Prognostic Value of Neoantigen Load in Immune Checkpoint Inhibitor Therapy for Cancer

Zou, Xue-lin; Li, Xiaobo; Ke, Hua Zhu; Zhang, Guangyan; Tang, Qing; Yuan, Jiao; Zhou, C.; Zhang, Jiliang; Zhang, Rui; Chen, Wei-yong

doi:10.3389/fimmu.2021.689076

Cited by 31 publications

(25 citation statements)

References 99 publications

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“…Regarding the immunotherapy’s mechanism of action, efficacy has been found to be directly related to tumor mutational burden and neoantigens formation ( 29 ). As reported by Castle et al.…”

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis

Gómez-Llobell

Raíndo

Medina³

et al. 2022

Front. Oncol.

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BackgroundExperience with immune checkpoint inhibitors (ICIs) in the treatment of acute myeloid leukemia (AML) is still limited and based on early clinical trials, with no reported randomized clinical data. In this study, we reviewed the available evidence on the use of ICIs, either in monotherapy or in combination with other treatments, in different AML settings, including newly diagnosed AML, relapsed or refractory (R/R) AML and maintenance treatment after allogeneic-HSCT (allo-HSCT).Materials and MethodsA systematic literature review was conducted using PubMed electronic database as primary source to identify the studies involving immune checkpoint inhibitors in first-line and R/R AML. We recorded Overall Response (ORR), Complete Response (CR) and Complete Response with incomplete count recovery (CRi) rates, overall survival (OS) and immune-related adverse events ≥ grade 3 (irAEs). Hereafter, we analyzed the overall profile of these ICIs by performing a meta-analysis of the reported outcomes.ResultsA total of 13 studies were identified where ICI was used in patients with AML. ORR across these studies was 42% (IC95%, 31% - 54%) and CR/CRi was 33% (IC95%, 22%-45%). Efficacy was also assessed considering the AML setting (first-line vs. relapsed/refractory) and results pointed to higher response rates in first-line, compared to R/R. Mean overall survival was 8.9 months [median 8 months, (IC95%, 3.9 - 15.5)]. Differences between first line and R/R settings were observed, since average overall survival in first line was 12.0 months, duplicating the OS in R/R which was 7.3 months. Additionally, the most specific adverse events (AEs) of these therapies are immune-related adverse events (irAEs), derived from their inflammatory effects. Grade ≥3 irAEs rate was low and similar among studies [12% (95%CI 8% - 16%)].ConclusionICIs in combination with intensive chemotherapy, hypomethylating agents or other targeted therapies are gaining interest in the management of hematological malignancies such as AML. However, results obtained from clinical trials are modest and limited by both, the type of design and the clinical trial phase. Hopefully, the prospective study of these therapies in late-stage development could help to identify patients who may benefit from ICI therapy.

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Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis

Gómez-Llobell

Raíndo

Medina³

et al. 2022

Front. Oncol.

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“…TMB is defined as the total number of somatic mutations present in defined coding regions of the tumor genome [ 33 ]. Tumor neoantigens load arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer [ 34 ]. The genome-wide neoantigen landscape for each sample was predicted by NetMHCpan (version 3.0) [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

SAAL1, a novel oncogene, is associated with prognosis and immunotherapy in multiple types of cancer

Yang

Han

Chen

et al. 2022

Aging

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Serum amyloid A-like 1 (SAAL1) was recently identified as a novel oncogene in hepatocellular carcinoma (HCC).To explore the potential role of SAAL1 in other cancers, we conducted a pan-cancer analysis of SAAL1 expression and its association with tumor microenvironment (TME) immunological profiles, sensitivity to chemotherapy agents, response to immunotherapy, and patient prognosis. SAAL1 was overexpressed in most malignant tumors in association with poor prognosis. Moreover, its expression was positively correlated with TME-relevant immune and mismatch signatures, immunostimulatory infiltrating cells (CD4 + memory T cells, activated NK cells, M1 macrophages, and cytotoxic CD8 + T cells), microsatellite instability (MSI), tumor mutational burden (TMB), neoantigen load, and immune checkpoint markers (PD-L1, LAG-3 and CTLA-4) in multiple cancers. SAAL1 overexpression was also associated with immunotherapy response and overall survival (OS) in bladder cancer (BLCA) patients who had received anti-PD-L1 treatment. Gene set enrichment analysis (GSEA) further showed significant enrichment of SAAL1 in immune cell signaling, cell cycle, and cell adhesion pathways. Moreover, we detected tumor-specific correlations between SAAL1 expression and either chemoresistance or sensitivity to common chemotherapeutics. Lastly, we showed that SAAL1 silencing suppresses both malignant phenotype and expression of PD-L1 in lung cancer A549 cells in vitro. These findings suggest that SAAL1 contributes to tumorigenesis and antitumor immunity mechanisms in different cancer types, and may thus serve as both a prognostic biomarker and potential target for cancer immunotherapy.

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“…Only over the last decade have patients with NECs been more consistently studied individually [ 26 ]. One of the biomarkers thought to be predictive of response to ICPIs in other solid tumors includes the degree of tumor infiltrating lymphocytes (TILs) [ 27 , 28 ]. Currently published data suggest that the majority of well-differentiated NETs are “immunologically cold”, with low tumor mutational burden and rare TILs compared to poorly-differentiated NECs, which have a higher degree of TILs [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC)

Mohamed

Vijayvergia

Kurian

et al. 2022

Cancers

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Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

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Prognostic Value of Neoantigen Load in Immune Checkpoint Inhibitor Therapy for Cancer

Cited by 31 publications

References 99 publications

Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis

Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis

SAAL1, a novel oncogene, is associated with prognosis and immunotherapy in multiple types of cancer

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC)

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