Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors – A systematic review and meta-analysis

Hussaini, S. M. Qasim; Chehade, Rania; Boldt, Gabriel; Raphael, Jacques; Blanchette, Phillip; Vareki, Saman Maleki; Fernandes, Ricardo

doi:10.1016/j.ctrv.2020.102134

Cited by 259 publications

(229 citation statements)

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“…Despite their clinical efficacy, ICIs can induce various immune-related AEs (irAEs), limiting their use in many patients [1,27,206,207]. ICIs may affect peripheral tolerance to autoantigens, resulting in autoantibody formation, which could be associated with irAEs in various organs [207]. Antigen sharing or cross reactivity leads to a T-cell-mediated response not only to tumor cells, but also to healthy cells [208].…”

Section: Future Perspectivementioning

confidence: 99%

“…Antigen sharing or cross reactivity leads to a T-cell-mediated response not only to tumor cells, but also to healthy cells [208]. ICIs can also release T-cells with subsequent production of proinflammatory cytokines such as interferon-γ and tumor necrosis factor, which may result in excessive off-tumor inflammation and autoimmunity [207]. Inflammatory responses are often associated with swelling, which would harm the delicate structures of the CNS and ultimately lead to brain damage [27].…”

Section: Future Perspectivementioning

confidence: 99%

“…Inflammatory responses are often associated with swelling, which would harm the delicate structures of the CNS and ultimately lead to brain damage [27]. Most irAEs tend to be mild and self-limiting; however, potentially life-threatening events can occur in a few severe cases (grade 3 or 4) [207,209]. Neurologic toxicities from ICIs, with an incidence of 1%-2%, include CNS paraneoplastic syndromes, encephalitis, multiple sclerosis, and hypophysitis [1].…”

Section: Future Perspectivementioning

confidence: 99%

“…Neurologic toxicities from ICIs, with an incidence of 1%-2%, include CNS paraneoplastic syndromes, encephalitis, multiple sclerosis, and hypophysitis [1]. Close follow-up and low thresholds for investigative work-ups are essential in ensuring that patients developing irAEs are promptly treated, such that any treatment interruption can be resumed in a timely manner [207,210]. Other known immunotherapy-related adverse events associated with ICIs include dermatitis (all-grade incidence of 17%), endocrinopathies (10%), colitis (2%), hepatitis (3%), and pneumonitis (3%) [1].…”

Section: Future Perspectivementioning

confidence: 99%

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Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

Lee

2021

IJMS

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Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

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Section: Future Perspectivementioning

confidence: 99%

Section: Future Perspectivementioning

confidence: 99%

Section: Future Perspectivementioning

confidence: 99%

Section: Future Perspectivementioning

confidence: 99%

See 2 more Smart Citations

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

Lee

2021

IJMS

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“…Instead, the authors of this study suggested that ipilimumab causes local Treg depletion within the tumor environment through antibody-dependent cellular cytotoxicity (ADCC) and highlighted the critical role of FCR ( 47 ). Notably, two-thirds of cancer patients treated with ipilimumab experience side effects that are characteristic symptoms experienced by CTLA-4-insufficient patients, including colitis ( 48 , 49 ).…”

Section: Introductionmentioning

confidence: 99%

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Gámez-Díaz

Seidel

2021

Front. Pediatr.

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and—most recently reported—DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

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Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy

et al. 2022

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ImportanceImmune-related adverse events (irAEs) due to immune checkpoint blockade (ICB) have been shown to be positively associated with survival. Among patients with metastatic melanoma, evidence supporting this association has been conflicting, while ipilimumab-nivolumab combination ICB has been examined only in small clinical cohorts.ObjectiveTo examine the association between irAEs and survival among patients with metastatic melanoma, in particular for those receiving combination ICB.Design, Setting, and ParticipantsA retrospective cohort of 492 consecutive patients with metastatic melanoma treated with ICB at 2 tertiary and 4 regional cancer centers in Alberta, Canada, from August 1, 2013, to May 31, 2020, was observed. Patients were aged 18 years or older with metastatic melanoma agnostic to primary site, who received 1 or more doses of an anti–programmed cell death protein 1 agent as single or combination ICB. Clinically significant irAEs requiring systemic corticosteroids and/or treatment delay were captured. To minimize immortal time bias, only patients surviving 12 weeks after ICB initiation were included in survival analyses. Statistical analysis was conducted on December 10, 2021.ExposuresDevelopment of irAEs requiring systemic corticosteroids and/or treatment delay.Main Outcomes and MeasuresThe primary outcome was overall survival (OS), with the association of irAE development with OS assessed via Kaplan-Meier and Cox proportional hazards regression analyses. The association of hospitalization for irAEs and ICB resumption after irAE with OS was examined.ResultsAmong 492 patients, the median age of those with irAEs was 61.8 years (IQR, 52.9-72.1 years), and the median age of those without irAEs was 65.5 years (IQR, 56.5-76.9 years), while sex distribution was comparable (137 of 198 men [69.2%] with irAEs vs 183 of 294 men [62.2%] without irAEs). There was an association between irAEs and OS both in the overall cohort (with irAEs: median OS, 56.3 months [95% CI, 38.2 months to not evaluable] vs without irAEs: median OS, 18.5 months [95% CI, 14.4-23.2 months]; P &lt; .001) and in the 124 patients (25.2%) receiving combination ICB (with irAEs: median OS, 56.2 months [95% CI, 52.2 months to not evaluable] vs without irAEs: median OS, 19.0 months [95% CI, 6.6 months to not evaluable]; P &lt; .001). Hospitalization for irAE did not alter this positive association with OS compared with outpatient treatment (median OS, not evaluable [95% CI, 31.5 months to not evaluable] vs median OS, 52.2 months [95% CI, 35.2 months to not evaluable]; P = .53), while resumption of ICB was associated with longer OS than not resuming ICB (median, 56.3 months [95% CI, 40.8 months to not evaluable] vs 31.5 months [95% CI, 21.0 months to not evaluable]; P = .009). A favorable independent association of irAEs with OS was confirmed in multivariable analysis (hazard ratio for death, 0.382 [95% CI, 0.254-0.576]; P &lt; .001).Conclusions and RelevanceThis study suggests an association between irAEs and OS for patients with metastatic melanoma, including those treated with combination ICB and those with severe irAEs requiring hospitalization. The potential benefit associated with ICB resumption after irAEs warrants further investigation.

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Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors – A systematic review and meta-analysis

Cited by 259 publications

References 55 publications

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy

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