Distinct Toxicity Profiles Research Articles

Targeting the RAS/MAPK pathway in children with glioma.

Pediatric gliomas are the most common brain tumor in children, encompassing both low-grade glioma (pLGG) and high-grade glioma (pHGG). Alterations in the RAS/MAPK pathway are the driver event in the majority of pLGG and account for a subset of pHGG. Identification of these alterations has resulted in the transition to targeted therapy as a treatment option. In pLGG, multiple trials have demonstrated superior outcomes using targeted therapy compared to traditional chemotherapy regimens. This has transformed care for these patients over the past decade with targeted therapy moving into front-line treatment regimens in certain scenarios. Despite these advances, novel targeted therapy approaches continue to present unique challenges to patient care, including optimal duration of therapy, distinct toxicity profiles and the unknown potential impact on the natural history of disease. While targeted therapy has revolutionized treatment of pLGG, additional questions remain in regard to pHGG including the role of targeted therapy in combination with other treatments, such as chemotherapy/radiation, and mechanisms of resistance. These developments are promising treatment options for pediatrics gliomas, enabling a move towards precision medicine. Herein, we review the role of RAS/MAPK targeted therapy for treatment of pediatric glioma along with the current controversies and outstanding questions.

A Podcast on Platinum Eligibility and Treatment Sequencing in Platinum-Eligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma.

The treatment landscape for patients with advanced urothelial carcinoma continues to evolve. Enfortumab vedotin plus pembrolizumab has received Food and Drug Administration approval based on recent phase 3 trial data showing superior efficacy compared with first-line platinum-based chemotherapy; however, its distinct toxicity profile may make it less suitable for some patients, and availability in some countries may be limited by cost considerations. Consequently, platinum-based chemotherapy is expected to remain an important first-line treatment option. Choice of platinum regimen (cisplatin- or carboplatin-based) is informed by assessment of clinical characteristics, including performance status, kidney function, and presence of peripheral neuropathy or heart failure. For patients without disease progression after completing platinum-based chemotherapy, avelumab first-line maintenance treatment is recommended by international guidelines. For patients who have disease progression, pembrolizumab is the preferred approach. Additionally, following results from a recent phase 3 trial, nivolumab plus cisplatin-based chemotherapy has also received Food and Drug Administration approval and is an additional first-line treatment option for cisplatin-eligible patients. Later-line options for patients with advanced urothelial carcinoma, depending on prior treatment, may include enfortumab vedotin, erdafitinib (for patients with FGFR2/3 mutations or fusions/rearrangements), sacituzumab govitecan, and platinum rechallenge. For the small proportion of patients ineligible for any platinum-based chemotherapy (i.e., unsuitable for cisplatin or carboplatin), immune checkpoint inhibitor monotherapy with pembrolizumab or atezolizumab is a first-line treatment option, although approved agents vary between countries. In summary, this podcast discusses recent developments in the treatment landscape for advanced urothelial carcinoma, eligibility for platinum-based chemotherapy, potential first-line treatment options, and treatment sequencing. Supplementary file1 (MP4 246907 KB).

Charting the Course: Sequencing Immunotherapy for Multiple Myeloma.

Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.

Spectral Fluorescence Pathology of Protein Misfolding Disorders.

Protein misfolding has been extensively studied in the context of neurodegenerative disorders and systemic amyloidoses. Due to misfolding and aggregation of proteins being highly heterogeneous and generating a variety of structures, a growing body of evidence illustrates numerous ways how the aggregates contribute to progression of diseases such as Alzheimer's disease, Parkinson's disease, and prion disorders. Different misfolded species of the same protein, commonly referred to as strains, appear to play a significant role in shaping the disease clinical phenotype and clinical progression. The distinct toxicity profiles of various misfolded proteins underscore their importance. Current diagnostics struggle to differentiate among these strains early in the disease course. This review explores the potential of spectral fluorescence approaches to illuminate the complexities of protein misfolding pathology and discusses the applications of advanced spectral methods in the detection and characterization of protein misfolding disorders. By examining spectrally variable probes, current data analysis approaches, and important considerations for the use of these techniques, this review aims to provide an overview of the progress made in this field and highlights directions for future research.

