New perspectives in cancer immunotherapy: targeting IL-6 cytokine family

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(11), P. e007530 - e007530

Published: Nov. 1, 2023

Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) they represent main communication bridge between cells, stroma, and immune system. Interleukin (IL)-6 represents keystone cytokine in link cancer. Many cytokines from IL-6 family, includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic cardiotrophin 1, cardiotrophin-like factor have shown to elicit tumor-promoting roles modulating TME, making them attractive therapeutic targets for treatment. The development checkpoint blockade (ICB) immunotherapies radically changed outcome some cancers including melanoma, lung, renal, although not without hurdles. However, ICB shows limited efficacy other solid tumors. Recent reports support that chronic signaling involved resistance immunotherapy. This review summarizes available preclinical clinical data regarding implication IL-6-related regulating TME response ICB. Moreover, potential benefit combining with therapies targeting members treatment discussed.

Language: Английский

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Corticosteroids and Cancer Immunotherapy

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(14), P. 2580 - 2587

Published: Jan. 17, 2023

Abstract Despite revolutionizing cancer management, immunotherapies dysregulate the immune system, leading to immune-mediated adverse events. These common and potentially dangerous toxicities are often treated with corticosteroids, which among most prescribed drugs in oncology for a wide range of noncancer indications. While steroids exert several mechanisms reduce activity, immunotherapies, such as checkpoint inhibitors (ICI), designed enhance system's inherent antitumor activity. Because ICI requires an intact robust response, immunosuppressive properties have led widespread concern that they may interfere responses. However, existing data effect systemic on immunotherapy efficacy remain somewhat conflicted unclear. To inform clinical decision-making improve outcomes, we review impact immunity, recent advances knowledge their unique populations settings, associated precautions, steroid-sparing treatment approaches.

Language: Английский

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Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance

npj Precision Oncology, Journal Year: 2023, Volume and Issue: 7(1)

Published: May 12, 2023

Abstract Immune checkpoint inhibitors (ICIs) have changed perspectives for patients with cancer, but come severe immune-related adverse events (irAEs). To prevent fatality or chronicity, these irAEs are often promptly treated high-dose immunosuppressants. Until recently, evidence on the effects of irAE management ICI efficacy has been sparse. As a result, algorithms mostly expert-opinion based and barely consider possible detrimental immunosuppressants efficacy. However, recent growing suggests that vigorous immunosuppressive comes unfavourable survival. With expansion indications ICIs, evidence-based treatment without hampering tumour control becomes more important. In this review, we discuss novel from pre-clinical clinical studies different regimens including corticosteroids, TNF inhibition tocilizumab cancer We provide recommendations research, cohort trials can help clinicians in tailored management, minimising patients’ burden while maintaining

Language: Английский

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Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(6), P. e006814 - e006814

Published: June 1, 2023

Background Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness anti-interleukin-6 receptor (anti-IL-6R) therapy for irAEs. Methods We performed a retrospective multicenter study evaluating patients diagnosed de novo irAEs flare pre-existing autoimmune disease following ICI were treated anti-IL-6R. Our objectives to assess improvement well overall tumor response rate (ORR) before after anti-IL-6R treatment. Results identified total 92 who received therapeutic antibodies (tocilizumab sarilumab). Median age was 61 years, 63% men, 69% anti-programmed cell death protein-1 (PD-1) alone, 26% anti-cytotoxic T lymphocyte antigen-4 anti-PD-1 antibodies. Cancer types primarily melanoma (46%), genitourinary cancer (35%), lung (8%). Indications using included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), one patient each scleroderma, nephritis, colitis, pneumonitis central nervous system vasculitis. Notably, 88% had corticosteroids, 36% other disease-modifying antirheumatic drugs (DMARDs) first-line therapies, but without adequate improvement. After initiation (as post-corticosteroids DMARDs), 73% showed resolution change ≤grade 1 median 2.0 months from Six (7%) stopped due events. Of 70 evaluable by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; ORR 66% prior versus (95% CI, 54% 77%), 8% higher complete rate. 34 melanoma, 56% increased 68% (p=0.04). Conclusion Targeting IL-6R could be an effective approach treat several irAE hindering antitumor immunity. This supports ongoing clinical trials efficacy tocilizumab (anti-IL-6R antibody) ICIs ( NCT04940299 , NCT03999749 ).

Language: Английский

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Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1629 - 1629

Published: March 6, 2023

Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein-1 and its ligand PD-L1, they increasingly used cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With approval more ICIs, irAE prediction has become a key factor improving patient survival quality life. Several biomarkers have been described potential predictors, some them already available for clinical use others under development; examples include circulating blood counts ratios, expansion diversification, cytokines, autoantibodies autoantigens, serum other biological fluid proteins, human leucocyte antigen genotypes, genetic variations gene profiles, microRNAs, gastrointestinal microbiome. Nevertheless, it is difficult to generalize application based on current evidence because most studies retrospective, time-limited restricted specific type cancer, or ICI. Long-term prospective cohorts real-life needed assess predictive capacity different biomarkers, regardless ICI type, organ involved site.

