A Phase 1/2, Open-Label, Dose-Escalation, Safety, Tolerability, and Efficacy Study of Epacadostat and Nivolumab in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies (ECHO-208)

The purpose of this study is to determine the safety, tolerability, and efficacy of epacadostat when given in combination with nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, in participant with advanced or metastatic malignancies.

Start Date21 Mar 2018

Sponsor / Collaborator

Incyte Corp.

NCT03341936 / Active, not recruitingPhase 2IIT

Neodjuvant Nivolumab and Lirilumab, Followed by Surgery, Followed by Adjuvant Nivolumab and Lirilumab, in Patients With Relapsed, Resectable Squamous Cell Carcinoma of the Head and Neck

This research study is studying a combination of two immunotherapy drugs, as a possible treatment for locoregionally recurrent squamous cell carcinoma of the head and neck.
The immunotherapy drugs involved in this study are:
Nivolumab (Opdivo™)
Lirilumab

Start Date15 Mar 2018

Sponsor / Collaborator

Dana-Farber Cancer Institute, Inc.

[+1]

NCT03203876 / CompletedPhase 1

A Phase 1 Study of the Safety and Pharmacokinetics of Anti-KIR Monoclonal Antibody (Lirilumab, BMS-986015) in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab,BMS-936558) or in Combination With Nivolumab and Anti-CTLA-4 Monoclonal Antibody (Ipilimumab, BMS-734016) in Advanced and/or Metastatic Solid Tumors

The purpose of this study is to determine whether lirilumab in combination with nivolumab or in combination with nivolumab and ipilimumab is safe in the treatment of advanced and/or metastatic solid tumors

Start Date14 Jul 2017

Sponsor / Collaborator

Bristol Myers Squibb Co.

[+1]

100 Clinical Results associated with KIR2DL2

100 Translational Medicine associated with KIR2DL2

0 Patents (Medical) associated with KIR2DL2

363

Literatures (Medical) associated with KIR2DL2

15 Oct 2024·Clinical Cancer Research

KIR2DL2/DL3+NKs and Helios+Tregs in Peripheral Blood Predict Nivolumab Response in Patients with Metastatic Renal Cell Cancer

Article

Author: Ieranò, Caterina ; Napolitano, Maria ; Scala, Stefania ; Coppola, Elisabetta ; Santagata, Sara ; Portella, Luigi ; Bello, Anna Maria ; Di Napoli, Marilena ; Rossetti, Sabrina ; D’Alterio, Crescenzo ; Trotta, Anna Maria ; Pignata, Sandro ; Carles, Joan ; Chiodini, Paolo ; Dubois, Bertrand ; Guardascione, Giuseppe ; Fordellone, Mario ; Caux, Christophe ; Boyle, Helen J. ; Rea, Giuseppina ; Feroce, Florinda ; Azzaro, Rosa ; Perdonà, Sisto ; Califano, Daniela

AbstractPurpose:To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and regulatory T-cell (Treg) were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial.Experimental Design:Fifty-seven mRCCs being treated with nivolumab, as at least second-line of therapy, and 62 healthy donors were longitudinally evaluated (0–1–3–6–12 months) for peripheral NKs and Tregs, phenotype, and function. Multivariable logistic regression was conducted to identify the independent predictors. The 0.632+ internal cross-validation was used to avoid overfitting. The best cutoff value based on a 3-month clinical response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan–Meier curves for PFS and OS were produced.Results:At pretreatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD1+NKs with reduced NK degranulation as well as high frequency of Tregs, PD1+Tregs, Helios+Tregs, and ENTPD1+Tregs. Responder patients, identified as a clinical response after 3 months of treatment, presented at pretreatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD1+Tregs, and high Helios+Tregs. Upon multivariate analysis, only KIR2DL2/DL3NKs and Helios+Tregs held as independent predictors of nivolumab responsiveness. The KIR2DL2/DL3+NKs >35.3% identified patients with longer OS, whereas the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, responder patients showed low CD3+, high NKs, KIR2DL2/DL3+NKs, and ICOS+Tregs. Among these subpopulations, CD3+ and KIR2DL2/DL3+NKs held as independent predictors of nivolumab efficacy. Low CD3+ (≤71%) was significantly associated with longer PFS, whereas high KIR2DL2/DL3+NKs (>23.3%) were associated with both PFS and OS.Conclusions:Pretreatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and 1-month posttreatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.

