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Welcome to the April 3, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. First on today's podcast, Tracking the functional profile of Aging Platelets Researchers demonstrate that over time, platelet function shifts away from hemostasis and toward a more immunomodulatory role. These findings could have important implications for transfusion medicine. Certain platelet related disease states after that use of odronextamab, a CD20 CD3 bispecific antibody in patients with diffuse large B cell lymphoma or DLBCL progressing after CAR T cell therapy. The study is the first to evaluate the efficacy and safety of this therapy in the post CAR T cell treatment setting. Finally, we will recap findings from a study of a novel CAR T cell product that utilizes specificity to two antigens common in diffuse large B cell lymphoma. But first, let's start with a research article titled Aging platelets shift their hemostatic properties to inflammatory functions. The first author is Afra Anjem of the University Hospital LMU Munich and the German center for Cardiovascular Research. Platelets are key players in hemostasis and thrombosis, but it is increasingly recognized that platelets also contribute to immune regulation and host defense. These tiny cell fragments arrive early at sites of inflammation, they form tight partnerships with innate immune cells, and they are instrumental for leukocyte vascular adhesion, immunosurveillance and extravasation. What's not clear is whether all platelets play a role in these diverse tasks. Could there be specific subsets that are specialized in hemostasis, thrombosis or inflammatory function? In prior research, one subset stands out young, newly produced platelets, sometimes referred to as reticulated platelets. Compared to more mature platelets, young platelets have increased RNA content. They are thought to be a more highly reactive subset that can contribute to thrombosis and failure of antiplatelet therapies. It is thought that as young platelets age, they start to lose function, resulting in defects in hemostasis and thrombosis. Most of the current findings on platelet aging have been unable to answer key questions on how platelet function changes over time from birth to decay. The research led by Anjum and colleagues employed an innovative pulse labeling method to study platelet aging in mice. This method tracked platelets with very distinct circulatory ages. Researchers also employed single cell based functional assays, genetic mouse models, and transfusion experiments to map phenotypic, functional and proteomic changes as platelets age in circulation. The results show that platelet function changes over time. As platelets age, they appear to move away from hemostatic potential and move toward pro inflammatory function. Anjum and co authors report that young platelets are essentially optimized for clot formation, but as they get older, platelets become more predisposed to carrying out immune related functions. The young reticulated platelets, newly released from megakaryocytes, had enhanced hemostatic and thrombotic potential platinum. Their ability to form blood clots diminished as platelets age. The aging platelets were more prone to exhibit some effector functions associated with immunity, platelet leukocyte aggregate formation, procoagulence transformation, the binding and killing of bacteria and expression of specific receptors linked to inflammation. Interestingly, these are not distinctly separate young and old subsets of platelets. According to authors, the changes they describe are most likely reflecting gradual changes relative changes in phenotype over the lifetime of a platelet in circulation. The researchers showed in vitro data that aged platelets were more likely to form platelet leukocyte aggregates as compared to their reticulated counterparts. Older platelets also showed increased adhesion to neutrophils as well as enhanced bactericidal function in this setting. These findings were reflected in vivo in a model of acute lung injury. The researchers observed increased pulmonary recruitment of aged platelets as well as increased pulmonary leukocyte infiltration and inflammation. In proteomic analyses, data demonstrated upregulation of immune pathways, including enhanced procoagulant function in the older platelets. Similarly, human platelet concentrates had reduced hemostatic function and increased immunomodulatory potential over time. And finally, in a mouse model of platelet transfusion, aged platelet concentrates had augmented inflammation altogether. Authors say platelets platelets change their phenotype as they age in circulation, skewing towards inflammatory function over time, and these findings could have important implications for transfusion medicine. For example, in some vulnerable patient populations it might be beneficial to transfuse freshly isolated and potentially less pro inflammatory platelets as opposed to older stored platelets. In agreement is platelet researcher Laura Gutierrez from the Carlos III Health Institute in Madrid, Spain. In her accompanying commentary, Gutierrez says these findings elegantly show how aging platelets shift their functional profile from hemostatic to inflammatory, a finding which might translate to changes in the management of conditions where the platelet life cycle is altered or where antiplatelet treatment is required. However, she counsels, open questions remain. For example, platelets newly produced through stress megakaryopoiesis may not share the same qualities and functional characteristics as platelets produced in the steady state. The with further research, Gutierrez concludes, we may be able to better predict responses to treatment or avoid adverse events that may result from platelet mediated exacerbated immune responses. Up next odrinextamab monotherapy after progression with CAR T cell therapy primary analysis of ELM1 study the first author is Max S. Topp of University Hospital Wurzburg in Germany. This article addresses an important question in DLBCL treatment, namely, what to do when CAR T cell therapy fails. The treatments of interest here are Axi, Cel, Tisacel, and Lysocell, each of which has been approved for DLBCL treatment in the third or later lines of therapy. However, CAR T cells are moving up they are now considered standard of care for second line therapy. Data from randomized phase three trials demonstrated the superiority of CAR T cells over chemotherapy and autologous transplant. Consequently, Axisel and Lysocel were approved in patients with disease refractory to first line chemoimmunotherapy or which has relapsed within 12 months. However, durable responses are not achieved in nearly half of patients and after relapse the median overall survival is about five months, which illustrates a key unmet need in the space. Researchers are exploring the use of bispecific antibodies that simultaneously bind CD3 on T cells and CD20 on B