The motto of the recently held Swiss Oncology & Hematology Congress (SOHC) was “Overcoming borders together”. A great deal of research has been and is being carried out to give oncology and hematology patients a good prognosis with a good quality of life. New findings in basic research are just as encouraging as future possibilities in diagnostics and therapy.
The increasing demand for platelet transfusions (PLT) requires a safe alternative to blood and PLT donations. In vitro production of platelets is currently being researched, but a commercially viable solution is hampered by the limitations of large-scale production and cost. A scalable solution that efficiently produces a platelet concentrate (PC) from mature megakaryocytes (MK) in less than two hours was presented at the congress [1]. For this purpose, human CD34+ cells were seeded in a xeno-free medium with thrombopoietin for differentiation into MK and transferred into the modified rotary bed reactor of HemostOD – consisting of a dish with microstructures – in a 200 mL bioreactor for two hours at 900 rpm. The control PLTs either came from healthy donors (blood PLT) or were generated using a microfluidic chip (CHIP-PLT). PLT activation was performed with ADP + PAR1 agonist peptide and analyzed by flow cytometry (FC). The pharmacokinetic study was conducted in immunodeficient clodronate-treated mice. It was shown that functional platelets in the HemostOD bioreactor become functional thrombocytes within two hours, which have the same properties as blood PLTs. The bioreactor in combination with the company’s proprietary human MK cell line thus has the potential to enable the production of platelets for clinical use on a large scale with an unlimited and stable source of megakaryocytes.
Joint health with hemophilia A
Joint damage in hemophilia A is caused by repeated intra-articular bleeding (IAB). As there is no treatment to reduce bleeding-related synovitis, preventing bleeding is crucial to maintaining joint health. This requires a more targeted therapy. It has already been shown that genetic ablation of protein S (PS) protects hemophilic mice from hemorrhages, especially IAB. Similarly, that PS reduction by a small interfering RNA prevents acute hemarthrosis in mice with hemophilia A (HA) and improves hemostasis in nonhuman primates with acquired hemophilia. In addition, PS reduction improved thrombin generation in human models of HA ex vivo. The effects of GA of PS on joint health have now been investigated using a mouse model of chronic hemarthrosis (CH) [2].
HA mice (F8-/-), HA mice with genetic ablation of PS (F8-/-Pros1-/-) and WT mice were subjected to CH by three joint hemorrhages induced seven days apart. Histology, immunostaining, electron microscopy (EM), joint lavage analyses and RNA sequencing of the synovium were performed at steady state (SS) and at CH. During CH, joint diameters increased in F8-/-, but not in F8-/-Pros1-/- and WT mice. Histology confirmed this result, as neither bleeding nor synovitis occurred in F8-/-Pros1-/- mice. Iron deposition was minimal in F8-/-Pros1-/- and there was no cartilage erosion. The lining layer (LL) was intact in F8-/-Pros1-/- with CH, as shown by histology and EM. In CH, macrophages were present in the LL of F8-/-Pros1-/- and WT mice and in the subLL of F8-/- mice. The level of inflammatory cytokines was lower in F8-/-Pros1-/- than in F8-/- joint rinses. In SS, mRNA encoding proteins involved in bone resorption was decreased, while proteins encoding cell communication and bone formation were increased in F8-/-Pros1-/- versus F8-/ mice. Post-CH, F8-/-Pros1-/- mice showed positive regulation of genes involved in macrophage activation, bone regeneration and tissue remodeling, and negative regulation of genes involved in angiogenesis and fibroblast growth. In contrast to F8-/- mice, the synovium of F8-/-Pros1-/- mice showed increased expression of pleiotrophin (PTN), a secreted growth/differentiation factor involved in bone development and tissue repair. PTN was strongly expressed in the synovial LL of F8-/-Pros1-/- compared to F8-/- and WT mice. These data show that PS is an important factor influencing joint health in HA.
Cell therapy for CLL
Stereotypic immunoglobulin (IG) light chain rearrangements using the IGLV3-21 gene with G110R mutation define a subset of patients with chronic lymphocytic leukemia (CLL) with aggressive clinical course, poor prognosis and limited therapeutic options. This G110R mutation is a highly specific driver in CLL and has the unique ability to enable autonomous B-cell receptor (BCR) signaling by mediating homotypic BCR self-interactions. To improve the treatment of these patients, a chimeric antigen receptor (CAR) T cell product selectively targeting the CLL-specific IGLV3-21-G110R neoepitope should be developed [3].