01 Aug 2024·HLA

Killer‐cell immunoglobulin‐like receptor polymorphism is associated with COVID‐19 outcome: Results of a pilot observational study

Article

Author: Bartol‐Sánchez, M. R. ; Alcoceba, M. ; Presa, D. ; Gil‐Etayo, F. J. ; López‐Sánchez, E. ; Sánchez, P. L. ; Chillón, M. C. ; González, M. ; Muñoz, J. L. ; García‐Sanz, R. ; Gutiérrez‐Zufiaurre, M. N. ; Niño‐Ramírez, J. E. ; Boix, F. ; González‐Calle, D. ; García‐Álvarez, M. ; López‐Bernús, A. ; Compán‐Fernández, O. ; Terradillos‐Sánchez, P. ; Eiros, R. ; Marcos, M.

The pathogenesis of COVID‐19 warrants unravelling. Genetic polymorphism analysis may help answer the variability in disease outcome. To determine the role of KIR and HLA polymorphisms in susceptibility, progression, and severity of SARS‐CoV‐2 infection, 458 patients and 667 controls enrolled in this retrospective observational study from April to December 2020. Mild/moderate and severe/death study groups were established. HLA‐A, ‐B, ‐C, and KIR genotyping were performed using the Lifecodes® HLA‐SSO and KIR‐SSO kits on the Luminex® 200™ xMAP fluoroanalyser. A probability score using multivariate binary logistic regression analysis was calculated to estimate the likelihood of severe COVID‐19. ROC analysis was used to calculate the best cut‐off point for predicting a worse clinical outcome with high sensitivity and specificity. A p ≤ 0.05 was considered statistically significant. KIR AA genotype protected positively against severity/death from COVID‐19. Furthermore, KIR3DL1, KIR2DL3 and KIR2DS4 genes protected patients from severe forms of COVID‐19. KIR Bx genotype, as well as KIR2DL2, KIR2DS2, KIR2DS3 and KIR3DS1 were identified as biomarkers of severe COVID‐19. Our logistic regression model, which included clinical and KIR/HLA variables, categorised our cohort of patients as high/low risk for severe COVID‐19 disease with high sensitivity and specificity (Se = 94.29%, 95% CI [80.84–99.30]; Sp = 84.55%, 95% CI [79.26–88.94]; OR = 47.58, 95%CI [11.73–193.12], p < 0.0001). These results illustrate an association between KIR/HLA ligand polymorphism and different COVID‐19 outcomes and remarks the possibility of use them as a surrogate biomarkers to detect severe patients in possible future infectious outbreaks.

01 Jul 2024·Current Molecular Medicine

Impact of HLA Class I Antigen, Killer Inhibitory Receptor, and FCGR3A Genotypes on Breast Cancer Susceptibility and Tumor Stage

Article

Author: Novelli, Giorgio ; Del Beato, Tiziana ; Sconocchia, Giuseppe ; Buonomo, Oreste ; Canossi, Angelica ; Papola, Franco ; Venditti, Adriano ; Rossi, Piero ; Aureli, Anna

Background:The identification in breast cancer (BC) of novel genetic biomarkers regulating natural killer (NK) cell function, including the HLA, KIR, and CD16A (FCGR3A), may be still a challenge.Objective:We aimed to evaluate whether the combined effect of these polymorphisms has an impact on BC susceptibility and progression.Methods:47 BC Italian patients and healthy individuals (39 females and 66 males/ females) were genotyped by Sanger sequencing (HLA-C exon 2-4 and FCGR3A- 158V/F, 48L/R/H) and PCR-SSP typing (KIR genes).Results:HLA-C gene allele analysis showed the group C1, with HLA-C*07:02:01 allele, to be significantly associated with tumor progression (16.7% vs. 4.0%, p=0.04, OR=4.867), and instead, group C2, with HLA-C*05:01:01, was protective against disease susceptibility (0.0% vs. 7.2%, p=0.019, OR=0.087). In addition, we highlighted a significant reduction of the KIR2DS4ins in BC patients (pcorr.=0.022) and an increased combined presence of KIR2DL1 and KIR2DS1 genes in advanced BC patients compared to earlier stages (66.7% vs. 19.2%, p=0.002). The concurrent lack of KIR2DL2 and KIR2DS4 genes in the presence of HLA-C2 alleles was significantly associated with increased susceptibility to BC (p=0.012, OR=5.020) or with lymph node involvement (p=0.008, OR=6.375). Lastly, we identified different combinations of the FCGR3A-48/158 variants and KIR genes in BC patients compared to controls.Conclusion:Our findings suggest that in the development of BC probably exists a disorder of the NK innate immunity influenced by KIR/HLA-C gene content and FCGR3A-158 polymorphisms and that the combined analysis of these biomarkers might help predict genetic risk scores for tailored screening of BC patients in therapy.

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