Revolutionizing cancer treatment: comprehensive insights into immunotherapeutic strategies.

Cancer, characterized by the uncontrolled proliferation of aberrant cells, underscores the imperative for innovative therapeutic approaches. Immunotherapy has emerged as a pivotal constituent in cancer treatment, offering improved prognostic outcomes for a substantial patient cohort. Noteworthy for its precision, immunotherapy encompasses strategies such as adoptive cell therapy and checkpoint inhibitors, orchestrating the immune system to recognize and selectively target malignant cells. Exploiting the specificity of the immune response renders immunotherapy efficacious, as it selectively targets the body's immune milieu. Diverse mechanisms underlie cancer immunotherapies, leading to distinct toxicity profiles compared to conventional treatments. A remarkable clinical stride in the anticancer resources is immunotherapy. Remarkably, certain recalcitrant cancers like skin malignancies exhibit resistance to radiation or chemotherapy, yet respond favorably to immunotherapeutic interventions. Notably, combination therapies involving chemotherapy and immunotherapy have exhibited synergistic effects, enhancing overall therapeutic efficacy. Understanding the pivotal role of immunotherapy elucidates its complementary value, bolstering the therapeutic landscape. In this review, we elucidate the taxonomy of cancer immunotherapy, encompassing adoptive cell therapy and checkpoint inhibitors, while scrutinizing their distinct adverse event profiles. Furthermore, we expound on the unprecedented potential of immunogenic vaccines to bolster the anticancer immune response. This comprehensive analysis underscores the significance of immunotherapy in modern oncology, unveiling novel prospects for tailored therapeutic regimens.

Current Management and Future Perspectives in Metastatic HER2-Positive Breast Cancer

ObjectiveMetastatic HER2-positive breast cancer remains a significant clinical challenge with a poor prognosis. The introduction of anti-HER2 therapies has significantly improved survival in early and advanced stages. However, patients with metastatic HER2-positive breast cancer eventually experience progression due to de novo or acquired resistance. This review article comprehensively analyzes the current management of metastatic HER2-positive breast cancer, addressing the complexities in determining the optimal HER2-targeted therapy sequence. Data SourcesDiscussion of selected peer-reviewed articles and expert opinion. ConclusionsWe explore the actual standard of care and the emerging therapeutic options that hold promise for further improving patient care and survival in this aggressive breast cancer subtype. This article highlights vital toxicities linked to anti-HER2 therapies, emphasizing their recognition across treatments as interstitial lung disease, diarrhea, or left ventricular dysfunction. Implications for Nursing PracticesOncology nurses have a key role to play in detecting potential adverse effects of anti-HER2 therapies. The development of new drugs, as antibody–drug conjugates, with a distinct toxicity profile makes it necessary for us to be updated on the management of these new toxicities.

Adverse Effects and Non-Relapse Mortality of BCMA-Directed Immunotherapies : An FDA Adverse Event Reporting System (FAERS) Database Study

