radiolabeled the protein with the β-emitter 177-Lu. Nu/J female mice were inoculated subcutaneously with the non-encapsulated lung carcinoma cell line SHP77, and the tumor size was measured 3 times per week until it reached 100-150 mm3. 24-hour biodistribution results revealed a tumor uptake of 18.8% injected dose per gram (%ID/gr). Mice were treated with 13.3 MBq and 13.6 MBq doses of 177-Lu-DOTAGA-IAB57 7 days apart to determine if there was a therapeutic effect and improved animal survival. A subgroup of mice was not treated and was considered controls. A time course biodistribution was performed to assess organs dosimetry. The dosimetry results were extrapolated to human organ exposure showing kidneys and liver uptakes of 2.2 and 4.6 Gy which is 10 times and 7 times below published exposure thresholds (23 Gy and 32 Gy respectively). Exposure at bone marrow (b.m., 0.1 Gy), spleen (1.5 Gy) and lungs (0.4 Gy) were 20 times, 27 times and 68 times below published toxicity thresholds (b.m.: 2 Gy; spleen: 40 Gy; lungs: 27 Gy). The RPT data showed a significant decrease in tumor size beginning on day 11 in the treated group compared to the control group. The decreased tumor size also coincided with a doubling in the survival rate. Overall, these results indicate that the IAB57 minibody targeting DLL3 is a promising and effective agent for RPT treatment of SCLC via β-emitting radionuclides. Citation Format: Kelley C. Atkinson, Leticia M. De Souza Cordeiro, Fang Jia, Argin Aivazian, Gareth E. Smith, Ian Wilson, Alessandro Mascioni. Therapeutic efficacy and dosimetry for a 177-lutetium radiolabeled minibody targeting DLL3 in a preclinical model of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB282.

BackgroundRadiation therapy (RT) may produce immunomodulatory effects that can interact with immunotherapy. Our pilot study (NCT05371132) uses 89Zr-Df-crefmirlimab, a radiolabeled CD8-specific minibody, to image intratumoral changes in CD8+ T cell activity during and after RT. Here, we present the results of our first four patients.MethodsEligible patients have no change in systemic treatment within two months prior to RT and no splenic disorders. Patients receive a 1 mCi dose of 89Zr-Df-crefmirlimab before and 1–2 weeks after a 5-fraction RT course. Each dose is followed by a whole-body positron emission tomography (PET) scan, and each radiation fraction is followed by a region-of-interest PET. Maximum standardized uptake values (SUVmax) of lesions are extracted from each CD8 ImmunoPET scan.Results3 metastatic renal cell carcinoma (mRCC) patients and 1 diffuse large B-cell lymphoma (DLBCL) patient have completed treatment. Median age was 64 years (range 61–65). Concurrent therapies included cabozantinib, nivolumab, and an experimental chemotherapy XL092 (table 1). The mRCC patients (P1-P3) received stereotactic body RT (30–40 Gy in 5 fractions) to one metastatic site. The DLBCL patient (P4) received RT (20 Gy in 5 fractions) to two lesions in the legs, in the bridging setting prior to chimeric antigen receptor (CAR) T-cell therapy. No toxicities attributable to the CD8 PET tracer were observed.Mean peak increase in SUVmax of the treated lesion in P1-P3 was 14.5 ± 8.1 (standard deviation). Mean size reduction by longest diameter of P1-P3 was 36.3% ± 20.2% (standard deviation). Each patient’s results are included in table 1. In P1, a normal lymph node saw an unusual 4.4 increase in SUVmax post-RT. At 8-month follow-up, this was found to have developed into a lesion (figure 1).In P4, peak increase in SUVmax was 1.2 and 2.7 in the left and right leg treated lesions, respectively. Images are shown in figure 2. Two non-target lesions proximal to the left leg target lesion that received ~1% of the dose achieved an increase in CD8 SUVmax of 1.2 and 1.7 during radiation and resolved post-RT pre-CAR T. CD8 ImmunoPET taken 7 days post-CAR T infusion did not demonstrate any significant CD8 PET signal. All lesions resolved by day 30 post-CAR T on FDG PET imaging.ConclusionsIncrease in intratumoral CD8+ T cell activity was observed during RT in mRCC and lymphoma patients. Follow-up may reveal the prognostic implications of visualizing the immunogenic effects of radiation using CD8 ImmunoPET.Trial RegistrationNCT05371132Ethics ApprovalThis clinical trial was approved by the City of Hope Institutional Review Board (IRB) and has IRB number 21221. All trial participants provided informed consent prior to taking part in this study. 725 Table 1Change in CD8 ImmunoPET SUVmax of treated lesions and reponse 725 Figure 1Images showing a hilar lymph node that displayed notable increase in CD8 PET SUVmax post-radiation, which developed into a metastasis 8 months later 725 Figure 2CD8 PET imaging of the irradiated lesion in the right leg of a lymphoma patient who received bridging radiation before CAR T cell infusion

Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein's dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of 111In-labelled DTPA-700DX-MB at 24 h post injection. Co-injection with an excess DTPA-700DX-MB reduced uptake, and autoradiography correlated with FAP expression in the stromal tumour region. Finally, in vivo therapeutic efficacy was determined in two simultaneous subcutaneous PDAC299 tumours; only one was treated with 690 nm light. Upregulation of an apoptosis marker was only observed in the treated tumours. In conclusion, DTPA-700DX-MB binds to FAP-expressing cells and targets PDAC299 tumours in mice with good signal-to-background ratios. Furthermore, the induced apoptosis indicates the feasibility of targeted depletion of FAP-expressing cells with photodynamic therapy.

