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

Discussion and Conclusion

We describe herein two cases of patients treated with the combination of ACT and an ICI; one patient was treated concurrently with ACT and an ICI, and the other patient obtained a partial response by administration of ACT and a DC vaccine followed by ICI administration for recurrence.

Although grade 1 hypothyroidism occurred in case 1 that required thyroid hormone supplementation, we observed no further severe adverse events in either case. Since we assumed that combination therapy with ACT and the ICI might increase the incidence and severity of adverse events, we used a much lower dose of nivolumab than the standard dose, that is, 0.3 or 0.6 mg/kg body weight (20 mg/kg body weight or 40 mg/kg body weight), respectively. The standard dose of nivolumab used in cancer therapy is usually 240 mg/kg body weight, so the dose administered in this trial was one-sixth or one-twelfth of the standard dose of nivolumab, for which no sufficient clinical data have been reported for evaluating the efficacy of nivolumab for esophageal cancer. However, it has been shown by in vitro analysis that even a low dose of nivolumab, 0.3 mg/kg body weight, was sufficient to inhibit PD-L1/PD-1 association.[17]

Several biomarkers that can predict the clinical response of nivolumab have been reported. PD-L1 expression is one of the candidates, since a number of gastrointestinal cancers overexpress this molecule.[18,19] Although PD-L1 expression determined by immunohistochemical staining has been correlated with prognosis and response to ICIs in several studies,[17,18] other studies demonstrated ICI efficacy in patients deemed to be PD-L1 negative.[20] Thus, the true relationship between PD-L1 expression and clinical efficacy has not yet been elucidated. Tumor mutation burden (TMB) has been demonstrated to be significantly associated with PD-1 and the PD-L1 blocking response. Cancers that have a higher TMB, that is, a higher neoantigen exposure to the immune system, seem more likely to respond to ICIs.[21] In both patients reported herein, analysis of their tumor specimens showed microsatellite stability and a PDL-1 expression level of 1% or lower. TILs are also found to be an independent marker for prolonging progression-free survival and overall survival in esophageal cancer, thus indicating the critical role of T cells in tumor immunity.[22] Nevertheless, these markers do not always determine the treatment response to ICIs, suggesting that other factors, such as host immunity, might affect the clinical response to ICIs. For example, an association has been demonstrated between pretreatment lymphocyte count and response to ICIs: patients with higher baseline lymphocyte counts showed better clinical benefits from ICIs.[23] Lymphocytes in peripheral blood have been reported to include T cells targeting neoantigens derived from tumor cells.[13,24] Thus, an adequate immune status of T cells in patients is necessary to obtain better efficacy of ICIs. Our previous studies revealed that the T cell immune status was impaired in advanced cancer patients and it was restored by ACT, suggesting the beneficial effect of combination therapy with ICIs and ACT.[16,24] Compatible with these observations, flow cytometric analysis revealed that the numbers of CD3+T lymphocytes and their subsets, including TCRαβ+, TCRγδT+, CD4+CD8T, and CD4CD8+T cells, increased after ICI and ACT combination therapy in both patients (Figure 3), and it might lead to favorable responses to ICIs.

Although the dose of nivolumab given to both patients was very low, it remains unclear whether clinical responses could be obtained at a much lower dose of the ICI alone or the combination of ACT and the ICI. A controlled study is necessary with a large number of patients to clarify this issue. In the case that even a very low dose of nivolumab is found to be effective, dose escalation studies may be required to reevaluate the doses of ICIs for cancer treatment.