Background: The FDA-approved BCMA-directed immunotherapies, which consist of chimeric antigen receptor T (CAR T) cell therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), alongside the bispecific antibody teclistamab, have improved outcomes for patients with relapsed/refractory multiple myeloma (MM). Despite their effectiveness, these treatments have distinct toxicity profiles, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and the risk of infections, all contributing to non-relapse mortality. In this study, we analyzed these adverse events using data from the FDA Adverse Event Reporting System (FAERS) database. Method: We conducted a comprehensive search of the FAERS database from 2019 to 2023 to identify adverse effect reports of interest, associated with ide-cel, cilta-cel, and teclistamab. To ensure data accuracy, we excluded duplicate reports and cases where multiple BCMA-directed agents were associated with a single incident. Reporting odds ratio (ROR) was calculated by dividing the odds of a certain event occurring with the agent by the odds of the same event occurring with all other BCMA agents in the same database. Furthermore, to assess NRM, we excluded reports of progressive or refractory MM from the analysis of fatal cases. Results: A total of 1314 individual cases, with 3377 reported adverse reactions, were identified. Among them, 353 cases were associated with cilta-cel, 496 with ide-cel, and 465 with teclistamab. The most frequently reported adverse events included CRS at 12.8%, followed by fatigue (3.9%), pyrexia (3.2%), ICANS (3.0%), and non-ICANS neurotoxicity (1.9%). Ide-cel showed the highest ROR for CRS (1.64, 95% CI 1.33-2.02), whereas the ROR for ICANS was lowest with teclistamab (0.55, 95% CI 0.32-0.93). Ide-cel showed the highest ROR for non-ICANS neurotoxicity (2.45, 95% CI: 1.86-3.23). Bell's palsy was exclusively associated with cilta-cel, with 11 reported cases, while Parkinsonism was reported in 6 cases with cilta-cel, 2 cases with ide-cel, and none with teclistamab.Teclistamab had a notably higher proportion of infection-related events, accounting for 23.7% of all reported cases, as compared to 13.7% for cilta-cel and 2.9% for ide-cel. The ROR for infection was highest with teclistamab at 5.21 (95% CI: 4.14 - 6.56). Out of the total reported deaths (n=225 cases), NRM was observed in 189 patients, accounting for 84% of all mortality cases. In the analysis of NRM , ide-cel was associated with 42 reported deaths, with CRS (n=17; 40%), ICANS (n=8; 19%), sepsis (n=7; 17%), and hemophagocytic lymphohistiocytosis (HLH) (n=6; 14%) being the most common reported adverse events in this group. For cilta-cel, 59 deaths were reported, with CRS (n=17; 29%), ICANS (n=13; 22%), and HLH (n=9; 15%) as the most common adverse events in patients who suffered NRM. In the case of teclistamab, among the 88 NRM cases, the most frequent adverse events reported were COVID-19 (11.4%), pneumonia (11.4%), sepsis (9.1%), and septic shock (9.1%). Teclistamab exhibited the highest OR for NRM at 1.73 compared to 1.28 with cilta-cel and 0.42 with ide-cel. The findings will be presented with updated data. Conclusion: Our analysis of the FAERS dataset demonstrates a prominent risk of CRS and ICANS with CAR-T therapy, as well as a high risk of infection related mortality with teclistamab. Non-ICANS neurotoxicity was more pronounced with ide-cel compared to cilta-cel, potentially influenced by the longer follow-up period and wider uptake of ide-cel as it was the first FDA-approved CAR T therapy. We also note a higher NRM with both cilta-cel and teclistamab compared to ide-cel. While the exact attributes of NRM cannot be accessed in the database, complications of CAR T therapy and infections were the most common events noted in the group with NRM. Our analysis is limited by the nature of the FAERS database, where reporting is not mandatory, and selection bias cannot be eliminated. Since these agents share a similar indication for MM, clinicians will need to carefully consider their distinct toxicity profiles when choosing and sequencing treatments.

Infections Drive Non-Relapse Mortality Following CAR-T Therapy across Disease Entities and CAR Products - a Meta-Analysis of Clinical Trials and Real-World Studies

