Oktober 14

We aimed at determining the molecular mechanisms involved in the therapeutic efficacy of 177Lu-labeled lilotomab satetraxetan (Betalutin®) directed against the CD37 receptor expressed by non-Hodgkin lymphoma (NHL) B-cells. Materials and methods. In vitro, Ramos, Raji and rituximab resistant Raji (Raji2R, all Burkitt lymphoma), DOHH2 (transformed follicular), Rec-1 (mantle), U2932 and OCILy8 (diffuse large B-cell) lymphoma cell lines were exposed for 18 hours to increasing activities (0-6 MBq/mL) of 177Lu-lilotomab, of the non-specific 177Lu-cetuximab or to unlabelled mAbs (0-40µg/mL). Clonogenic survival, proliferation, expression level of phosphorylated CDK1, cell cycle progression and apoptosis were investigated. In vivo, mice bearing subcutaneous Ramos, DOHH2, Raji, Raji2R or OCILy8 tumour xenografts, were treated with 177Lu-mAbs, with rituximab or lilotomab and tumour growth was monitored. Results. We showed in all lymphoma cell lines that unlabelled rituximab was more cytotoxic than lilotomab. When lilotomab was radiolabeled, 177Lu-lilotomab was more cytotoxic than rituximab in the so determined radiosensitive DOHH2 cells while its cytotoxicity in Ramos cells was less pronounced. The higher response to 177Lu-lilotomab in DOHH2 cells than in Ramos cells was mainly mediated by lack of G2/M cell cycle arrest in DOHH2 cells followed by strong induction of apoptosis. Inhibition of CDK1 Tyr15 phosphorylation using MK1775 or PD166285 drugs radiosensitized Ramos cells. These results were supported by in vivo data. In Ramos tumour xenograft models, 250 MBq/kg (1.25 mg/kg) 177Lu-lilotomab and 10 mg/kg rituximab could not delay tumor growth compared with untreated mice. 177Lu-lilotomab significantly delayed tumour growth compared with rituximab (used at the same concentration) only if injected activity was increased up to 500 MBq/kg. Conversely, in DOHH2 tumour xenografts, 100 MBq/kg (0.5 mg/kg) 177Lu-lilotomab was more efficient than rituximab. The in vivo use of MK1775 was shown to radiosensitize Ramos tumour xenografts to 177Lu-lilotomab. Experiments analysis is ongoing for OCILy8, Raji and Raji2R cell lines.
Conclusion: These results indicate that 177Lu-lilotomab is an efficient therapeutic tool for NHL, particularly for tumors showing reduced inhibitory CDK1 phosphorylation.

Ja, det er fint med facts, men når de kommer som halve kryptiske setninger uten henvisninger, samt ofte gammelt, blir det vanskelig å forholde seg til.

Ellers kan dere kose dere videre med denne:

Theranostics – Nuclear medicine´s fountain of youth

October 09, 2018

By: Ken Herrmann and Wolfgang P. Fendler

The term “theranostics” reigns among medicine´s hottest buzz words, being almost as popular as “artificial intelligence” and “immunoncology”. According to PubMed, the term was introduced in an abstract in 2002. Today more than 3800 hits are reported for “theranostic” or “theragnostic”. In short, theranostics is defined as “diagnostic testing employed for selecting targeted therapy.”

Interestingly, Nuclear Medicine has long applied the theranostic concept by using radioactive iodine for diagnostic imaging and therapy of thyroid cancer. In 1943 Seidlin, et al. used a Geiger counter to localize sites of metastases under 131I treatment. Whereas radioactive iodine-based theranostics are established worldwide, it took more than 70 years to successfully translate a new generation of theranostics into the clinic. Similar to radioiodine treatment, Lutathera and other theranostic probes are highly efficacious, with few serious adverse events. It was only earlier this year that Lutathera, a 177Lu-labelled somatostatin receptor agonist, was approved for clinical use in patients with rare neuroendocrine tumors (NET) by the FDA and a bit earlier by the EMA. The medical and economic excitement associated with the introduction of Lutathera represents just a small glimpse of what can be expected when new theranostic pairs are made available to diagnose and treat more prevalent malignancies such as prostate, breast, lung and/or pancreatic cancer. For prostate cancer the target of interest is the prostate specific membrane antigen (PSMA). PSMA is over-expressed by the majority of prostate cancers and was also described to have prognostic value. The introduction of specific PSMA ligands conjugable with diagnostic (68Ga-, 18F-) or therapeutic (177Lu-, 90Y-, 225Ac-) radionuclides resulted in an overwhelming demand by referring physicians and patients (Figure 1) .

