| 31. |
- Irenaeus, Sandra, et al.
(författare)
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Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors.
- 2021
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Ingår i: Cancer Gene Therapy. - : Springer Science and Business Media LLC. - 0929-1903 .- 1476-5500. ; 28:10-11, s. 1188-1197
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Tidskriftsartikel (refereegranskat)abstract
- AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand which has previously been evaluated in patients with urothelial cancer and malignant melanoma. Herein, we present the results of repeated intratumoral injections of AdCD40L in seven patients with metastatic solid cancer. One patient who developed urothelial cancer derived from a renal transplant was treated with repeated injections of AdCD40L alone. The remaining patients suffered from cholangiocarcinoma, kidney, breast, rectal, or ovarian cancer and received AdCD40L repeatedly (4x) in combination with cyclophosphamide. The treatment was safe and generally well-tolerated. Two patients had clinical benefit of the treatment and one of them was accepted for re-treatment. Circulating proinflammatory cytokines were commonly increased after treatment, but save for TNFα, significances were not reached which could be due to the low number of patients. Similar to earlier findings in AdCD40L-treated melanoma patients, IL8 plasma levels were high in the present study. In conclusion, gene therapy by repeated intratumoral AdCD40L injections alone, or in combination with cyclophosphamide, is feasible and safe in patients with solid cancers. The potential of intratumoral CD40L gene transfer as treatment of cancer was illustrated by the clinical improvement in two out of seven patients.
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| 32. |
- Irenaeus, Sandra, et al.
(författare)
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Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:45, s. 78573-78587
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Tidskriftsartikel (refereegranskat)abstract
- Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy.Methods: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival.Results: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood.Conclusions: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.
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| 33. |
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| 34. |
- Jahn, Ulrika, et al.
(författare)
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177Lu-DOTATATE peptide receptor radionuclide therapy : dose response in small intestinal neuroendocrine tumors
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:7-8, s. 662-670
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Peptide receptor radionuclide therapy (PRRT) has during the last few years been frequently used in patients with progressive, disseminating, well-differentiated neuroendocrine tumors (NETs).Objective: To study whether the absorbed dose in small intestinal NET (SI-NET) metastases from PRRT with 177Lu-DOTATATE is related to tumor shrinkage.Materials and Methods: Dosimetry for 1 tumor was performed in each of 25 SI-NET patients based on sequential SPECT/CT 1, 4, and 7 days after 177Lu-DOTATATE infusion. The SPECT data were corrected for the partial volume effect based on previous phantom measurements, and the unit density sphere model from OLINDA was used for absorbed dose calculations. Morphological therapy response was assessed by CT/MRI regarding tumor diameter, tumor volume, total liver tumor volume, liver volume, and overall tumor response according to RECIST 1.1. Plasma chromogranin A and urinary 5-hydroxy-indole-acetic-acid were measured during PRRT and follow-up to assess biochemical response.Results: At the time of best response with respect to tumor diameter and volume shrinkage, the median absorbed dose was 128.6 Gy (range 28.4–326.9) and 140 Gy (range 50.9–487.4), respectively. All metrics regarding tumor shrinkage and biochemical response were unrelated to the absorbed dose. A correlation was, however, found between the administered radioactivity and the tumor volume shrinkage (p = 0.01) and between the administered radioactivity and RECIST 1.1 response (p = 0.01).Conclusions: It was not possible to demonstrate a tumor dose-response relationship in SI-NET metastases with the applied dosimetry method, contrary to what was previously shown for pancreatic NETs.
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| 35. |
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| 36. |
- Jahn, Ulrika, et al.
(författare)
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Impact of administered amount of peptide on tumor dosimetry at the first cycle of peptide receptor radionuclide therapy (PRRT) in relation to total tumor somatostatin receptor expression
- 2023
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 13:1, s. 45-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe accumulation of 177Lu-DOTATATE might be influenced by the amount of administered peptide in relation to the tumor somatostatin receptor expression. The effect of the administered peptide mass on the resulting absorbed dose in tumors and normal organs has not previously been assessed in relation to the patients’ tumor load.MethodPatients with small intestinal (n = 141) and pancreatic (n = 62) neuroendocrine tumors (NETs) who underwent PRRT were selected for retrospective evaluation. All patients had received 7.4 GBq 177Lu-DOTATATE, and the amount of administered peptide in the preparation varied from 93 to 456 µg. The absorbed dose in tumors and normal tissue at the first PRRT cycle was calculated, based on SPECT-measurements at day 1, 4, and 7 post-infusion. The total tumor somatostatin receptor expression (tTSSTRE) was calculated on SPECT after 24 h by multiplying the functional tumor volume, delineated by 42% cut-off VOIs of the highest activity, with the SUVmean for the respective tumor VOIs. Spearman’s rank correlation analyzed any relationship between the administered amount of peptide and the absorbed dose in tumors and normal organs, in relation to the patients’ tTSSTRE.ResultsThere was no correlation between the amount of peptide and any of the tested parameters in relation to tTSSTRE.ConclusionIn this retrospective analysis, no correlation between the amount of administered peptide in the 177Lu-DOTATATE preparation and the absorbed radiation doses in tumors and normal tissues was demonstrated in relation to the total tumor SSTR expression.