Introduction: Chimeric antigen receptor (CAR) T cell therapy has markedly improved treatment outcomes for patients with relapsed/refractory B-cell malignancies. However, CAR-T cells are also associated with a distinct toxicity profile including cytokine release syndrome (CRS) and neurotoxicity (ICANS). Due to their nature as a ‘living drug’, CAR-T cells can also exert profound and long-lasting immune deficits - predisposing for a broad range of infectious complications. While there is a growing body of evidence concerning treatment response and relapse mechanisms, data on non-relapse mortality (NRM) remains scarce. To gain further insights into drivers of non-relapse related deaths after CAR-T therapy, we performed a meta-analysis of published clinical trials and real-world studies (RWS). Methods: For our literature search of clinical trials, we included all studies which led to approval of the six commercially available CAR-T products (axi-cel, tisa-cel, ide-cel, cilta-cel, liso-cel, brexu-cel) and the corresponding phase I-II (Ph I/II) trials. For RWS, articles had to be published until June 2023 and had to fulfill the following criteria: (1) use of commercially available CAR products in a real-world setting, (2) inclusion of > 100 patients, (3) reports on adult patients. Studies which did not differentiate between relapse and non-relapse related deaths were excluded. Data extraction included basic study characteristics (patient numbers, follow-up time, CAR product), NRM, causes of death, and treatment-association. Results: From a total number of 511 screened studies, 15 clinical trials (Ph I/II: 9, Ph III: 6) and 9 RWS compromising 5,313 patients fulfilled the inclusion criteria. As expected, median follow-up was longer for Ph III trials compared to RWS (Ph III: 18.0 (16.3-34.9) months, RWS: 12.9 (9.7-14.2) months, p=0.04), and comparable to Ph I/II trials (17.5 (15.9-28) months, p>0.9). Among all studies, the most common entity was large B-cell lymphoma (LBCL, 3,770 patients), followed by multiple myeloma (MM, 959), mantle cell lymphoma (MCL, 339) and indolent lymphomas (IL, 245). The distribution of encountered CAR products in the study cohort was: 10 axi-cel, 6 tisa-cel, 4 ide-cel, 4 liso-cel, 3 brexu-cel, and 2 cilta-cel. Of note, over half of the studies did not report any measure of NRM (58%), highlighting deficits in toxicity reporting among CAR-T cell studies. We observed considerable heterogeneity in reporting of NRM with follow-up times ranging from 3 to 12 months and NRM rates ranging between 3.0-9.1%. To integrate studies without a reported NRM, we calculated a point estimate of NRM by dividing non-relapse related deaths by the total number of respective patients ( Fig. 1A). Importantly, the comparison of reported NRMs and NRM point estimates was similar (p=0.89). We noted a trend towards higher NRM estimates in patients with MM (9.4% IQR 6.5-12%) followed by MCL (8.7% IQR 8.1-9.7%), LBCL (6.2% IQR 4.4-8.4%) and IL (4.1% IQR 3.1-5.1%, Kruskal-Wallis p=0.12). NRM was lowest with tisa-cel (3.4% IQR 2.8-4.3%) and highest with cilta-cel (14.3% IQR 13.1-15.4%, Kruskal-Wallis p=0.014). Numerically increased NRM was noted for CD28z- vs. 4-1BB harboring CAR products (8.2 vs. 6.2%, p=0.13) and for phase III studies (Ph I/II vs. III vs. RWS: 6.6 vs. 11.9 vs. 6.2%, Kruskal-Wallis p=0.16). To further elucidate the etiology of non-relapse related deaths, we categorized all reported deaths into one of the following categories: CRS, neurotoxicity, infection, hemorrhage, secondary malignancy, HLH, organ failure not otherwise specified (NOS), others/unknown. In total, 441 deaths were reported of which nearly half were caused by infections (n=210, 47.6%). The CAR-T specific adverse events CRS, ICANS, or HLH led to death in 11.1% of cases. Of interest, secondary malignancies contributed to death in 6.1% of cases and hemorrhages in 3% of cases. We observed a similar distribution of CAR-specific toxicities across entities ( Fig. 1B chi 2 p=0.78). Conclusions: Infections were by far the main determinant of non-relapse mortality across all disease entities, underlining the profound immune deficits conferred during CAR-T therapy. The high incidence of secondary malignancies of 6% is concerning and warrants further systematic study. High-quality and long-term reporting of NRM is critical to recognize emerging side effects and to identify potential toxicity signals of novel CAR products.

Current status of sinonasal cancer survivorship care.

Sinonasal cancer is a heterogeneous orphan disease of diverse histologies, each with distinct clinical, oncologic, and toxicity profiles. Because of the comparative rarity of these cancers, sinonasal cancers are treated as a grouped diagnosis despite their clinical and biological heterogeneity. Multimodality treatment with a combination of surgery, chemotherapy, and/or radiotherapy is the standard-of-care for advanced-stage patients but there are few surveillance or follow-up practice guidelines or formalized survivorship care pathways. A scoping literature review was conducted via PubMed, EMBASE, and Google Scholar. A total of 112 studies were included, which were grouped along the following topics: surveillance, second primary tumors, quality of life, and symptom burden. Sinonasal cancer tends to exhibit a higher rate of local failure and occur in a delayed fashion compared to mucosal malignancies of the head and neck. Moreover, the site of failure and time-varying risk of recurrence is histology-specific. Following multimodality treatment of the skull base, patients may experience endocrine, visual, auditory, sinonasal, olfactory, and neurocognitive deficits, as well as psychosocial impairments that impact multiple physical and neuropsychological domains, resulting in diminished quality of life. Sinonasal cancer patients would benefit from tailored, histology-specific survivorship programs to address the recurrence, second primary, and functional impairments resulting from disease and treatment toxicity.

