Pulmonary pleomorphic carcinoma with few PD‐1‐positive immune cells and regulatory T cells that showed a complete response to nivolumab

Okamura, Kazuaki; Fukuda, Yuichi; Soda, Hiroshi; Ogawara, Daiki; Iwasaki, Keisuke; Fuchi, Shinichiro; Suyama, Takayuki; Yoshida, Masahiro; Harada, Tatsuhiko; Fukuda, Minoru; Mukae, Hiroshi

doi:10.1111/1759-7714.12557

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…26 In addition, disease progression during first-line chemotherapy for NSCLC was reported to correlate with high levels of circulating MDSCs. 27 Combining these findings with the results of our previous studies, 4, 25,28 we hypothesize that both the exhaustion levels of cytotoxic T cells and interference with myeloid cells may affect the efficacy of nivolumab and subsequent salvage chemotherapy (Fig 3).…”

Section: Discussionsupporting

confidence: 76%

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Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

et al. 2018

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Several recent studies have shown that salvage chemotherapy following PD‐1 blockade produces high antitumor activity in some patients with non‐small lung cancer (NSCLC). However, the underlying synergistic mechanisms remain uncertain. The blood neutrophil‐to‐lymphocyte ratio (NLR) and absolute neutrophil count (ANC) can reflect the number of circulating myeloid‐derived suppressor cells and tumor‐associated neutrophils. The immunosuppressive status of the tumor microenvironment could be monitored by the time‐series patterns of NLR and ANC. The dynamics of NLR and ANC during nivolumab treatment were retrospectively explored in 15 patients: 8 patients receiving subsequent salvage chemotherapy (2 groups: 3 non‐responders and 5 responders), and 7 responders to nivolumab alone (2 groups: 4 partial response and 3 complete response). The dynamics of NLR and ANC during nivolumab differed among these four groups (NLR P = 0.045, ANC P = 0.067). NLR and ANC during nivolumab treatment increased over time in non‐responders to salvage chemotherapy, with an inverse relationship between drug response and NLR or ANC at four to six weeks among the four groups. We hypothesize that the early dynamics of NLR and ANC during nivolumab may be associated with the late efficacy of subsequent salvage chemotherapy. Further studies involving a large cohort are needed to confirm these findings, which could provide insight into the role of myeloid immunosuppressor cells in combination PD‐1 blockade and chemotherapy.

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Section: Discussionsupporting

confidence: 76%

“…A hypothetical model of the possible underlying mechanisms of nivolumab and subsequent salvage chemotherapy, based on the results of our previous and present studies . PD‐1 expression levels on tumor‐infiltrating lymphocytes (TILs) probably indicate the exhaustion of lymphocytes.…”

Section: Discussionmentioning

confidence: 88%

Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

et al. 2018

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“…We reported that a case of lung cancer regressed spontaneously and subsequently relapsed with an increase in the number of Tregs in the circulation . We also reported that lung cancer cases showing a remarkable response to nivolumab contained < 5% Tregs in the tumor . Tregs inhibited nivolumab‐stimulated release of interferon‐γ from effector T cells in vitro .…”

Section: Discussionmentioning

confidence: 90%

“…21,22 We also reported that lung cancer cases showing a remarkable response to nivolumab contained < 5% Tregs in the tumor. 23,24 Tregs inhibited nivolumab-stimulated release of interferon-γ from effector T cells in vitro. 25 Although PD-1 blockade did not affect the function of Tregs, 26 several anti-cancer drugs are known to reduce the number of Tregs and restore the activity of effector T cells.…”

