FIGURE 2 - uploaded by Anoshia Afzal
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(A) Trichrome highlights perivascular and interstitial fibrosis and areas of myocyte necrosis in right ventricle. Note the purple cells highlighting single cell necrosis in an area of inflammation. (B) CD117-positive cells were frequently observed that highlight scattered mononuclear/mast cells. (C) CD3-positive T-cells are seen scattered throughout the myocardium; however, no clusters of T cells are present. (D) Alcian blue highlights scattered mononuclear/mast cells CD, cluster of differentiation
Source publication
Chimeric antigen receptor (CAR) T-cell therapy is expanding to a wider patient population; however, cytokine release syndrome (CRS) is the most important adverse event of these therapies. Patients suffering from high-grade CRS also develop signs of cardiac dysfunction and
frequently manifest vascular leakage with peripheral and pulmonary edema. We...
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Citations
... Additionally, current literature report potentially severe GI-related AEs in 28% of patients treated with CAR-T cell therapy [16]. Adverse cardiovascular and pulmonary events (such as tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, venous thromboembolism, and myocarditis) have also been reported, and have been fatal [17,18]. These complications have long been believed to be mainly cytokine mediated. ...
As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells—such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells—in patients’ tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20μL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue.
... Severe cardiovascular events, defined as a composite of heart failure, cardiogenic shock and myocardial infarction, are associated with a nearly fourfold higher non-relapse mortality and nearly threefold higher overall mortality [25••]. There have also been case reports of myocarditis following CAR-T infusion, with myocardial histology demonstrating lymphocytic infiltration, although the rate of such cardiac inflammation is less common than observed with other immunotherapy such as immune checkpoint inhibitors [32][33][34]. And, there have also been case reporting of CAR-T associated vasospasm although whether such a presentation is driven by an anaphylaxis reaction rather than direct toxicity is not well understood [35]. ...
... This inflammatory milieu is further associated with endothelial cell dysfunction and resultant fluid shifts, with markers of endothelial dysfunction portending worse survival, and likely also contributory to exacerbating cardiac dysfunction [39]. And, given the elevated rates of myocardial involvement of leukemias and lymphomas, it is possible that some case reports of myocarditis following CAR-T infusion are related to on-target, on-tumor effects of CAR-T seeking out tumor cells in myocardium [32][33][34]. On-target, off-tumor effects encompass the theoretical risk of a direct CAR-T attack on normal tissue expressing a shared epitope with the malignancy, although current FDA approved CAR-T constructs were developed with the goal to avoid such cross targeting in healthy versus cancer tissue. Finally, off-tumor, off-target effects may also play a role in the development of cardiovascular complications. ...
Purpose of Review
Chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BiTE) are novel therapies used to treat hematologic malignancies, lung cancer and melanoma. With the increasing use of these novel therapies, the incidence and prognosis of their cardiovascular side effects needs to be further elucidated.
Recent Findings
Randomized trials have highlighted the systemic effects of CAR-T and BiTE therapy including cytokine release syndrome (CRS) and resultant hypotension and respiratory failure. Cohort studies have elucidated the cardiovascular effects associated with CAR-T and BiTE therapy including heart failure, cardiomyopathy, arrythmia, myocardial infarction, stroke and cardiovascular death.
Summary
Cardiovascular events after CAR-T and BiTE therapy can occur and are often associated with CRS. CAR-T recipients experiencing severe cardiovascular events may have worse survival. Further prospective studies are needed to understand the full scope of cardiovascular effects and mitigation strategies for these therapies.
Background: CAR-T-related deaths observed worldwide are rare. The underlying
pathogenetic mechanisms are the subject of study, as are the findings that
enable diagnosis. A systematic literature search of the PubMed database and a
critical review of the collected studies were conducted from the inception of this
database until January 2023. The aim of the study is to determine when death is
related to CAR-T cell therapy and to develop a shareable diagnostic algorithm.
Methods: The database was searched by combining and meshing the terms
(“CAR-t” OR “CART”) AND (“Pathology” OR “Histology” OR “Histological” OR
“Autopsy”) AND (“Heart” OR “Cardiac” OR “Nervous System” OR “Kidney” OR
“Liver”) with 34 results and also the terms: [(Lethal effect) OR (Death)] AND
(CAR-T therapy) with 52 results in titles, abstracts, and keywords [all fields]. One
hundred scientific articles were examined, 14 of which were additional records
identified through other sources. Fifteen records were included in the review.
Results: Neuronal death, neuronal edema, perivascular edema, perivascular
and intraparenchymal hemorrhagic extravasation, as well as perivascular
plasmatodendrosis, have been observed in cases with fatal cerebral edema.
A cross-reactivity of CAR-T cells in cases of fatal encephalopathy can
be hypothesized when, in addition to the increased vascular permeability, there
is also a perivascular lymphocyte infiltrate, which appears to be a common
factor among most authors.
Conclusion: Most CAR-T-related deaths are associated with blood–brain barrier
breakdown, central nervous system cell damage, and infiltrated T cells. Further
autopsies and microscopic investigations would shed more light on the lethal
toxicity related to CAR-T cells. A differential diagnosis of CAR-T-related death
is crucial to identifying adverse events. In this article, we propose an algorithm
that could facilitate the comparison of findings through a systematic approach.
Despite toxicity cases, CAR-T therapy continues to stand out as the most
innovative treatment within the field of oncology, and emerging strategies hold
the promise of delivering safer therapies in future.
Although the frequency of myocarditis in the general population is very difficult to accurately determine due to the large number of asymptomatic cases, the incidence of this disease is increasing significantly due to better defined criteria for diagnosis and the development of modern diagnostic methods. The multitude of different etiological factors, the diversity of the clinical picture, and the variability of the diagnostic findings make this disease often demanding both for the selection of the diagnostic modality and for the proper therapeutic approach. The previously known most common viral etiology of this disease is today overshadowed by new findings based on immune-mediated processes, associated with diseases that in their natural course can lead to myocardial involvement, as well as the iatrogenic cause of myocarditis, which is due to use of immune checkpoint inhibitors in the treatment of cancer patients. Suspecting that a patient with polymorphic and non-specific clinical signs and symptoms, such as changes in ECG and echocardiography readings, has myocarditis is the starting point in the diagnostic algorithm. Cardio magnetic resonance imaging is non-invasive and is the gold standard for diagnosis and clinical follow-up of these patients. Endomyocardial biopsy as an invasive method is the diagnostic choice in life-threatening cases with suspicion of fulminant myocarditis where the diagnosis has not yet established or there is no adequate response to the applied therapeutic regimen. The treatment of myocarditis is increasingly demanding and includes conservative methods of treating heart failure, immunomodulatory and immunospressive therapy, methods of mechanical circulatory support, and heart transplantation. The goal of developing new diagnostic and therapeutic methods is to reduce mortality from this complex disease, which is still high.
