PMC6336603_01
Treatment history. Timeline, therapy, and response to regimen from presentation of metastatic disease to present.
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PD-1 antibodies. Please refer to Figure 1 for the full treatment history. Repeated CT scan in late January 2014 showed two enlarged lymph nodes in the right side of the neck (Fig. 2A, box 1). Due to the rapidity of the disease progression as seen in the CT image from January 2014 (Fig. 2A, box 1), the patient was treated with a BRAF inhibitor, vemurafenib (960 mg twice a day) on February 13, 2014. After nine cycles of nivolumab, CT scans showed a decrease in pulmonary metastasis (Fig. 2B, box 1), but detected the presence of multiple lesions in the spleen (Fig. 2C, box 1) and presence of hilar and mediastinal adenopathy.
Response to therapy monitored by computed tomography. (A) Neck lesion and surrounding lymph nodes: (1) Before BRAFi treatment (January 2014). (2) Recurrence of melanoma after BRAFi treatment (December 2014). (3) After anti-CTLA-4 treatment (April 2015). (B) Pulmonary lesions: (1) After nivolumab and before pembrolizumab treatment (August 2015). (2) During pembrolizumab treatment (March 2016). (3) During pembrolizumab treatment (April 2018). (C) Spleen lesions: (1) Before pembrolizumab treatment (October 2015, size 3.5 cm). (2) During pembrolizumab treatment. (March 2016, size 3 cm). (3) During pembrolizumab treatment (April 2018, size 1.5 cm).
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Computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) scans were utilized to assess response throughout the therapy from 2013 to 2018 (Fig. 2A-C). Repeated CT scan in late January 2014 showed two enlarged lymph nodes in the right side of the neck (Fig. 2A, box 1). Due to the rapidity of the disease progression as seen in the CT image from January 2014 (Fig. 2A, box 1), the patient was treated with a BRAF inhibitor, vemurafenib (960 mg twice a day) on February 13, 2014. However, in December 2014, about 10 months post combination therapy with BRAF and MEK inhibitors, melanoma recurred in the neck (Fig. 2A, box 2). After completing four doses of ipilimumab, a CT scan was obtained which showed two new hypermetabolic foci within the right neck (Fig. 2A, box 3) suspicious for neoplasm with interval enlargement of the innumerable pulmonary nodules with associated hypermetabolism, compatible with pulmonary metastases. After nine cycles of nivolumab, CT scans showed a decrease in pulmonary metastasis (Fig. 2B, box 1), but detected the presence of multiple lesions in the spleen (Fig. 2C, box 1) and presence of hilar and mediastinal adenopathy. CT imaging showing complete pulmonary lesions disappearance after pembrolizumab initiation. Figure 2C (box 2) also shows the disappearance of most spleen lesions after about 5 months of pembrolizumab treatment. Currently, the patient has only one solitary splenic lesion remaining (Fig. 2C, box 3).
Immunohistochemical staining of the neck, lymph node, and spleen lesions. (A) Visualization of PD-L1 expression in the neck and lymph node lesions before combination therapy with BRAF and MEK inhibitors (December 3, 2013). The areas circled with red dashed lines indicate the presence of immune cells (IM) adjacent to tumor cells (T). Moderate expression of PD-L1 appears in both immune cells and tumor cells. (B) Colocalization of PD-L1 and macrophage marker CD68 in the neck lesion. Several tumor infiltrating macrophages (black arrows) also express PD-L1. (C) Visualization of PD-L1 expression in the neck and spleen lesions from the same patient resistant to a combination therapy with BRAF and MEK inhibitors (September 4, 2015). High levels of PD-L1 are present in tumor infiltrating immune cells and tumor cells. (D) Same observation as panel B above, from the 2015 sample of the neck lesion.
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PD-L1 assays were achieved by immunohistochemistry (Fig. 3A-D). PD-L1 expression and tumor-infiltrating macrophage marker CD68 appeared in the tumor (Fig. 3A-B) before BRAF and MEK inhibitors treatment in December 2013. PD-L1 levels were moderate in both tumor cells and immune cells (IM, circled with red dash lines) adjacent to tumor cells of a neck skin lesion. After completing four doses of ipilimumab, a CT scan was obtained which showed two new hypermetabolic foci within the right neck (Fig. 2A, box 3) suspicious for neoplasm with interval enlargement of the innumerable pulmonary nodules with associated hypermetabolism, compatible with pulmonary metastases. CT imaging showing complete pulmonary lesions disappearance after pembrolizumab initiation. Figure 2C (box 2) also shows the disappearance of most spleen lesions after about 5 months of pembrolizumab treatment. Currently, the patient has only one solitary splenic lesion remaining (Fig. 2C, box 3).