Persistent anti-NY-ESO-1-specific T cells and expression of differential biomarkers in a patient with metastatic gastric cancer benefiting from combined radioimmunotherapy treatment: a case report

Abstract

Combined radioimmunotherapy is currently being investigated to treat patients with cancer. Anti-programmed cell death-1 (PD-1) immunotherapy offers the prospect of long-term disease control in solid tumors. Radiotherapy has the ability to promote immunogenic cell death leading to the release of tumor antigens, increasing infiltration and activation of T cells. New York esophageal squamous cell carcinoma-1 (NY-ESO-1) is a cancer–testis antigen expressed in 20% of advanced gastric cancers and known to induce humoral and cellular immune responses in patients with cancer. We report on the dynamic immune response to the NY-ESO-1 antigen and important immune-related biomarkers in a patient with metastatic gastric cancer treated with radiotherapy combined with anti-PD-1 pembrolizumab antibody.Our patient was an 81-year-old man diagnosed with locally advanced unresectable mismatch repair-deficient gastric cancer having progressed to a metastatic state under a second line of systemic treatment consisting of an anti-PD-1 pembrolizumab antibody. The patient was subsequently treated with local radiotherapy administered concomitantly with anti-PD-1, with a complete response on follow-up radiologic assessment. Disease control was sustained with no further therapy for a period of 12 months before relapse. We have identified an NY-ESO-1-specific interferon-γ (IFN-γ) secretion from the patients’ T cells that was significantly increased at response (****p˂0.0001). A novel promiscuous immunogenic NY-ESO-1 peptide P39 (P153–167) restricted to the four patient’s HLA-DQ and HLA-DP alleles was identified. Interestingly, this peptide contained the known NY-ESO-1-derived HLA-A2-02:01(P157–165) immunogenic epitope. We have also identified a CD107+ cytotoxic T cell subset within a specific CD8+/HLA-A2-NY-ESO-1 T cell population that was low at disease progression, markedly increased at disease resolution and significantly decreased again at disease re-progression. Finally, we identified two groups of cytokines/chemokines. Group 1 contains five cytokines (IFN-γ, tumor necrosis factor-α, interleukin-2 (IL-2), IL-5 and IL-6) that were present at disease progression, significantly downregulated at disease resolution and dramatically upregulated again at disease re-progression. Group 2 contains four biomarkers (perforin, soluble FAS, macrophage inflammatory protein-3α and C-X-C motif chemokine 11/Interferon–inducible T Cell Alpha Chemoattractant that were present at disease progression, significantly upregulated at disease resolution and dramatically downregulated again at disease re-progression. Combined radioimmunotherapy can enhance specific T cell responses to the NY-ESO-1 antigen that correlates with beneficial clinical outcome of the patient.

Editorial: Dynamic Biomarkers of Response to Anti-Immune Checkpoint Inhibitors in Cancer

“…It is a highly immunogenic tumor-specific antigen inducing both humoral and T cell responses and it is considered as an attractive target for immunotherapy. In fact, NY-ESO-1 can be considered as a dynamic biomarker and a potential target of immunotherapy ( 4 ). Indeed, it has been demonstrated that melanoma patients treated with ipilimumab had an increased rate of NY-ESO-1-specific immunity that was associated with improved clinical benefit of the treatment, especially in patients developing both NY-ESO-1-specific antibody and specific CD8+ T cells ( 5 ).…”

“…Our results showed that NY-ESO-1-specific T cells response was increased after the fifth cycles of treatment (stable disease) but had a significant decline at progression, and that PD-1+ T cells population was markedly reduced after anti-PD-1 treatment ( 6 ). Recently, we have characterized a dynamic NY-ESO-1- specific T cells population that was significantly increased at treatment response in a patient with a metastatic gastric cancer who displayed a long-lasting response to combined radio-immunotherapy ( 4 ).…”

“…Several studies have demonstrated that phenotypic characteristics of immune cells play an important role in predicting the prognosis of cancer patients and their response to different anti-cancer therapies, specifically ICB. Indeed, in a patient with metastatic gastric cancer who responded to combined radio-immunotherapy, we have identified a peripheral CD107+ cytotoxic T cells subset within a specific CD8/HLA-A2-NY-ESO-1 T cell population that was low at disease progression (2.5%), markedly increased at disease resolution (12.9%) and significantly decreased again at disease re-progression (3.6%) ( 4 ). In a retrospective study including 79 cancer patients who received anti-PD-1 therapy, Yuan et al.…”

“…On the other hand, some cytokines/chemokines contributing to immune inhibition were downregulated after nivolumab treatment; 2 biomarkers were increased at progression (IL-6: ****p < 0.0001 and IL-8: ****p < 0.0001) ( 6 ). We have also shown that downregulation of IFN-γ, tumor necrosis factor-α (TNF-α) and few interleukins (IL-2, IL-5 and IL-6) concomitant with an upregulation of perforin, soluble FAS, macrophage inflammatory protein-3α (MIP-3α) and C-X-C motif chemokine 11/Interferon–inducible T Cell Alpha Chemoattractant) correlated with disease resolution in a metastatic gastric patient treated with combined radioimmunotherapy ( 4 ).…”

Locally advanced gastroesophageal junction cancer with pathological complete response to neoadjuvant therapy: a case report and literature review

“…Radioimmunotherapy is also currently being investigated, with radiotherapy having been shown to modulate the immune microenvironment of the tumor and upregulate the expression of PD-L1 on tumor and immune cells to treat patients with cancer (51). In a case report of one patient, radiotherapy combined with pembrolizumab was able to provide a disease control condition (with no further therapy) for a period of 12 months before relapse (52), implying that radioimmunotherapy may have potential in combination therapy. Various combined treatment methods for advanced recurrent or metastatic gastric cancer are being actively explored, and positive results may provide options for the perioperative period.…”