Con dos propósitos en mente, el artículo analiza la colecciónque la provincia de Valdivia envió a la Exposición de Artes eIndustria realizada en Santiago de Chile en 1872. En primerlugar, intenta demostrar que fueron los efectos de la políticade colonización los que habilitaron una diferenciación entrelas colecciones enviadas por esta provincia y otras exhibidaspor sus pares del centro, norte y extremo sur del país. Por otro,se afirma que aunque es una colección que podría representarel proyecto civilizador de una élite económica, industrial eintelectual local, en el escenario de la exposición de Santiagotransmuta en proyecto nacionalista, con lo cual se contribuyea la consolidación de un imaginario común.

This work has started with the motivation to understand the sound and psychic condition of the voice In the constitution of the subject, as well as the pathological failure of this structure in autism. We started with the understanding that the subject is the effect of the encounter between the meaningless sense of the real and the meaning of the symbolic/imaginary. The mother figure, by the means of the sound mirror, welcomes what happens in the child s body and assigns corresponding language significants. This mediation is loaded with musical ingredients. The mother seeks to facilitate and promote the invocation by the \"baby talk\". The failure in the circuit of invocation in autistic children was also approached, preventing the constitution of the psychic function of the voice. Thinking the sound-musical context as an operator phenomenon, essencial to subjectivity, made it possible to consider the mediator potencial of music included in treatment. This field research involved to children with constitucional deadlocks, and their motores, in clinical care, whose therapeutic setting made use of sound and musical resources. We intended an approximation of the way the voice, as a lost object, and the word, associate. Furthermore, the possibility of causing a modification of the place of the subject in the circuit of invocation, became a matter from the musical intervention. It is possível to understand that the positioning of the subject is stated in tis musicality: what in it stands says of its way of functioning and of its work of appeasement of the suffering and the trauma of insertion in the field of language. Music nostalgically rescues the origins of the subject in the real and, at the same time, proposes a go further, towards the word. The impact of the loss of juissance, eased through music, shows it as a facilitator of lashing between real and symbolic. The subject modulaton refers to the modulation of the subject in its estruture and in tis position from the intervention with the musical. The modulation of the invocatory drive in the process of structuring of the subject was possible when we took the music as an essential tool of clinical work.

Abstract Introduction: Positron emission tomography (PET) imaging is a non-invasive tool to quantitatively describe the drug distribution in vivo. To answer the question whether radiolabeled antibody-drug conjugates (ADCs) can be utilized as PET imaging probes, and to explore PET imaging sensitivity for detecting antigen expression, we conducted preclinical microPET/CT imaging studies with radiolabeled SGN-35 in SCID mice bearing tumors with varying levels of CD30 expression. Methods: SGN-35 was either directly labeled with 124Iodine or conjugated with the chelator desferrioxamine (DFO) and subsequently labeled with 89Zirconium. Karpas 299, TF1-α, and Daudi were selected as the representative high (CD30high), low (CD30low) and negative (CD30neg) CD30 expressing tumor cell lines, respectively. Expression of CD30 and receptor copy number on each cell line was confirmed by quantitative FACS assay. One mouse from each CD30 expression group was administered a single IV bolus dose of either 124I-SGN-35 (0.5 mg/kg) or 89Zr-Df-SGN-35 (1 mg/kg), and serially imaged 0 - 2 hours (dynamic scan), and at 4, 24, 48, 72, 96 and 144 hours (10 min static scans). An additional 3 mice with CD30high and CD30low tumors, and 2 mice with CD30neg tumors, were dosed and imaged at 72, 96 and 144 hours (10 min static scans). Blood samples (10 μL) were taken from mice at 0, 4, 24, 48, 72, 96 hours and by cardiac puncture at 144 hours for pharmacokinetic (PK) analysis. Additional mice (n=4 per group) were sacrificed at 72 and 144 hours to determine tissue biodistribution via gamma counting. Results: The elimination of 124I-SGN-35 and 89Zr-Df-SGN-35 followed 2-compartment PK, and the calculated elimination T1/2 was 3.6-3.9 days. In mice bearing CD30high tumors with ∼291,000 CD30 copies per cell, the tumor:blood ratio of 124I-radioactivity after a dose of 124I-SGN-35 fell from 1.24 after 72 hours to 0.78 after 144 hours, whereas after a dose of 89Zr-Df-SGN-35, mean tumor:blood ratio of 89Zr-radioactivity increased from 7.38 at 72 hours to 15.05 (157.5 %ID/g) at 144 hours. The 124I-radioactivity and 89Zr-radioactivity tumor:blood ratio in the CD30neg tumors was 0.2 and 0.5 after 144 hours, respectively. The tumor:blood ratio of 89Zr-radioactivity continued to increase from 0.57 after 72 hours to 0.90 (13.4 %ID/g) at 144 hours after a dose of 89Zr-Df-SGN-35 in TF1-α (CD30low) tumor bearing mice. Conclusions: These results indicate that 89Zr-Df-SGN-35 retains the specific anti-CD30 immune-reactivity and PK of the parent SGN-35 molecule. 89Zr labeling generated superior imaging results compared with 124I labeling. With respect to specificity, a favorable tumor:blood ratio was observed in the CD30high tumor bearing mice in contrast to the lack of accumulation of 89Zr-radioactivity in the CD30 negative tumors. The accumulation of 89Zr-radioactivity in CD30low TF1-α tumors suggests that 89Zr-Df-SGN-35 is a very sensitive CD30 targeted PET/CT imaging agent. Citation Format: Aaron Moss, Jean Gudas, Tina Albertson, Nancy Whiting, Che-Leung Law. Preclinical microPET/CT imaging of 89Zr-Df-SGN-35 in mice bearing xenografted CD30 expressing and non-expressing tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2014-104