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| 37. |
- Jahn, Ulrika
(författare)
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Peptide Receptor Radionuclide Therapy in Neuroendocrine Neoplasms : Aspects of tumour characteristics, receptor recycling and peptide mass
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine neoplasm (NEN) can arise in any part of the body, but most commonly in the lungs, bronchi, and the gastrointestinal tract including the pancreas. They combine neuroendocrine and tissue-of-origin-specific characteristics; explaining different symptoms depending on the organ of origin. NEN is divided into slow-growing neuroendocrine tumours (NETs) and the rarer aggressive neuroendocrine cancers (NECs). Some hormone producing NETs give rise to symptoms (functioning), generally detected earlier than the non-functioning NETs, which often are larger and metastatic at diagnosis. NETs commonly express an abundance of somatostatin receptors (SSTR). Synthetic copies of somatostatin (somatostatin analogues, SSA), supress hormonal symptoms such as diarrhoea and flush. The SSA-SSTR ligand-receptor complex interaction instantly internalises into the cells, separate, and the SSTR re-surface. Gallium-68 (68Ga)-labelled SSAs are used for PET/CT-camera visualisation of NETs, and SSA labelled with a therapeutic radionuclide, provide a means for internal radio-therapy, peptide receptor radionuclide therapy (PRRT).The aim of the thesis was to compare the tumour response to PRRT in small intestinal NET (SI-NET) and pancreatic NET (P-NET). Study I, II and IV are retrospective and include patients who underwent PRRT with 177Lu-DOTA-TATE at the Uppsala University Hospital. Study I, quantified and related the radiation dose in 25 SI-NETs to tumour shrinkage using two- and three-dimensional measurements, although no dose-response relationship was demonstrated. A relationship between tumour shrinkage and the total administered activity was however found. Study II compared the tumour response between SI-NETs from study I with P-NETs included in an earlier report, now re-evaluated by adding more tumour parameters, and with longer observation time. There radiation dose in P-NETs was the same as in SI-NETs. The radiation dose in P-NETs was highest at the first PRRT cycles, and then decreased significantly in consecutive cycles, which was not observed in SI-NETs.The prospective study III, mapped the recirculation time of SSTR in SI-NETs and normal organs. Twelve tumours were measured at repeated 68Ga-DOTA-SSA-PET examinations. Larger tumours (>4 cm) showed a faster SSTR turn-over rate than small tumours, demonstrating a turnover resembling that in the normal organs. These results open the possibility that pre-treatment could protect normal tissues during PRRT, and probably increase radioactivity tumour uptake and hence, the radiation dose.The retrospective study IV investigated the effects of various amounts of SSA delivered in the PRRT preparation, although the absorbed radiation dose to tumours and normal tissues, was unrelated to the amount of peptide and to the patient’s total tumour burden.
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| 38. |
- Jahn, Ulrika, et al.
(författare)
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Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE : Differences in Tumor Dosimetry, Vascularity and Lesion Metrics in Pancreatic and Small Intestinal Neuroendocrine Neoplasms
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Dosimetry during peptide receptor radionuclide therapy (PRRT) has mainly focused on normal organs and less on the tumors. The absorbed dose in one target tumor per patient and several response related factors were assessed in 23 pancreatic neuroendocrine neoplasms (P-NENs) and 25 small-intestinal NEN (SI-NENs) during PRRT with 177Lu-DOTATATE. The total administered activity per patient was (mean ± standard error of mean (SEM) 31.8 ± 1.9 GBq for P-NENs and 36 ± 1.94 GBq for SI-NENs. The absorbed tumor dose was 143.5 ± 2 Gy in P-NENs, 168.2 ± 2 Gy in SI-NENs. For both NEN types, a dose-response relationship was found between the absorbed dose and tumor shrinkage, which was more pronounced in P-NENs. A significant drop in the absorbed dose per cycle was shown during the course of PRRT. Tumor vascularization was higher in P-NENs than in SI-NENs at baseline but equal post-PRRT. The time to progression (RECIST 1.1) was similar for patients with P-NEN (mean ± SEM 30 ± 1 months) and SI-NEN (33 ± 1 months). In conclusion, a dose response relationship was established for both P-NENs and SI-NENs and a significant drop in the absorbed dose per cycle was shown during the course of PRRT, which warrants further investigation to understand the factors impacting PRRT to improve personalized treatment protocol design.
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| 39. |
- Jahn, Ulrika, et al.