A Study of Management of Adverse Reaction to Iodinated Contrast Media used in Computed Tomography at UCMS-TH

INTRODUCTION: Iodinated contrast media is used in computed tomography imaging to enhance the visibility of blood vessels and tissues. They have distinct clinical effectiveness and toxicity profiles. Although low osmolar contrast media have made iodinated contrast media safer in recent years, adverse reactions can sometimes occur. The management of adverse reactions to iodinated contrast media is an important aspect of patient care during computed tomography examinations. The purpose of this study was to evaluate the management of adverse reactions to iodinated contrast media during contrast-enhanced computed tomography examinations at Universal College of Medical Sciences and Teaching Hospital, Bhairahawa, Nepal. MATERIALS AND METHODS: A prospective, observational study was conducted on 323 patients at Department of Radiodiagnosis and Medical Imaging, Universal College of Medical Sciences and Teaching Hospital, Bhairahawa, Nepal, from December 15, 2022 to May 15, 2023. All data was obtained from the Department of Radiodiagnosis and Medical Imaging, as per the study inclusion criteria. The data were analyzed with statistical package for the social sciences version 20. RESULTS: The mean age of study participants was 48.49±19.78 years. There were 34.67% male and 65.33% female patients involved in this study. Universal College of Medical Sciences and Teaching Hospital favoured a more strict approach, to determine the normal renal function and withhold metformin before iodinated contrast media exposure. 36.84% of patients had a history of previous adverse reactions, before undergoing contrast-enhanced computed tomography scans. Following iodinated contrast media administration, 94.74% experienced nausea and vomiting which was followed by mild urticarial (88.54%) and dyspnea (19.81%). Premedication protocol was predominantly implemented with antihistamine, pheniramine (73.1%), and corticosteroid, hydrocortisone (26.9%). Mild urticaria was treated with pheniramine (87.1%), nausea and vomiting was treated with metoclopramide (83.01%), dyspnea was treated by epinephrine, hydrocortisone and oxygen (9.38%). CONCLUSIONS: Universal College of Medical Sciences and Teaching Hospital has established a standard protocol for the management of adverse reactions experienced by patients during iodinated contrast media administration. Premedication with antihistamines and corticosteroids was recommended for highrisk patients.

Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.

Effect of the killing style of individual CAR T cells on the clinicopathological behavior of therapeutic products in the clinic.

2548 Background: CAR T cell products that signal through CD28 and 41BB are highly effective against B lineage leukemia, despite exhibiting distinct efficacy and toxicity profiles in patients. Specifically, CD28 has been linked to higher upfront lytic activity and toxicity, while 41BB induces longer CAR T cell persistence and more durable progression free survival. We reasoned that the killing style of individual CAR T cells can explain the clinicopathological behavior of CAR T cell products in the clinic. Methods: We studied the cellular kinetics of CD28 and 41BB signaling CD19 CAR T cell products approved in the clinic, their single cell killing behavior in high throughput, the molecular composition of the lipid rafts inside the CAR immune synapse (CARIS) they form with their target cells, and their CARIS mechanical properties, then corroborated these findings in one kinetic model to explain their distinct clinicopathological behavior in the clinic. Results: We discovered that tumor encounter polarizes CD28 CAR T cell products to a predominance of more differentiated CD8 effectors that rely on short-lived highly lethal synapses with tumor cells. CD28 CAR T cell mediated synapses are characterized by fast mechanical buildup and resolution and brisk shuttling of CAR and other associated molecules into the CARIS and rapid polarization of the killing machinery in a manner that supports a mastery of serial killing mediated by perforin and granzymes. In contrast, 41BB responds to tumor stimulation by a Th2 -polarizing cytokine milieu that robustly expands a balanced CD4/CD8 population of effectors preserving a central memory phenotype. 41BB CAR T cells engage in lengthier synapses characterized by slower accumulation of CAR molecules in a mechanically tonic CARIS and rather collaborative yet lengthy Fas ligand-mediated killing process. Conclusions: We show here that CAR T cell signaling domains mediate distinct killing dynamics that can explain their behavior in patients. By understanding and potentially modulating these dynamics, the CAR T cell functionality and toxicity can be rationally optimized.

