ORCID Profile
0000-0003-0167-1685
Current Organisation
University of Oxford
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Publisher: American Association for Cancer Research (AACR)
Date: 23-10-2020
DOI: 10.1158/1078-0432.CCR-20-0446
Abstract: Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older in iduals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be. We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy. We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2. VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
Publisher: Research Square Platform LLC
Date: 12-04-2022
DOI: 10.21203/RS.3.RS-1531341/V1
Abstract: Although treatment with immune checkpoint blockade (ICB) has transformed outcomes for patients with melanoma (1, 2), it frequently triggers immune related adverse events (irAEs), causing serious morbidity and presenting a major hurdle to immuno-oncology (3, 4). The degree to which germline genetic variation predisposes to irAEs is unknown. Here, studying a cohort of 214 patients receiving ICB for melanoma, we observe increased risk of severe irAEs in carriers of the minor allele of rs16906115, intronic to IL7. We find rs16906115 forms a B cell specific expression quantitative trait locus to IL7 in patients only, with risk allele carriers demonstrating increased B cell IL7 expression, immunoglobulin class switching and somatic hypermutation. Notably, increased B cell IL7 expression is independently associated with risk of irAEs. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB induced CD8+ T cell subset responses, with allelic effects on gene expression and clonality. Risk allele carriers display significantly reduced CD8+ T cell mitotic responses to ICB, with skewing of T cell clonality and increased counts of large clones previously associated with disease response. These observations highlight key roles for both B cells and IL-7 in ICB response and toxicity, and demonstrate the power of agnostic human genetic studies to reveal novel determinants of response to cancer immunotherapy.
Publisher: Elsevier BV
Date: 03-1997
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1038/S41591-022-02095-5
Abstract: Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7 . We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, ergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8 + T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.EJCA.2022.06.041
Abstract: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8. In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8. Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115 AJCC-8, P = 0.1051 P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS). CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.ANNONC.2021.10.010
Abstract: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR) 17 partial response (PR)] 79.6% had discontinued pembrolizumab due to progressive disease (PD) median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5% 11/16 responses (8 CRs 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR) 76.3% had discontinued pembrolizumab due to PD median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2% 6/16 were ongoing (3 CR, 3 PR). Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 09-05-2023
DOI: 10.1158/1078-0432.22787545
Abstract: DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/1078-0432.C.6637744
Abstract: AbstractPurpose: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients and Methods: Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. Results: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72 95% confidence interval, 0.60–0.86 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8 sup + /sup T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. Conclusions: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. /
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-10-2021
DOI: 10.1126/SCIIMMUNOL.ABJ8825
Abstract: The cytotoxicity and clone size of CD8 + T cell pretreatment are prognostic for immune checkpoint blockade.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41467-021-21207-2
Abstract: Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10 −5 ) and overall survival (HR = 1.61, p = 1.67 × 10 −4 ), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates ( p AUROC = 7.03 × 10 −4 ), or published prognostic signatures ( p AUROC 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p 2.2 × 10 −16 ), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-06-2020
DOI: 10.1126/SCITRANSLMED.AAZ8084
Abstract: Integration of variant reads across patient-specific mutation loci enables sensitive ctDNA quantification in plasma cell-free DNA sequencing data.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/1078-0432.CCR-22-3145
Abstract: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72 95% confidence interval, 0.60–0.86 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-05-2023
DOI: 10.1158/1078-0432.22787545.V1
Abstract: DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238
Publisher: Elsevier BV
Date: 10-2021
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mark Middleton.