(författare)
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Receptor depletion and recovery in small-intestinal neuroendocrine tumors and normal tissues after administration of a single intravenous dose of octreotide measured by Ga-68-DOTATOC PET/CT
- 2021
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin receptors (SSTR) that can be targeted with somatostatin analogs (SSA). When activated with a single dose of SSA, the receptor-ligand complex is internalized, and the receptor is by default recycled within 24 h. Ongoing medication with long-acting SSAs at Ga-68-DOTA-SSA-PET has been shown to increase the tumor-to-normal organ contrast. This study was performed to investigate the time-dependent extended effect (7 h) of a single intravenous dose of 400 mu g short-acting octreotide on the tumor versus normal tissue uptake of Ga-68-DOTATOC.Methods: Patients with small-intestinal NETs received a single intravenous dose of 400 mu g octreotide and underwent dynamic abdominal Ga-68-DOTATOC-PET/CT at three sessions (0, 3 and 6 h) plus static whole-body (WB) PET/CT (1, 4 and 7 h), starting each PET/CT session by administering 167 +/- 21 MBq, 23.5 +/- 4.2 mu g (mean +/- SD, n = 12) of Ga-68-DOTATOC. A previously acquired clinical whole-body Ga-68-DOTATOC scan was used as baseline. SUV and net uptake rate K-i were calculated in tumors, and SUV in healthy organs.Results: Tumor SUV decreased significantly from baseline to 1 h post-injection but subsequently increased over time and became similar to baseline at 4 h and 7 h. The tumor net uptake rate, K-i, similarly increased significantly over time and showed a linear correlation both with SUV and tumor-to-blood ratio. By contrast, the uptake in liver, spleen and pancreas remained significantly below baseline levels also at 7 h and the receptor turn-over in tumors thus exceeded that in the normal tissue, with restitution of tumor Ga-68-DOTATOC uptake mainly completed at 7 h. These results however differed depending on tumor size, with significant increases in K-i and SUV between the 1st and 2nd PET, in large tumors (>= 4 mL) but not in small (> 1 to < 4 mL) tumors.Conclusion: SSTR recycling is faster in small-intestinal NETs than in liver, spleen and pancreas. This opens the possibility to protect normal tissues during PRRT by administering a single dose of cold peptide hours before peptide receptor radionuclide therapy (PRRT), and most likely additionally improve the availability and uptake of the therapeutic preparation in the tumors.
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| 40. |
- Jawlakh, Hiba, et al.
(författare)
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Ga-68-DOTATOC-PET/MRI and C-11-5-HTP-PET/MRI are superior to Ga-68-DOTATOC-PET/CT for neuroendocrine tumour imaging
- 2021
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Ingår i: Journal of neuroendocrinology. - : John Wiley & Sons. - 0953-8194 .- 1365-2826. ; 33:6
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Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to assess gadoxetate disodium contrast-enhanced (CE) positron emission tomography (PET)/magnetic resonance imaging (MRI) with Ga-68-DOTATOC and C-11-5-Hydroxy-tryptophan (C-11-5-HTP) in comparison with iodine CE Ga-68-DOTATOC-PET/computed tomography (CT) for neuroendocrine tumour imaging. Detection rate and reader's confidence were evaluated for each separate image volume: CE-CT, CE-MRI including diffusion-weighted imaging, Ga-68-DOTATOC-PET performed at PET/CT, Ga-68-DOTATOC-PET performed at PET/MRI and C-11-5-HTP-PET, and for the three combined hybrid examinations Ga-68-DOTATOC-PET/MRI, C-11-5-HTP-PET/MRI and Ga-68-DOTATOC-PET/CT. In 11 patients, 255 lesions were depicted. Ga-68-DOTATOC-PET performed at PET/MRI depicted 72.5%, Ga-68-DOTATOC-PET performed at PET/CT depicted 62.7%, C-11-5-HTP-PET depicted 68.2% and CE-CT depicted 53% of lesions. Ga-68-DOTATOC-PET performed at PET/MRI (P < 0.001) and PET/CT (P = 0.02), C-11-5-HTP-PET (P < 0.001) and MRI (P < 0.001) were superior to CT. Ga-68-DOTATOC-PET/MRI and C-11-5-HTP-PET/MRI detected 92.5% and 92% of lesions, respectively, and both outperformed Ga-68-DOTATOC-PET/CT (65%) (P < 0.001). For liver metastasis imaging, MRI alone was unsurpassed (P < 0.01) and Ga-68-DOTATOC-PET/MRI and C-11-5-HTP-PET/MRI outperformed Ga-68-DOTATOC-PET/CT (P < 0.001). For lymph node metastasis diagnosis, Ga-68-DOTATOC-PET performed at PET/MRI and PET/CT and C-11-5-HTP-PET detected 94%, 94% and 94% of lesions, respectively, and outperformed MRI and CE-CT alone (P < 0.001). For bone metastasis imaging, Ga-68-DOTATOC-PET performed at PET/MRI and PET/CT and C-11-5-HTP-PET performed equally well (P = 0.05) and better than MRI. Reader's confidence was better for Ga-68-DOTATOC-PET/MRI and C-11-5-HTP-PET/MRI than for Ga-68-DOTATOC-PET/CT. The tumour maximum standardised uptake value and tumour-to-liver ratio were both approximately twice as high as for Ga-68-DOTATOC than for C-11-5-HTP. Ga-68-DOTATOC-PET/MRI and C-11-5-HTP-PET/MRI provided the highest detection rates and reader's confidence and were both superior to Ga-68-DOTATOC-PET/CT, mainly because of the MRI component. The imaging contrast with Ga-68-DOTATOC was superior to that of C-11-5-HTP.
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