Esophageal Cancer Responsive to the Combination of Immune Cell Therapy and Low-dose Nivolumab

Two Case Reports

Rishu Takimoto; Takashi Kamigaki; Takuji Gotoda; Toshimi Takahashi; Sachiko Okada; Hiroshi Ibe; Eri Oguma; Shigenori Goto

Disclosures

J Med Case Reports. 2021;15(191) 

In This Article

Case Presentation

Case 1

A female Asian (Japanese) patient was diagnosed as having esophageal cancer in February 2016 at 66 years of age. Biopsy and computed tomography (CT) revealed squamous cell carcinoma of the esophagus at clinical stage IV (UICC, T4N2M0). She received concurrent chemoradiation therapy (CCRT) with fluoropyrimidine/platinum from March to April 2016, then underwent subtotal esophagectomy in June 2016. Histopathological analysis of surgical tumor specimens revealed that her esophageal cancer was at clinical stage II (UICC, T3N0M0). She remained disease free until November 2016, when routine CT revealed a new pulmonary nodule and mediastinal lymph node swelling, 2.0 cm in diameter, in her left lung. She visited our clinic to receive ACT in December 2016 after radiotherapy for the lymph node metastasis in her lung from January to February 2017. During radiotherapy, she also received ACT using αβT lymphocytes four times at 2–3-week intervals until April 2017. Then chemotherapy using fluoropyrimidine/platinum/docetaxel was administered until January 2018. However, routine CT revealed multiple lung metastases in February 2018. In July 2018, she enrolled in a clinical trial at our institution (clinical trial number UMIN000028756) (Figure 1a). Before starting the clinical trial, we evaluated PD-L1 expression level using her tumor specimens and found that the PD-L1 expression level in the tumor tissue was less than 1%. The tumor was negative for microsatellite instability (MSI; data not shown). She received ACT twice at a 2-week interval, followed by nivolumab at a dose of 0.3 mg/kg body weight with ACT four times at 2-week intervals, as part of induction therapy. A follow-up CT scan on 19 September 2018 (9 weeks after nivolumab initiation) showed partial response, with 48% mass reduction of the lung metastases and mediastinal lesion (Figure 1b). She was allowed to continue with nivolumab treatment at a dose of 40 mg/kg body weight as maintenance therapy at 3-week intervals. Over her clinical course in 2018, there was radiographic evidence of slight improvement (Figure 1c), and maintenance nivolumab therapy was continued because the patient was clinically well and alive. Mild, asymptomatic hypothyroidism developed, which required thyroid hormone supplementation, but she showed no other clinically significant treatment-related toxicity.

Figure 1.

Clinical course of case 1. Axial computed tomography images corresponding to the timelines of therapy and disease status. Yellow circles indicate the mediastinal lesion, and red circles indicate lung metastatic lesions. a (top) status before treatment with nivolumab. b Regression of both mediastinal and lung metastatic lesions after combination adoptive cell therapy (ACT) and immune checkpoint inhibitor (ICI) therapy. Responses were durable during maintenance therapy with the ICI (c). Black and red arrows indicate ACT and nivolumab administration, respectively (bottom)

