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The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

The introduction of chimeric antigen receptor T (CAR-T) cell and bispecific antibody (BsAb) therapies has revolutionized multiple myeloma (MM) treatment, offering exceptional efficacy, and culminating in recent regulatory approval. However, these therapies have brought unique toxicity challenges, manifesting not only with the well-established cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but also with the emergence of other common and equally distinctive toxicities, including cytopenias, hypogammaglobulinemia, infections, and the rare but life-threatening immune effector cell-like lymphohistiocytosis syndrome (IEC-HS). These adverse events are characterized by unique mechanisms of action that differ from those of previous treatments for MM, thereby requiring specialized knowledge to optimize day-to-day management and ultimately maximize therapeutic benefits while ensuring patient safety. Additionally, the toxicity profiles of these T-cell engager therapies are becoming increasingly important in treatment decisions, with implications for patient selection and therapy sequencing. In this review, we provide a comprehensive overview of the current state-of-the-art regarding the incidence, etiopathogenetic mechanisms, and clinical manifestations of these increasingly less non-prototypical but still lesser-known side effects than CRS and ICANS, in order to offer clear and actionable insights into their effective management, while emphasizing critical points for future improvement, in view of the increasing number of MM patients who will benefit from the newly approved and upcoming immunotherapies.

We describe the case of a 74‐year‐old female diagnosed with extensive‐stage small cell lung cancer. Initially, she received carboplatin, etoposide and atezolizumab, followed by amrubicin as second‐line treatment and nogitecan as third‐line treatment. Stereotactic radiotherapy was delivered to subsequent brain metastases. Two years after the initial treatment, new brain and lung metastases developed. Whole‐brain radiotherapy was administered, followed by tarlatamab (1 mg on Day 1, 10 mg on Days 8 and 20). After the third dose of tarlatamab, the patient developed disorientation. Brain magnetic resonance imaging revealed shrinkage of the metastatic lesions, rapid cerebral atrophy, ventricular enlargement and periventricular hyperintensity on fluid‐attenuated inversion recovery imaging. Dexamethasone was initiated without neurological improvement. The early‐onset cerebral atrophy and leukoencephalopathy in the current case was attributed to whole brain radiotherapy and tarlatamab. Patients with brain metastases may be at increased risk of neurological events associated with tarlatamab. We reported a case of rapid brain atrophy and leukoencephalopathy development after treatment with tarlatamab. Patients with brain metastases, regardless of treatment history, may be at increased risk of neurological events. Close monitoring and prompt management of adverse neurological events are warranted in such cases.

Background Mantle cell lymphoma is a diverse B-cell lymphoma with varying clinical behaviors. Treating relapsed or refractory mantle cell lymphoma is challenging, with Bruton’s tyrosine kinase inhibitors proving effective but not curative. Post-Bruton’s tyrosine kinase inhibitor failure, the prognosis remains unfavorable. Brexucabtagene autoleucel, a US Food and Drug and European Medicines Agency-approved anti-CD19 chimeric antigen receptor T-cell therapy, marks a significant breakthrough offering hope in this challenging scenario. Case presentation This article presents an analysis of the management of short-term chimeric antigen receptor T-cell therapy-associated toxicities, focusing on a specific case of a patient with refractory mantle cell lymphoma. The report underscores the complexities of chimeric antigen receptor T-cell treatment and sheds light on strategies employed to mitigate toxic effects. The case involves a white Caucasian 59-year-old male affected by relapsed mantle cell lymphoma who underwent various treatments, including autologous anti-CD19 chimeric antigen receptor T-cell therapy (brexucabtagene autoleucel). The patient experienced immune effector cell-associated hematotoxicity along with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, necessitating intervention. The management involved a combination of tocilizumab, corticosteroids, and anakinra, which effectively alleviated symptoms. Additionally, the article highlights the patient’s case of intestinal perforation following CAR-T therapy. Although there is a correlation between gastrointestinal perforation and interleukin 6 receptor inhibitors, the adverse event was attributed to the patient’s preexisting diverticulitis and the immunosuppressive drugs administered leading to cytomegalovirus reactivation. The study emphasizes the evolving landscape of chimeric antigen receptor T-cell therapy and the significance of addressing toxicities associated with this innovative treatment approach. It underscores the value of anakinra as a potential corticosteroid-sparing therapy for immune effector cell-associated neurotoxicity syndrome and raises the need for further research to optimize the management of immune effector cell-associated hematotoxicity and associated complications. The potential preventive use of drugs to mitigate toxicities also warrants exploration, albeit with the current dearth of evidence. Conclusions In conclusion, this article offers valuable insights into the challenges of managing chimeric antigen receptor T-cell-related toxicities through a detailed case presentation and highlights the significance of adopting multidisciplinary approaches to enhance patient outcomes and safety. Further research is needed to refine strategies and advance the understanding of these complex treatment-associated toxicities.

Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hema-tologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been pub-lished. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

This study advances current knowledge in the field of host-microbe interactions by demonstrating that the two families of immune effectors, antimicrobial peptides and lysozymes, actively regulate the gut microbiota composition and abundance. Consequences of the loss of these antimicrobial peptides and lysozymes are exacerbated during aging, and their loss contributes to increased microbiota abundance and shifted composition in old flies. The gut microbiota affects the physiology and metabolism of animals and its alteration can lead to diseases such as gut dysplasia or metabolic disorders. Several reports have shown that the immune system plays an important role in shaping both bacterial community composition and abundance in Drosophila , and that immune deficit, especially during aging, negatively affects microbiota richness and diversity. However, there has been little study at the effector level to demonstrate how immune pathways regulate the microbiota. A key set of Drosophila immune effectors are the antimicrobial peptides (AMPs), which confer defense upon systemic infection. AMPs and lysozymes, a group of digestive enzymes with antimicrobial properties, are expressed in the gut and are good candidates for microbiota regulation. Here, we take advantage of the model organism Drosophila melanogaster to investigate the role of AMPs and lysozymes in regulation of gut microbiota structure and diversity. Using flies lacking AMPs and newly generated lysozyme mutants, we colonized gnotobiotic flies with a defined set of commensal bacteria and analyzed changes in microbiota composition and abundance in vertical transmission and aging contexts through 16S rRNA gene amplicon sequencing. Our study shows that AMPs and, to a lesser extent, lysozymes are necessary to regulate the total and relative abundance of bacteria in the gut microbiota. We also decouple the direct function of AMPs from the immune deficiency (IMD) signaling pathway that regulates AMPs but also many other processes, more narrowly defining the role of these effectors in the microbial dysbiosis observed in IMD-deficient flies upon aging. IMPORTANCE This study advances current knowledge in the field of host-microbe interactions by demonstrating that the two families of immune effectors, antimicrobial peptides and lysozymes, actively regulate the gut microbiota composition and abundance. Consequences of the loss of these antimicrobial peptides and lysozymes are exacerbated during aging, and their loss contributes to increased microbiota abundance and shifted composition in old flies. This work shows that immune effectors, typically associated with resistance to pathogenic infections, also help shape the beneficial gut community, consistent with the idea that host-symbiont interactions use the same “language” typically associated with pathogenesis.

Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8 + T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.

Metastatic behavior varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between nonmetastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFNγ-producing immune effector monocytes to the lung. IFNγ up-regulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and neutrophils.

Significance We demonstrated codetection of 42 immune effector proteins in single cells, representing the highest multiplexing recorded to date for a single-cell secretion assay. Using this platform to profile differentiated macrophages stimulated with lipopolysaccharide reveals previously unobserved deep functional heterogeneity and varying levels of pathogenic activation, which is conserved throughout the cell activation process and prevails as it is extended to other Toll-like receptor (TLR) ligands and to primary human macrophages. The results indicate that the phenotypically similar cell population could still exhibit a large degree of intrinsic heterogeneity at the cell function level. This technology enables full-spectrum dissection of immune functional states in response to pathogenic stimulation and allows for more comprehensive and accurate monitoring of cellular immunity. Despite recent advances in single-cell genomic, transcriptional, and mass-cytometric profiling, it remains a challenge to collect highly multiplexed measurements of secreted proteins from single cells for comprehensive analysis of functional states. Herein, we combine spatial and spectral encoding with polydimethylsiloxane (PDMS) microchambers for codetection of 42 immune effector proteins secreted from single cells, representing the highest multiplexing recorded to date for a single-cell secretion assay. Using this platform to profile differentiated macrophages stimulated with lipopolysaccharide (LPS), the ligand of Toll-like receptor 4 (TLR4), reveals previously unobserved deep functional heterogeneity and varying levels of pathogenic activation. Uniquely protein profiling on the same single cells before and after LPS stimulation identified a role for macrophage inhibitory factor (MIF) to potentiate the activation of LPS-induced cytokine production. Advanced clustering analysis identified functional subsets including quiescent, polyfunctional fully activated, partially activated populations with different cytokine profiles. This population architecture is conserved throughout the cell activation process and prevails as it is extended to other TLR ligands and to primary macrophages derived from a healthy donor. This work demonstrates that the phenotypically similar cell population still exhibits a large degree of intrinsic heterogeneity at the functional and cell behavior level. This technology enables full-spectrum dissection of immune functional states in response to pathogenic or environmental stimulation, and opens opportunities to quantify deep functional heterogeneity for more comprehensive and accurate immune monitoring.