Language: Английский

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Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis

Annals of the Rheumatic Diseases, Journal Year: 2023, Volume and Issue: 82(7), P. 920 - 926

Published: April 5, 2023

Objectives To compare the safety and effectiveness of biologic conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). Methods The retrospective multicentre observational study included patients with a diagnosis ICI-IA treated tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor (IL6Ri) and/or methotrexate (MTX); pre-existing autoimmune disease were excluded. primary outcome was time to cancer progression from ICI initiation; secondary control DMARD initiation. Cox proportional hazard models used medication groups, adjusting confounders. Results 147 (mean age 60.3 (SD 11.9) years, 66 (45%) women). treatment TNFi in 33 (22%), IL6Ri 42 (29%) MTX 72 (49%). After adjustment initiation initiation, significantly shorter compared (HR 3.27 (95% CI 1.21 8.84, p=0.019)) while result HR 2.37 0.94 5.98, p=0.055). Time faster 1.91 1.06 3.45, p=0.032)) 1.66 0.93 2.97, p=0.089). A subset analysis melanoma gave similar results both control. Conclusion is associated more rapid than MTX, but may be progression.

Language: Английский

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Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(9), P. 1011 - 1020

Published: Jan. 22, 2024

PURPOSE Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because immunosuppression and risk treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS Adult melanoma or basal, squamous, Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) PRED 5 mg once daily. Patients then received NIVO 480 IV every 4 weeks. The primary composite end point partial complete (tumor) response (CR) stable disease per RECIST v1.1 without at 16W. progressive (PD) could receive IPI 1 mg/kg 3 weeks × followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels measured approximately 2 as potential predictor rejection. RESULTS Among eight evaluable patients, none met the trial's point. All experienced PD on PRED; TRAL occurred one patient. Six PRED. Best overall responses: two CR (one TRAL) four TRAL). In total, 7 8 pre-NIVO tumor biopsies contained paucity infiltrating cells. on-NIVO demonstrated moderate infiltrates; both later TRAL, dd-cfDNA elevations 10 15 days before increases serum creatinine. CONCLUSION most skin cancer, provides insufficient protection compromises immune-mediated regression after administration IPI. Elevated can signal rejection earlier than rises

Language: Английский

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Immune‐Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges

Liver International, Journal Year: 2025, Volume and Issue: 45(2)

Published: Jan. 27, 2025

ABSTRACT Over the past decade, immune checkpoint inhibitors (ICIs) have transformed treatment of cancer, though they come with risk immune‐related adverse (irAEs) events such as hepatotoxicity or Immune‐mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation ICI and initiation immunosuppression. Cytotoxic T Lymphocytes (CTLs) play central role in ILICI; however, are just part picture immunotherapy broadly impacts all aspects microenvironment can directly indirectly activate innate adaptive cells. Clinically, our understanding this entity grows, we encounter new challenges. The presentation heterogeneous respect to latency, pattern injury (hepatitis vs. cholangitis) severity. This review focuses on knowledge regarding factors, including refractory steroids. An emerging topic, possibility rechallenge while accepting some risk, patients who experience but require immunotherapy, also discussed. provides an update current knowns unknowns highlights several gaps where studies needed.

Language: Английский

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Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: May 13, 2022

Abstract Background Cytokines have been reported to alter the response immune checkpoint inhibitors (ICIs) in patients with tumor accordance their plasma concentrations. Here, we aimed identify key cytokines which influenced responses and stimulated resistance ICIs tried improve immunological develop novel clinical treatments non-small cell lung cancer (NSCLC). Methods The promising predictive were analyzed via multi-analyte flow assay. Next, explored correlation baseline level of outcomes 45 NSCLC treated ICIs. mechanism potential candidate cytokine predicting inducing was then investigated. Results We found a low concentration IL-6 specimens or tissues could derive more benefit from based on patient cohort. Further analyses revealed that favorable relationship between PD-L1 expression seen specimens. vitro showed enhanced by JAK1/Stat3 pathway, induced evasion. Notably, an adverse levels CD8 + T cells. And positive association myeloid-derived suppressor cells, M2 macrophages regulator cells also samples, may result inferior murine models suggested dual blockade attenuated growth. detected inhibitor infiltration yielded inflammatory phenotype. Conclusions This study elucidated role promoting immunotherapy NSCLC. Our results indicated treatment targeting be beneficial for Graphical

Language: Английский

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COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(9), P. e005111 - e005111

Published: Sept. 1, 2022

Background Immune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies alternatives lacking. We examined whether interleukin-6 blockade by tocilizumab reduced ICI-induced colitis arthritis. Patients methods with solid cancer experiencing Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade >1 colitis/diarrhea (n=9), arthritis or both (n=2) were recruited (8 mg/kg) every 4 weeks until worsening unacceptable toxicity. allowed receive systemic other immunosuppressive drugs within 14-day screening period. The primary endpoint was clinical improvement arthritis, defined as ≥1 CTCAE reduction 8 weeks. Secondary endpoints improvements glucocorticoid-free remission at week 24; safety; radiologic, endoscopic, histological changes; changes in plasma concentrations C reactive protein, cytokines (IL-6, IL-8, IL-17), YKL-40. Results Nineteen patients available analysis; one patient excluded pancreatic insufficiency-induced diarrhea. received treatment pembrolizumab (n=10) nivolumab (n=4) monotherapy ipilimumab (n=5) combined. Seven had been initially glucocorticoids, two them also infliximab. Ten continued ICI therapy during treatment. achieved 15 19 (79%) patients. Additional 10, another stabilized symptoms. At 24, ongoing without (n=12), including complete (n=10), noted. Five grades 3–4 treatment-related events, which manageable reversible. Conclusions Tocilizumab showed promising a safety profile Our findings support feasibility randomized trials immune-related events. Trial registration number NCT03601611 .

Language: Английский

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