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


J Med Case Reports. 2021;15(191) 

In This Article


Esophageal cancer is an aggressive malignancy and the most common cause of cancer-related death worldwide.[1] Although treatment strategies such as surgery, chemotherapy, radiotherapy, and chemoradiotherapy have been developed in recent years, the prognosis for patients with recurrent or advanced-stage esophageal cancer remains poor.[2] The limited improvement in treatment outcome obtained by conventional therapies has prompted the search for innovative strategies for the treatment of this cancer, especially molecular or immune-targeting treatments.

The programmed death 1 (PD-1) pathway serves as a checkpoint to limit T-cell-mediated immune responses. Two ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PDL-L2), engage the PD-1 receptor and induce PD-1 signaling and associated T-cell exhaustion, resulting in reversible inhibition of T-cell activation and proliferation.[3] Tumor cells can co-opt the PD-1 pathway to evade immune responses by expressing PD-L1 on the cell surface and engaging PD-1 receptor-positive immune effector cells.[4] Thus, PD-1 and PD-L1 have attracted considerable attention for their roles in tumor immunology and as immune-based therapeutic targets.[3,5] A number of clinical trials of PD-1/PD-L1 signal-blockade agents as immune checkpoint inhibitors (ICIs) have recently demonstrated dramatic antitumor efficacy in patients with numerous types of malignancy, including esophageal cancer.[6,7]

Although PD-L1 expression in tumor tissues prior to treatment correlates with clinical outcomes, the density of tumor-infiltrating lymphocytes (TILs) in the invaded margin of the tumor may better predict the response to anti-PD-1/PD-L1 therapy.[8] Recent research has shown four different types of tumor microenvironment based on the presence or absence of TILs and PD-L1 expression.[9] Tumors that are both PD-L1 and TIL positive are most likely to benefit from single-agent anti-PD-1/PD-L1 blockade because such tumors possess preexisting TILs that are turned off by PD-L1 engagement. Thus, better understanding of PD-L1 expression and TIL status in esophageal cancer tissues may have considerable clinical implications.

Adoptive T-cell therapy using TILs has been found to mediate durable, complete cancer regression in patients with melanoma and epithelial cancers.[10–12] Collectively, these responses were likely based on the recognition of unique, patient-specific mutated neoantigens through the T-cell receptor (TCR).[12] However, isolation of TILs from cancer tissue is not always feasible. It was recently demonstrated that peripheral blood lymphocytes contained TIL-like cells recognizing tumor-specific antigens and could be a source of noninvasive options for immune cell therapy.[13] Previously, we and others reported that adoptive T-cell therapy using peripheral blood mononuclear cells (adoptive cell therapy, ACT), which are activated and proliferated through a culture process involving stimulation with an immobilized anti-CD-3 antibody and interleukin-2 (IL-2), has shown certain efficacy against various cancers without severe adverse events,[14,15] indicating that the efficacy of ACT might partially be derived from TILs associated with peripheral blood cells.

Although ICIs have great potential for cancer immunotherapy, their efficacy is still limited by some toxicities. Synergies between ICI therapy and other immunotherapies including cancer vaccines or ACT are currently being investigated in several clinical trials.[15] Here, we report the cases of two patients with advanced esophageal cancer who were successfully treated and responded to the combination of ACT and an ICI, nivolumab, suggesting that this combination might be a possible treatment strategy for advanced esophageal cancer.