Section: Discussionmentioning

confidence: 97%

Presence of few PD‐1‐expressing tumor‐infiltrating immune cells is a potential predictor of improved response to salvage chemotherapy following nivolumab for non‐small cell lung cancer: An exploratory case series

et al. 2018

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BackgroundThe combination of PD‐1 inhibitors and cytotoxic drugs is reported to enhance anti‐tumor activity in non‐small cell lung cancer; however, the underlying synergistic mechanisms remain uncertain. This retrospective case series was designed to investigate objective response and survival rates of salvage chemotherapy following nivolumab and explore the immunohistochemical profiles of tumor‐infiltrating immune cells.MethodsThe medical records of 37 patients administered nivolumab were retrospectively reviewed. Overall response rate and progression‐free survival were compared among three groups: salvage chemotherapy following nivolumab, nivolumab therapy alone, and chemotherapy preceding nivolumab.ResultsEight cases met the study criteria. Salvage chemotherapy following nivolumab improved the overall response rate to 62.5% (95% confidence interval [CI] 34.4–90.6%; P = 0.004) and median progression‐free survival to six months (95% CI 4.6–7.4; P = 0.016), compared to nivolumab alone and preceding chemotherapy. The response to salvage chemotherapy was not associated with tumor PD‐L1 expression. A partial response was achieved in four cases with ≤ 5% and ≤ 2.9 cells/mm2 of PD‐1+ immune cells, whereas stable disease and progressive disease were observed in three cases with ≥ 30% and ≥ 12.7 cells/mm2. Responders had fewer PD‐1+ immune cells than non‐responders (percentage P = 0.028; density P = 0.034).ConclusionSalvage chemotherapy following nivolumab improved anti‐tumor activity regardless of tumor PD‐L1 status, but nivolumab following chemotherapy did not. The presence of few PD‐1+ tumor‐infiltrating immune cells may serve as a potential predictor of response to salvage chemotherapy. Further studies involving a large cohort are needed to clarify how nivolumab re‐sensitizes the tumor immune microenvironment to chemotherapy.

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“…Therefore, there is a trend for improving treatment results by using immune checkpoint inhibitors in combination with chemotherapeutic drugs. Recently, there have been some case reports of patients with polymorphic cancer responding to immune checkpoint inhibitors (9-13), while others have failed (9)(10)(11)(12)(13). We herein report a case of pleomorphic carcinoma of the lung treated with pembrolizumab and platinum-containing chemotherapy.…”

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confidence: 89%

Combination of Pembrolizumab With Platinum-containing Chemotherapy for Pleomorphic Carcinoma of the Lung

Okauchi

Sasatani

Shiozawa

et al. 2020

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Background/Aim: Pleomorphic carcinoma of the lung is a rare, highly malignant subtype of lung cancer, with a more aggressive clinical course compared with other types of non-small-cell lung cancer (NSCLC). Platinum-containing chemotherapy has been the standard therapy for patients with NSCLC and pembrolizumab is one of the novel and reliable agents for these patients. Case Report: We herein report the case of a 60-year-old man with advanced chemo-naïve pleomorphic carcinoma of the lung who was successfully treated with a combination of pembrolizumab with platinumcontaining chemotherapy. Conclusion: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of this tumor, our case demonstrates the potential utility of the combination of pembrolizumab with platinum-containing chemotherapy. Our result also suggest that this combination of therapy may be key to the treatment of pleomorphic carcinoma of the lung. Pleomorphic carcinoma of the lung is a rare, highly malignant tumor, accounting for 0.1-0.4% of all primary lung cancer cases (1-3). It has a more aggressive clinical course compared with other types of non-small-cell lung cancer (NSCLC) (4-6), as well as a poorer outcome (4, 7, 8).

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Pulmonary pleomorphic carcinoma with few PD‐1‐positive immune cells and regulatory T cells that showed a complete response to nivolumab

Cited by 16 publications

References 21 publications

Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

Dynamics of blood neutrophil‐related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non‐small cell lung cancer: A hypothesis‐generating study

Presence of few PD‐1‐expressing tumor‐infiltrating immune cells is a potential predictor of improved response to salvage chemotherapy following nivolumab for non‐small cell lung cancer: An exploratory case series

Combination of Pembrolizumab With Platinum-containing Chemotherapy for Pleomorphic Carcinoma of the Lung

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