To this end, the heavy and light IG chains of a murine IGLV3-21-G110R antibody were translated into the format of a single chain variable fragment (scFv) and second generation murine and humanized CAR constructs were produced. The constructs were transduced into T cells from healthy donors and CLL patients. The generated scFv had the same binding affinity as the original antibody. CAR-T cells directed against IGLV3-21-G110R derived from healthy donors and CLL patients eliminated IGLV3-21-G110R-expressing cell lines and primary CLL cells, but not polyclonal healthy B cells in in vitro co-culture assays, as detected in live cell killing and IFN-γ secretion assays. No differences in efficacy were observed between the murine and humanized CAR backbone. In vivo experiments showed significantly reduced growth of transplanted cell lines or primary PBMCs from CLL patients in xenograft models, accompanied by prolonged survival and even eradication of the disease in 17% of mice.
New hope for AML patients
There are currently only a few approved drugs available for AML patients in relapse. The situation is exacerbated by the rapidly progressive nature of AML at relapse, which severely limits the timeframe for selecting an optimal treatment regimen. Pharmacoscopy, an image-based ex vivo screening of drugs, has previously been proposed as a novel tool for treatment selection in a variety of hematologic malignancies, but has never been prospectively tested in relapsed AML patients [4]. Now, patient-derived leukemic samples were subjected to pharmacoscopy screening to make treatment recommendations for 30 relapses in 24 AML patients who had exhausted all standard treatment options. It was investigated whether pharmacoscopy can be used within the narrow time frame available for AML relapse, how often the recommended therapies can be started with adequate financial coverage, and whether they provide lasting clinical benefit.
Pharmacoscopy provided treatment recommendations within a median of five days after sampling. In 17 out of 30 screening cases (56.7%), patients received treatment recommended by pharmacoscopy. The six most frequently recommended drugs in descending order were navitoclax, venetoclax, omacetaxine, cladribine, carfilzomib and panobinostat. Patients who received a recommended regimen had higher rates of complete remission and longer overall survival than patients who received therapy selected by conventional methods. The performance of a drug regimen during ex vivo drug screening can be quantified by the integrated pharmacoscopy score (i-PCY). This score proved to be an excellent predictor of clinical response: patients who received a regimen with an i-PCY score above the mean had a significantly higher rate of complete remission and significantly longer overall survival.
Assisted suicide in patients with pancreatic cancer
The legalization of assisted suicide (AS) is one of the most discussed topics in the field of medical ethics worldwide. There is limited data on the long-term development and trends in patients who have undergone euthanasia for pancreatic cancer [5]. An analysis of all deaths, all cancer-related deaths, all PC-related deaths and all AS deaths was carried out using data from the Federal Statistical Office over a period of 20 years. In fact, the most common underlying disease for AS was oncological in nature. The most common subtype was lung cancer, followed by colorectal cancer, breast cancer and prostate cancer. Of the five most common oncologic diseases underlying cancer-related AS, PC was the fifth most common subtype. During the study period, the number of PC-related AS increased significantly. The proportion of PC-related AS in relation to all PC-related deaths increased from 0.2% at the beginning of the study period to 2.4%. During the 20-year study period, the proportion of people who chose a PC-related AS increased twelvefold. Nevertheless, AS is still rare in PC patients and only accounts for less than 3% of all PC-related deaths.
Congress: Swiss Oncology and Hematology Congress (SOHC) 2023
Literature:
- Humbert M, et al.: Modified Rotating Bed Reactor Compatible with an Industrializable and Scalable Manufacturing of Lab-Grown Platelets. Abstract 185. Swiss Medical Weekly 2023;153 (Suppl. 274): 2.
- Eladani RP, et al.: Genetic ablation of anticoagulant protein S promotes joint health in hemophilia A. Abstract 274. Swiss Medical Weekly 2023;153 (Suppl. 274): 2.
- Schultheiss C, et al.: Mutation-specific CAR T cells as precision cell therapy for IGLV3-21-G110R expressing high-risk chronic lymphocytic leukemia. Abstract 183. Swiss Medical Weekly 2023;153 (Suppl. 274): 3.
- Schmid J, et al.: Pharmacoscopy-guided treatment for acute myeloid leukemia patients that have exhausted all registered therapeutic options – a novel approach to an unmet clinical need. Abstract 238. Swiss Medical Weekly 2023;153 (Suppl. 274): 6.
- Rahimzadeh P, et al.: Assisted Suicide in Patients with Pancreatic Cancer: Swiss Data from a 20-year Experience (1999–2018). Abstract 180. Swiss Medical Weekly 2023;153 (Suppl. 274): 8.
InFo ONKOLOGIE & HÄMATOLOGIE 2024; 12(1): 24-25 (published on 11.3.24, ahead of print)
