Uncoupling Therapeutic Efficacy from Immune-Related Adverse Events in Immune Checkpoint Blockade

Hu, Wenquan; Wang, Guosheng; Wang, Yian; Riese, Matthew J.; You, Ming

doi:10.1016/j.isci.2020.101580

Cited by 26 publications

(21 citation statements)

References 228 publications

(256 reference statements)

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“… 11 The correlation between ICI-induced irAEs and clinical response has not been fully explored. 12 Efficacy relating to irAEs reveals a complex picture, as in this patient, disease progression was accompanied by discontinuation of ICI-combination therapy.…”

Section: Discussionmentioning

confidence: 82%

Immunotherapy-Related Cystitis: Case Report and Review of the Literature

Zhu¹,

Wang²,

Stebbing³

et al. 2021

OTT

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Immune checkpoint inhibitors (ICIs) including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and anti-programmed death cell protein 1 (anti-PD1) have extended patient survival benefit and revolutionized cancer treatment. As ICIs rely on immune regeneration to eliminate tumor cells, they can also lead to an imbalance of immune reactions often called immune-related adverse events (irAEs). Rare irAEs such as ocular or cardiac toxicity or vasculitis are seen in less than 1% of patients receiving ICIs. Immune-related cystitis remains a rare occurrence. Herein, we describe a patient with extensive-stage small cell lung cancer (SCLC) and a history of syphilis with a complete response to second-line treatment using nivolumab plus paclitaxel who complained of urinary irritation symptoms. At biopsy, we found infiltration of CD3 + and CD8 + lymphocytes in the urothelium. Although there are reports describing immune-related cystitis in cancer patients, our case has comprehensive pathological confirmation and a differentiation diagnosis. In this report, we review other cases to elucidate clinical characteristics and discuss suitable management of this rare irAE.

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Section: Discussionmentioning

confidence: 82%

Immunotherapy-Related Cystitis: Case Report and Review of the Literature

Zhu¹,

Wang²,

Stebbing³

et al. 2021

OTT

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“…Self-reactive T-lymphocytes due to the loss of T-cell tolerance are considered key players of most irAEs, acting either directly or indirectly via stimulating the production of autoantibodies by B-lymphocytes [ 16 ].…”

Section: The Biological Background Of Ir Thyroid Disordersmentioning

confidence: 99%

“…Strategies to separate antitumor immunity from immunotoxicity are currently under evaluation—namely, the development of bispecific or antibody-based alternative structures binding two distinct immunomodulatory targets and the administration of ICPi directly within the tumor microenvironment [ 16 ].…”

Section: Current Challenges and Future Perspectivesmentioning

confidence: 99%

The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries

Deligiorgi

Sagredou

Vakkas

et al. 2021

Cancers

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Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.

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“…101 As these monoclonal antibodies with dual specificity can be retained in the tumour microenvironment, sparing the normal tissues, they promote antitumour effects without causing irAEs. 102 Another way to uncouple the antitumour activity from irAEs is by selective depletion of regulatory T cells in the tumour microenvironment with the help of pH-sensitive anti-CTLA-4 antibodies that do not result in CTLA-4 depletion in normal tissues. 103 A third approach under investigation for uncoupling irAEs from the antitumour effects is known as Probody ® therapeutics (CytomX Therapeutics, South San Francisco, CA, USA), which is characterized by the development of recombinant, proteolytically activated antibody prodrugs that will become active only when they get exposed to tumour-associated proteases in the tumour microenvironment.…”

Section: Areas Of Uncertaintymentioning

confidence: 99%