Assessment of Retinal Pigment Epithelium Alterations and Chorioretinal Vascular Network Analyses in Patients under Treatment with BRAF/MEK Inhibitor for Different Malignancies: A Pilot Study.

In the last two decades, an increasing number of so-called molecular-targeted therapies have become available for the treatment of patients with advanced malignancies. These drugs have included inhibitors of proteins in the MAPK pathway, such as BRAF and MEK inhibitors, which are characterized by a distinct toxicity profile. The eye is particularly susceptible to adverse effects due to MEK inhibitors, and the term MEKAR (MEK-inhibitor-associated retinopathy) indicates the presence of subretinal fluid, mimicking central serous chorioretinopathy (CSC). The pathogenesis of the retinal alterations related to MAPK pathway inhibitors is still unclear, and questions are still open. The present study aims to assess the presence of retinal pigment epithelium alterations as predictive parameters for retinal toxicity, analyzing, at the same time, the chorioretinal vascular network in patients undergoing BRAF/MEK inhibitor treatment for different malignancies.

Quantitative super-resolution imaging of pathological aggregates reveals distinct toxicity profiles in different synucleinopathies

Protein aggregation is a hallmark of major neurodegenerative disorders. Increasing data suggest that smaller aggregates cause higher toxic response than filamentous aggregates (fibrils). However, the size of small aggregates has challenged their detection within biologically relevant environments. Here, we report approaches to quantitatively super-resolve aggregates in live cells and ex vivo brain tissues. We show that Amytracker 630 (AT630), a commercial aggregate-activated fluorophore, has outstanding photophysical properties that enable super-resolution imaging of α-synuclein, tau, and amyloid-β aggregates, achieving ∼4 nm precision. Applying AT630 to AppNL-G-F mouse brain tissues or aggregates extracted from a Parkinson's disease donor, we demonstrate excellent agreement with antibodies specific for amyloid-β or α-synuclein, respectively, confirming the specificity of AT630. Subsequently, we use AT630 to reveal a linear relationship between α-synuclein aggregate size and cellular toxicity and discovered that aggregates smaller than 450 ± 60 nm (aggregate450nm) readily penetrated the plasma membrane. We determine aggregate450nm concentrations in six Parkinson's disease and dementia with Lewy bodies donor samples and show that aggregates in different synucleinopathies demonstrate distinct potency in toxicity. We further show that cell-penetrating aggregates are surrounded by proteasomes, which assemble into foci to gradually process aggregates. Our results suggest that the plasma membrane effectively filters out fibrils but is vulnerable to penetration by aggregates of 450 ± 60 nm. Together, our findings present an exciting strategy to determine specificity of aggregate toxicity within heterogeneous samples. Our approach to quantitatively measure these toxic aggregates in biological environments opens possibilities to molecular examinations of disease mechanisms under physiological conditions.

545P The synergistic effect of treosulfan and irinotecan in the treatment of platinum-resistant ovarian cancer

Until now, patients with platinum-resistant ovarian cancer have a poor prognosis with limited response to second-line single agent chemotherapy. Reported response rates are poor and encompasses 13-20%. Insufficient treatment efficacy reflects short survival. There is a need to investigate new combined chemotherapy regimens. The mechanism of action and the distinct toxicity profile of each agent are relevant variables in new regimen design . The appropriate pharmacological and toxicological properties of irinotecan and treosulfan allow us to evaluate the efficiency and safety of their combination.

Comparison of CD3e Antibody and CD3e-sZAP Immunotoxin Treatment in Mice Identifies sZAP as the Main Driver of Vascular Leakage.