Recent developments have triggered a lot of industry interest in theranostics. The acquisition of Advanced Accelerator Applications by Big Pharma (Novartis) for $3.9 billion USD, the recent surge of the Endocyte Inc. stock after licensing a theranostic to be applied to prostate cancer, as well as the reimbursement level of around $47,500 USD per dose of Lutathera highlight the emerging economic relevance of theranostics and therefore nuclear medicine. However, opportunities are associated with challenges such as setting up the required infrastructure, training the healthcare professionals, establishing the appropriate position of a new therapeutic within established treatment algorithms and many more. There are approximately 40 dedicated theranostic centers in Germany supplying a population of 80 million citizens. Translating this number to a population of 320 million in the U.S. suggests a need of around 160 theranostic centers. Few early adopters, such as UCLA, UCSF and MSKCC, among others, are currently setting up dedicated theranostic centers in the U.S. Others are hesitant due to unknown regulatory (FDA approval) and reimbursement status, which renders development of solid business plans difficult. In addition, only few in the U.S. have been appropriately trained in theranostics. There is, therefore, an unmet need to train a wide spectrum of healthcare professionals, including nurses, technologists, physicists, radiation safety officers, and medical doctors. At the same time this also provides an opportunity to attract young, motivated people, including specialists from other fields, such as medical oncology, gastroenterology, endocrinology, and urology to nuclear medicine.

Supply of theranostic compounds remains another significant roadblock to widespread adoption. Some experts, using conservative models, predicted an annual need of around 30,000 doses of Lutathera for NET and around 160,000 doses of 177Lu-PSMA for prostate cancer patients. Based on 250 work days per year this results in an average of 760 doses per day and, including a safety margin, the need to produce 800-1000 doses per day. However, the current production infrastructure as well as the 177Lu-supply are far from ready to meet this demand. This crisis provides an opportunity for industry, insurances, health care providers and health care professionals to come up with mutually beneficial solutions.

As outline above, the demand for theranostics will be high. However, with the development and emergence of additional novel theranostics the demand is likely to become even higher. These new compounds will be applicable to NET and other somatostatin receptor expressing tumors (177Lu-Satoreotide), neurotensin-1 receptor ligands, possibly for pancreactic cancer among others (177Lu-3BP-227), CD37-binding antibodies for hematological malignancies (Betalutin) and the recently approved 131MIBG (Azedra) for neuroblastoma and pheochromocytoma. More recently introduced ligands targeting tumor stroma (Fibroblast Activation Protein (FAPI)) may find even wider application in various cancers.

Ken Herrmann
In summary, theranostics provides unique new opportunities and challenges for nuclear medicine and industry regulators, insurances and healthcare systems. But there is no time to hesitate – the future is now!

Wolfgang P. Fendler
About the authors: Ken Herrmann and Wolfgang P. Fendler work in the department of Nuclear Medicine, Universitätsklinikum Essen, Essen, Germany. Ken Herrmann is also associated with the Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California

Disse posterne er allerede nøye drøftet her: https://forum.hegnar.no/thread/12608/view Nano to postere på EANM 2018 og jeg foreslår at videre drøftelser fortsatt skjer på den tråden. Fint du jobber frem facts og info Frontmasta!

Har ikke åpnet flasken, men dårlige briller og liten skjerm................... PAPIRET ( studien ) FÅR DERE AV MALENE

Eventuelt er det EANM18 han tenker på O C T O B E R 1 3 – 1 7 , 2 0 1 8

Der skal NANO presentere følgende:

OP-069
Therapeutic efficacy of 177Lu-lilotomab
satetraxetan in non-Hodgkin B-cell Lymphoma
is controlled by G2/M cell cycle progression
A. Pichard1, S. Marcatili2, I. Navarro-Teulon1, H.
Heyerdahl3, S. Patzke3, V. Stenberg3, M. Bardiès2, J.
Dahle3, J. Pouget1; 1IRCM/INSERMU1194, Montpellier,
FRANCE, 2CRCT Toulouse, Toulouse, FRANCE, 3Nordic
Nanovector ASA, Oslo, NORWAY.

og

OP-252
Tumor Absorbed Dose and Changes in FDG
PET Parameters in Non-Hodgkin Lymphoma
Patients Treated With 177Lu-Lilotomab
Satetraxetan
A. Løndalen1,2, J. Blakkisrud1,3, J. Dahle4, M. E.
Revheim1,2, H. Holte5, A. Kolstad5, C. Stokke1,6;
1Division of Radiology and Nuclear Medicine, Oslo
University Hospital, Oslo, NORWAY, 2Faculty of
Medicine, University of Oslo, Oslo, NORWAY, 3Dept.
of Physics, University of Oslo, Oslo, NORWAY, 4Nordic
Nanovector ASA, Oslo, NORWAY, 5Dept. of Oncology,
Radiumhospitalet, Oslo University Hospital, Oslo,
NORWAY, 6Dept. of Life Sciences and Health, Oslo
Metropolitan University, Oslo, NORWAY.

Program her:
https://eanm18.eanm.org/content/uploads/documents/EANM_2018_Final_Programme_ONLINE.pdf

Med andre ord, det har allerede skjedd.
Hva er det du vil frem til her?

Nesten bare 1 år å vente da :o
Tror jeg du med skru igjen korken på flasken din :D