Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?

Lemiale, Virginie; Meert, Anne-Pascale; Vincent, François; Darmon, Michaël; Bauer, Philippe P.R.; Louw, Andry Van de; Azoulay, Élie

doi:10.1186/s13613-019-0487-x

Cited by 56 publications

(32 citation statements)

References 98 publications

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“…Indeed, other complications may be easily ruled out with a simple diagnostic strategy relying on a close collaboration between oncologists and intensivists. Then immunosuppressive treatment including steroids should be quickly prescribed to reverse irAE [ 20 , 31 , 32 ] Systemic steroids are recommended for grade 3 and 4 immune-related adverse events [ 20 , 21 , 32 , 33 ]. For steroid-refractory irAEs, a personalized management based on the predominant immune infiltrate is advised [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

Joseph

Simonaggio

Stoclin

et al. 2020

Ann. Intensive Care

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Background Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019. Results Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004). Conclusions Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

Joseph

Simonaggio

Stoclin

et al. 2020

Ann. Intensive Care

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“…These challenges involve slow pharmacokinetics of mAbs, leading to immune-related adverse effects (iRAEs), as well as the high cost of therapy development. 49 This calls for low-cost, easily modifiable synthetic analogs with favorable pharmacokinetics properties, using alternative molecules to develop immunotherapeutic agents. In this regard, nucleic acid aptamers are promising alternative molecules.…”

Section: Discussionmentioning

confidence: 99%

A Homodimeric Aptamer Variant Generated from Ligand-Guided Selection Activates the T Cell Receptor Cluster of Differentiation 3 Complex

Freage

Jamal

Williams

et al. 2020

Molecular Therapy - Nucleic Acids

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Recently, immunotherapeutic modalities with engineered cells and monoclonal antibodies have been effective in treating several malignancies. Nucleic acid aptamers can serve as alternative molecules to design immunotherapeutic agents with high functional diversity. Here we report a synthetic prototype consisting of DNA aptamers that can activate the T cell receptor cluster of differentiation 3 (TCR-CD3) complex in cultured T cells. We show that the activation potential is similar to that of a monoclonal antibody (mAb) against TCR-CD3, suggesting potential for aptamers in developing efficacious synthetic immunomodulators. The synthetic prototype of anti-TCR-CD3ε, as described here, was designed using aptamer ZUCH-1 against TCR-CD3ε, generated by ligand-guided selection (LIGS). Aptamer ZUCH-1 was truncated and modified with nuclease-resistant RNA analogs to enhance stability. Several dimeric analogs with truncated and modified variants were designed with variable linker lengths to investigate the activation potential of each construct. Among them, a dimeric aptamer with dimensions approximately similar to those of an antibody showed the highest T cell activation, suggesting the importance of optimizing linker lengths in engineering functional aptamers. The observed activation potential of dimeric aptamers shows the vast potential of aptamers in designing synthetically versatile immunomodulators with tunable pharmacokinetic properties, expanding immunotherapeutic designs by using nucleic acid-based ligands such as aptamers.

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“…While all three strategies are successful in treating disease, particularly cancer, growing evidence suggests that immunotherapeutic approaches have their challenges. These challenges involve slow pharmacokinetics of mAbs, leading to immune-related-adverse-effects (iRAE), as well as the high cost of therapeutic development (49). This calls for low-cost, easily modifiable synthetic analogs with favorable pharmacokinetic properties, using alternative molecules to develop immunotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex

Freage

Jamal

Williamns

et al. 2020

Preprint

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Recently, immunotherapeutic modalities with engineered cells and monoclonal antibodies have been effective in treating several malignancies. However, growing evidence suggests that immune-related adverse events (irAE) lead to severe and long-term side effects. Most iRAEs involve prolonged circulation of antibodies. To address this problem, nucleic acid aptamers can serve as alternative molecules to design immunotherapeutics with high functional diversity and predictable circulation times. Here, we report the first synthetic prototype consisting of DNA aptamers, which can activate T-cell receptor cluster of differentiation 3 (TCR-CD3) complex in cultured T-cells. We show that activation potential is similar to that of a monoclonal antibody (mAb) against TCR-CD3, suggesting the potential of aptamers in developing efficacious synthetic immunomodulators. The synthetic prototype of anti-TCR-CD3ε, as described herein, was designed using aptamer ZUCH-1 against TCR-CD3ε, generated by Ligand Guided Selection (LIGS). Aptamer ZUCH-1 was truncated and modified with nuclease-resistant RNA analogs to enhance stability. Several dimeric analogs with truncated and modified variants were designed with variable linker lengths to investigate the activation potential of each construct. Among them, dimeric aptamer with approximate dimensions similar to those of an antibody showed the highest T-cell-activation, suggesting the importance of optimizing linker lengths in engineering functional aptamers. The observed activation potential of dimeric aptamers shows the vast potential of aptamers in designing synthetically versatile immunomodulators with tunable pharmacokinetic properties, expanding immunotherapeutic designs with the use of nucleic acidbased ligands such as aptamers. Evaluating the decrease in activation of TCR-CD3 in Jurkat E6.1 cells in the presence of the dimers (6S, 8S) and the absence of anti-CD28 antibodyCells were prepared by washing three times with 3 mL RPMI-1640 medium. 2 × 10 5 Jurkat E6.1 cells were incubated with OSJ-D-6S or OSJ-D-8S dimer in 150 µL cell suspension buffer in the absence of anti-CD28 antibody at 37°C with 5% CO 2 in a surface-modified polystyrene 96 well flat bottom plate. Cells were stained with 5 µL of 100 µg/mL CD69 mouse anti-human Cy5.5 antibody for 45 mins on ice then washed one time with 2 mL RPMI-1640 and reconstituted in 250 µL RPMI-1640 medium. The expression of activation marker CD69 was monitored in FL4 at each time points using flow cytometry by counting 5000 events. Evaluating the lack of activation of TCR-CD3 in Jurkat E6.1 cells using the random dimerCells were prepared by washing three times with 3 mL RPMI-1640 medium. 2 × 10 5 Jurkat E6.1 cells were incubated for 2, 4 and 6 hours with 0.15 nmole random dimer in 150 µL cell suspension buffer in the presence of 10 µL of 25 µg/mL unlabeled anti-CD28 at 37°C with 5% CO 2 in a surface-modified polystyrene 96 well flat bottom plate. Following incubation, cells were stained with 5 µL of 100 µg/mL CD69 mouse anti-human Cy5.5 antibody for...

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Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?

Cited by 56 publications

References 98 publications

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

A Homodimeric Aptamer Variant Generated from Ligand-Guided Selection Activates the T Cell Receptor Cluster of Differentiation 3 Complex

A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex

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