Anti-CD3-epsilon (CD3e) monoclonal antibodies (mAbs) and CD3e immunotoxins (ITs) are promising targeted therapy options for various T-cell disorders. Despite significant advances in mAb and IT engineering, vascular leakage syndrome (VLS) remains a major dose-limiting toxicity for ITs and has been poorly characterized for recent “engineered” mAbs. This study undertakes a direct comparison of non-mitogenic CD3e-mAb (145-2C11 with Fc-silentTM murine IgG1: S-CD3e-mAb) and a new murine-version CD3e-IT (saporin–streptavidin (sZAP) conjugated with S-CD3e-mAb: S-CD3e-IT) and identifies their distinct toxicity profiles in mice. As expected, the two agents showed different modes of action on T cells, with S-CD3e-mAb inducing nearly complete modulation of CD3e on the cell surface, while S-CD3e-IT depleted the cells. S-CD3e-IT significantly increased the infiltration of polymorphonuclear leukocytes (PMNs) into the tissue parenchyma of the spleen and lungs, a sign of increased vascular permeability. By contrast, S-CD3e-mAbs-treated mice showed no notable signs of vascular leakage. Treatment with control ITs (sZAP conjugated with Fc-silent isotype antibodies) induced significant vascular leakage without causing T-cell deaths. These results demonstrate that the toxin portion of S-CD3e-IT, not the CD3e-binding portion (S-CD3e-mAb), is the main driver of vascular leakage, thus clarifying the molecular target for improving safety profiles in CD3e-IT therapy.

Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (−)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects.

Approaches to First-Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

Four immuno-oncology (IO)-based combinations have demonstrated overall survival benefit as frontline treatment of metastatic clear cell renal cell carcinoma (mccRCC). Choosing among the available combinations depends on treating physician's interpretation of existing data without level I evidence to inform choice of therapy. Landmark trials of mccRCC are reviewed and perspective on treatment options is provided. The four IO-based combinations reviewed are ipilimumab/nivolumab (IO/IO), pembrolizumab/axitinib (IO/TKI), nivolumab/cabozantinib (IO/TKI), and pembrolizumab/lenvatinib (IO/TKI). The ipilimumab/nivolumab combination is notable for durable efficacy after extended 4-year follow-up. IO/TKI combinations have clinical efficacy across all IMDC risk groups with higher response rates and longer progression-free survival (PFS) but also had higher ≥ grade 3 adverse events rate. Patient tumor burden, performance status, and IMDC risk group are factors in choosing an IO-based treatment. IO/IO and IO/TKI combinations for mccRCC have distinct efficacy and toxicity profiles. Future studies are needed to identify biomarkers to optimize patient outcomes.

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is characterized by the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory B-cell malignancies. Patients with grade ≥2 CRS presented with a significantly higher median body mass index (BMI), waist circumference, waist-to-height ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with grade 0-1 CRS versus grade ≥2 CRS. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥2 CRS. Receiver operating characteristic analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.

Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

BackgroundCytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children.MethodsWe conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet.ResultsAmong 969 children, the median (interquartile range) age was 6.5 (3.1–11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (odds ratio [OR], 0.95; 95% CI, 0.92–0.98), male sex (OR, 0.71; 95% CI, 0.51–0.99), non-Black, non-White race (OR, 0.56; 95% CI, 0.36–0.87), umbilical cord blood donor source (OR, 0.28; 95% CI, 0.08–0.97), and CMV seropositivity (R-/D+: OR, 0.17; 95% CI, 0.07–0.41; R+/D-: OR, 0.14; 95% CI, 0.09–0.21; R+/D+: OR, 0.08; 95% CI, 0.04–0.15) were associated with lower odds of 100-day CMV-free survival. Compared with foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (incidence rate ratio [IRR], 0.38; 95% CI, 0.15–0.97), electrolyte AEs (IRR, 0.42; 95% CI, 0.24–0.75), endocrine AEs (IRR, 0.52; 95% CI, 0.34–0.79), and renal AEs (IRR, 0.36; 95% CI, 0.19–0.65).ConclusionsCMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.