TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti‐CTLA4 treatment

Li, Huahua; Li, Jia; Zhang, Chenyue; Zhang, Chenxing

doi:10.1002/cam4.3376

Cited by 37 publications

(46 citation statements)

References 58 publications

(123 reference statements)

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“… 33 A similar association between TERT promoter mutations and higher TMB was recently described in a pan-cancer analysis. 35 The same study also described a longer median OS in a subset of patients with TERT promoter mutations treated with anti-CTLA4 agents. Other genomic biomarkers associated with increased TMB (eg, DNA damage repair gene alterations or the presence of an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) enzyme mutational signature) have been found to predict response to ICI therapy.…”

Section: Discussionmentioning

confidence: 83%

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor

Kouchkovsky

Zhang

Philip

et al. 2021

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.MethodsWe undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.ResultsWe identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).ConclusionsThe presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

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Section: Discussionmentioning

confidence: 83%

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor

Kouchkovsky

Zhang

Philip

et al. 2021

J Immunother Cancer

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“…Therefore, it is very important to select appropriate patients with PDL1 expression high. In addition, it has been reported that some specific gene mutations may have an intimate relationship with the efficacy of immunotherapy [11,[17][18][19][20]. In our study, we first clarify the relationship between PDL1 expression and specific gene mutation types; then, we analyze the relationship between these gene mutation types and survival among patients receiving atezolizumab; importantly, we found that PDL1 high expression without TP53, KEAP1 and EPHA5 mutations could better predict survival for NSCLC patients receiving atezolizumab.…”

Section: Discussionmentioning

confidence: 82%

PDL1 high expression without TP53, KEAP1 and EPHA5 mutations could better predict survival for patients with NSCLC receiving atezolizumab

et al. 2021

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“…Tumors from both responders and nonresponders had single nucleotide variants in these genes, and we found no clear correlation between the number or types of genes mutated and response to therapy (Supplementary Figure S5). Notably, Li et al recently identified an association between a higher TMB and TERT mutations, conferring an improved prognosis in patients with metastatic melanoma receiving CTLA-4 blockade, and thus, for combined targeting of telomerase and CTLA-4 in these patients (29).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, Li et al. recently identified an association between a higher TMB and TERT mutations, conferring an improved prognosis in patients with metastatic melanoma receiving CTLA-4 blockade, and thus, for combined targeting of telomerase and CTLA-4 in these patients ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial

et al. 2021

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BackgroundIpilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma.Patients and MethodsIn this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production.ResultsTwelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years.ConclusionTreatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.

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TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti‐CTLA4 treatment

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 37 publications

References 58 publications

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor

PDL1 high expression without TP53, KEAP1 and EPHA5 mutations could better predict survival for patients with NSCLC receiving atezolizumab

Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial

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