cells, triggering T cell activation and B cell destruction. Two bispecific antibodies are approved for use in relapsed or refractory dlbcl, glofidamab, and epcoritamab. Others are in development, including odranextamab, an FC silenced human CD20 CD3 bis antibody. In a single ARM multicenter phase 1 study dubbed ELM1 odranextamab demonstrated an overall response rate of 53% in patients with relapsed or refractory DLBCL. Importantly, those patients were naive to prior CAR T cell therapy. The present report is focused on use of odonextimab in patients progressing after CAR T therapy. This prespecified expansion cohort of ELM1 included 60 heavily pretreated patients with a median of three prior lines of therapy. Nearly half had relapsed within 90 days of CAR T therapy, and about 70% were refractory to CAR T. Patients received intravenous odranextamab weekly for four cycles, followed by maintenance until progression the primary endpoint of the study was objective response rate by independent central review. After a median follow up of 16.2 months, the overall response rate was 48.3% and the complete response rate was 31.7%. The median duration of response to odranextamab was 14.8 months and the median duration of complete response was not reached. The median progression free survival was 4.8 months and median overall survival was 10.2 months. At 12 months, 26.5% of patients were progression free including 77% of those with complete response. A total of 48.3% of patients experienced cytokine release syndrome, though none of these events were grade three or greater. There were no cases of immune effect or cell associated neurotoxicity syndrome. As might be expected, grade three or greater infections were seen in 20% and most of these cases required intravenous antibiotics. Exploratory analyses demonstrated that CD20 expression did not correlate with odranextamab response and there appeared to be no negative effect on T cell fitness which was maintained during treatment. In a commentary, Jason Weston of the MD Anderson Cancer center describes the role of odreneximab as a quote, promising option for a population with limited alternatives. Weston says this expansion cohort of the ELM1 study is significant because previous analyses of post CAR T cell patients were limited by small sample sizes and were based on subsets of trials, not dedicated cohorts. Also, this study begins to address the question of whether bispecific antibodies and CAR T cells have different resistance mechanisms. Based on this study, some patients not benefiting from CAR T cell therapy may nevertheless benefit from odranexamab. The final article on today's podcast is phase one trial of Prislon captigene autoleusol a CD 1920 car T for relapsed refractory B cell non Hodgkin lymphoma and the first author is Wen Xianyu of Zhejiang University School of Medicine in China. A total of 5 anti CD 19 car T cell products are available globally to treat relapsed or refractory B cell non Hodgkin lymphomas. They have significantly improved outcomes not only in DLBCL but also in follicular lymphoma and mantle cell lymphoma, though as previously discussed, not all patients will respond and many progress within a few years of treatment. One of the mechanisms of resistance is loss or downregulation of the Target antigen, namely CD19 low or negative CD19 expression has been linked to suboptimal outcomes including poor event free survival. Yu and co authors tested a dual targeting strategy, a bispecific CAR T that simultaneously targets CD19 and CD20. The aim was to overcome antigen expression issues and potentially improve the efficacy of treatment. That much has been demonstrated already not only in preclinical investigations but also in some early stage trials of CD19 CD20 bispecific car T cell therapy for B cell malignancies. The subject of the present study is called Prizlon Cell. This is a novel bispecific CAR T cell product that targets and eliminates CD19 CD20 positive tumor cells. In a preliminary report, Prislon CEL showed promising efficacy and a favorable safety profile in patients with relapsed or now you and co investigators report long term results of a single arm open label phase one study. The study included 48 patients with CD19 and or CD20 positive relapsed or fractory B NHL, including 44 who had large B cell lymphoma. Following a three day lymphodepletion regimen with cyclophosphamide and fludarabine. They received a single intravenous dose of Prislon cell. The primary endpoints were dose limiting toxicity and treatment emergent adverse events. No dose limiting toxicities were observed. The Most common grade 3 or higher treatment emergent adverse events were neutropenia occurring in 83.3% and leukopenia in 50%. Nearly all patients experienced CRS, however, only one case was grade 3 and the remainder of cases were grade 1 to 2. Immune effector cell associated neurotoxicity syndrome was observed in 6.3% of patients. All cases were grade 1 2. The overall response rate was 95.1% and the complete response rate was 85.1% in just the LBCL patients. Overall and complete Response rates were 90.7% and 86% respectively, with a median follow up of 30 months. The estimated two year rates of duration of remission, progression free survival and overall survival were 66%, 62.6% and 76.5% respectively. Authors conclude that prizloncel had a favorable safety profile and deep durable responses in this phase one study and could become a promising treatment option for patients with relapsed or refractory B cell NHL also in blood. A commentary on this study by Alberto Musetti and Anna Sereda, both from the Catalan Institute of Oncology in Barcelona, Spain. Musetti and Serrada say this Prislon cell has demonstrated promising clinical results. They say Prislon Cell directly addresses antigen heterogeneity and loss, which are key drivers of resistance in single antigen CAR T cell therapies. They describe dual targeting of CD19 and CD20 as a rational approach given that CD20 loss is relatively rare compared to CD19, and they say that efficacy, although not the primary endpoint of the study, was nonetheless intriguing. They say the durability of responses at two years was especially compelling. The study also provided insights into prison cell pharmacokinetics as described further in blood. These include robust expansion and long term persistence of CAR T cells that were observed. However, Commentary authors say there are still shortcomings to the manufacturing processes that need to be overcome to maximize the therapeutic potential of this CAR T cell product. Trials of Prizlancel ongoing in China and the United States could provide further validation of these findings and novel options for relapsed refractory B cell lymphomas. You have been listening to the Blood Podcast. The articles mentioned in this podcast can be found@bloodjournal.org and are linked in the show notes of this episode. Be sure to join us next week for another episode. Thank you for listening.