Case 2

A male Asian (Japanese) patient was diagnosed as having esophageal cancer in June 2016 at 77 years of age. CT and biopsy of specimens revealed squamous carcinoma of the esophagus at clinical stage IV (UICC, T4N2M1). He received CCRT with fluoropyrimidine/platinum from July to November 2017. In December 2017, gastroscopy revealed complete remission of esophageal cancer. He remained disease free until April 2018, when routine CT revealed multiple metastases in his bilateral lungs and lymph nodes of the right hilum (Figure 2a). He was administered docetaxel as second-line chemotherapy from May to September 2018, but his lung metastases were found to have progressed (Figure 2b). He visited our clinic to receive ACT in October 2018, followed by ACT using αβT lymphocytes three times at 2–3-week intervals until December 2018. He then received dendritic cells (DCs) pulsed with MUC1, MAGE3, and survivin, which were expressed on his tumor cells as tumor antigens, 12 times at 2–3-week intervals from 26 December 2018 to 28 June 2019 (Figure 2). During ACT and pulsed DC therapy, he developed brain metastasis in November 2018 and underwent stereotactic radiosurgery for brain metastasis. Routine CT revealed that the sizes of multiple lung and lymph node metastatic lesions were reduced, which were evaluated as partial response on the basis of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in January 2019 (Figure 2c). Furthermore, the sizes of brain metastatic lesions were decreased in April 2019. In September 2019, follow-up CT revealed regrowth of metastatic lesions in the lung and hilar lymph nodes, and he started to receive ACT once a month (Figure 2d). Immunohistochemical staining revealed that the PD-L1 expression level in the tumor was 1%, and the tumor was negative for MSI (data not shown). Following ACT, he received nivolumab at a dose of 0.6 mg/kg body weight four times at 2-week intervals as part of induction therapy. A follow-up CT scan on 27 November 2019 (8 weeks after nivolumab initiation) showed partial response, with 60% reduction of the lung mass and hilar lymph node swelling (Figure 2e). He was allowed to continue with nivolumab treatment at a dose of 40 mg/kg body weight as maintenance therapy at 3-week intervals. Over his clinical course in 2019, radiographic evidence showed continuous improvement of lesions, and his treatment was continued with maintenance nivolumab therapy (Figure 2f) because the patient was clinically well and alive. There was no evidence of adverse events during combination therapy

Figure 2.

Clinical course of case 2. Axial CT images corresponding to the timelines of therapy and disease status. Red circles indicate the lung and hilar metastatic lesions. a (top) Status during administration of docetaxel (DTX). b Progression of lung metastasis before treatment with adoptive cell therapy (ACT). c Regression of lung metastasis after treatment with ACT and dendritic cell (DC) vaccine. d Progression of lung and hilar lymph node metastases before administration of nivolumab. e Regression of lung metastasis 8 weeks after immune checkpoint inhibitor (ICI) and ACT combination treatment. Responses were durable during maintenance therapy with the ICI (f). Narrow black arrows, bold black arrows, and red arrows indicate ACT, DC vaccine, and nivolumab administration, respectively (bottom)

Flow Cytometric Analysis of Patients' Peripheral Blood Mononuclear Cells Before and After Combination Immunotherapy With ACT and ICI

The total number of cells used for ACT ranged from 7.3 to 10.9 × 109 (average 8.3 ± 1.7 × 109 cells/infusion) in case 1 and from 3.9 to 7.8 × 109 (average 6.1 ± 1.7 × 109 cells/infusion) in case 2, and the characteristics of αβT cells prepared from each patient were not significantly changed at the first and fourth cultivation (data not shown). The numbers of white blood cells (WBCs) and CD45+ leukocytes in peripheral blood did not change after ICI and ACT combination immunotherapy (Figure 3). The numbers of CD3+, TCRαβ+, TCRγδT+, CD4+CD8T, and CD4CD8+T cells were significantly lower than those in healthy subjects before ACT,[16] and increased after ICI and ACT combination immunotherapy (Figure 3). There were no significant differences in the numbers of CD3CD56+, IFN-γ+IL4 (Th1), IFN-γ-IL4+ (Th2), and Foxp3+ (Treg) cells among the CD3+CD4+ subset cells (Figure 3).

Figure 3.

Flow cytometry of peripheral blood mononuclear cells (PBMCs) before and 2 weeks after combination therapy with ICI and ACT. The phenotype of PBMCs was analyzed as described in "Patients and methods." The phenotype and mean ± standard deviation (shaded box) in healthy subjects are shown in each graph. The solid line indicates the number of cells in case 1, and the dotted line indicates that in case 2

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