Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma

Shirasawa, Masayuki; Yoshida, Tatsuya; Takayanagi, Daisuke; Shiraishi, Kouya; Yagishita, Shigehiro; Sekine, Katsutoshi; Kanda, Shintaro; Masuda, Ken; Shinno, Yuki; Okuma, Yusuke; Goto, Yasushi; Horinouchi, Hidehito; Hamada, Akinobu; Yamamoto, Noboru; Watanabe, Shun‐ichi; Ohe, Yuichiro; Motoi, Noriko

doi:10.1016/j.cllc.2021.02.003

Cited by 13 publications

(13 citation statements)

References 39 publications

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“…A total of 5123 articles were obtained through the initial search strategy. After screening abstract and reviewing full texts, 33 articles [ [7] , [8] , [9] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] ] published from 2014 to 2021 were considered as eligible in final analyses ( Fig. 1 A).…”

Section: Resultsmentioning

confidence: 99%

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

et al. 2021

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Background The responses of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing tumor cells. This study aims to evaluate the prognostic role of CD8+ TILs in cancer patients treated with ICIs. Methods We systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 12 Jul 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting efficacy and survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The study protocol is prospectively registered on PROSPERO (registration number CRD42021233654). Findings Findings: A total of 33 studies consisting of 2559 cancer patients were included. The result showed that high CD8+ TILs were significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41–0.67; p < 0.001), PFS (HR, 0.52; 95% confidence interval: 0.40–0.67; p < 0.001) and ORR (OR, 4.08; 95% confidence interval: 2.73–6.10; p < 0.001) in patients treated with ICIs. Subgroup analyses suggested that patients with high CD8+ TILs had a better clinical benefit, regardless of different treatments (ICI mono therapy, or combination therapy), cancer types (NSCLC, melanoma and others), and CD8+ T cells locations (intra-tumor, stroma, and invasive margin). The higher baseline circulating CD8+ T cells from peripheral blood did not contribute to the improved OS (HR, 0.93; 95% confidence interval: 0.67–1.29; p = 0.67) and PFS (HR, 0.89; 95% confidence interval: 0.60–1.32; p = 0.56) compared with the low baseline. Interpretation Interpretation: Our results suggested that high intra-tumoral, stromal, or invasive marginal, but not circulating CD8+ T cells, can predict treatment outcomes in patients with ICIs therapy across different cancers, in either single-agent ICIs or combination with other therapies. Funding Funding: China National Science Foundation (Grant No. 82,022,048, 81,871,893), Key Project of Guangzhou Scientific Research Project (Grant No. 201,804,020,030), High-level university construction project of Guangzhou medical university (Grant No. 20,182,737, 201,721,007, 201,715,907, 2,017,160,107); National key R & D Program (Grant No. 2017YFC0907903 & 2017YFC0112704) and the Guangdong high level hospital construction "reaching peak" plan.

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Section: Resultsmentioning

confidence: 99%

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

et al. 2021

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“…Furthermore, analyzing lymphocytes for additional markers, Ohtaki et al showed a favorable prognosis for cases with FoxP3 expressing tumor-associated lymphocytes, whereas the presence of CD4+ helper lymphocytes conferred an unfavorable prognosis (48). This was confirmed by the study of Shirasawa et al, who also included lymphocyte density into their study (49). Combining immunotherapy with chemo-and radiotherapy was shown to improve survival (50).…”

Section: Aspects For a Therapymentioning

confidence: 69%

Diagnosis and Molecular Profiles of Large Cell Neuroendocrine Carcinoma With Potential Targets for Therapy

Popper

Brčić

2021

Front. Oncol.

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Large cell neuroendocrine carcinoma (LCNEC) together with small cell carcinoma (SCLC) and typical and atypical carcinoids form the group of pulmonary neuroendocrine tumors. LCNEC and SCLC are high-grade carcinomas. Although both can be found outside the thoracic cavity, they are most common in the lung. LCNEC differs from SCLC by morphologic pattern, and by cytological features such as nuclear size, nucleoli, chromatin pattern, but also by genetic differences. Originally thought to represent a single entity, it became evident, that three subgroups of LCNEC can be identified at the molecular level: a SCLC-like type with loss of retinoblastoma 1 gene (RB1) and TP53 mutations; a non-small cell lung carcinoma (NSCLC)-like type with wildtype RB1, TP53 mutation, and activating mutations of the phosphoinositol-3 kinase (PI3K-CA), or loss of PTEN; and a carcinoid-like type with MEN1 gene mutation. These subtypes can be identified by immunohistochemical staining for RB1, p53, and molecular analysis for PI3K and MEN1 mutations. These subtypes might also respond differently to chemotherapy. Immuno-oncologic treatment has also been applied to LCNEC, however, in addition to the evaluation of tumor cells the stroma evaluation seems to be important. Based on personal experiences with these tumors and available references this review will try to encompass our present knowledge in this rare entity and provoke new studies for better treatment of this carcinoma.

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“…Patients included in Klein's study were treated with combination ICI therapy (nivolumab and ipilimumab), whereas patients in the other studies were mostly treated with monotherapy. In the monotherapy group, studies by Lu [37] and Shirasawa [41] reported higher values for the ORR (20.0 and 38.5%, respectively) than the others (less than 9.8%). In Lu's study, patients were eligible for inclusion if they had NEN with a high ki-67 index (≥10%).…”

Section: Response-related Endpointmentioning

confidence: 82%

“…The study search process is outlined in Figure 1. The characteristics of the 10 included studies [19,[35][36][37][38][39][40][41][42][43], which involved a total of 464 NEN patients, are summarized in Table 1. Seven of these studies were nonrandomized clinical trials (two phase I studies and five phase II studies), and three were retrospective studies.…”

Section: Study Search and Characteristicsmentioning

confidence: 99%

Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

Park

Kim

et al. 2022

Cancers

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We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated with ICIs. The overall response rate (ORR) was pooled using a random-effects model. Meta-regression was performed to explore factors influencing the ORR. Individual patient data (IPD) meta-analysis of survival was performed using stratified Cox regression. Ten studies (464 patients) were included. The overall pooled ORR was 15.5% (95% confidence interval (CI), 9.5–24.3%), and it varied according to the primary site (thoracic, 24.7%; gastro–entero–pancreatic, 9.5%), tumor differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%), and drug regimen (combination, 25.3%; monotherapy, 10.1%). All these variables significantly influenced the ORR. Tumor differentiation was associated with both overall survival and progression-free survival (hazard ratio of poorly differentiated tumors, 4.2 (95% CI, 2.0–8.7) and 2.6 (95% CI, 1.6–4.4), respectively). Thus, the treatment efficacy of ICIs for advanced/metastatic NENs varied according to primary site, tumor differentiation, and drug regimen. Poorly differentiated NENs showed a better ORR than well-differentiated NENs but had a negative impact on survival.

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Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma

Cited by 13 publications

References 39 publications

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

Diagnosis and Molecular Profiles of Large Cell Neuroendocrine Carcinoma With Potential Targets for Therapy

Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

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