Gamma delta T-cell infusion plus chemotherapy induces long-term remission of gastric cancer after immunochemotherapy failure: A case report

Abstract

BACKGROUND

Pathologic complete response is rarely achieved in metastatic gastric cancer, particularly after progression on standard systemic therapy. Gamma delta (γδ) T cells recognize tumor cells in a major histocompatibility complex-independent manner and may enhance the antitumor effects of complement chemotherapy.

CASE SUMMARY

A 58-year-old man with gastric adenocarcinoma was found to have peritoneal metastases at the time of surgery and underwent palliative subtotal gastrectomy. He received first-line capecitabine/oxaliplatin plus nivolumab for approximately 6 months but subsequently developed new hepatic metastasis and progressive lymphadenopathy. Second-line therapy with ramucirumab plus paclitaxel was discontinued after two cycles because of peripheral neuropathy. The patient was then treated with ramucirumab plus trifluridine/tipiracil combined with autologous γδ T-cell infusions for seven cycles. After 4 months of treatment, contrast-enhanced computed tomography demonstrated disappearance of the hepatic lesion, resolution of peritoneal metastases, and marked regression of lymphadenopathy. Liver wedge resection confirmed the absence of viable tumor cells. The patient has remained recurrence-free for more than 24 months following completion of therapy.

CONCLUSION

The combination of chemotherapy and autologous γδ T-cell infusion may achieve durable remission in selected patients with refractory metastatic gastric cancer.

Key Words: Gamma delta T-cell; Immune checkpoint therapy; Chemotherapy; Trifluridine/tipiracil; Ramucirumab; Antigen presentation; Prognosis; Metastatic; Advanced gastric cancer; Case report

Core Tip: Long-term survival after progression on immunochemotherapy is uncommon in metastatic gastric cancer. We report a patient with stage IV gastric adenocarcinoma who achieved radiologic and pathologic complete response after the addition of autologous gamma delta (γδ) T-cell infusions to ramucirumab and trifluridine/tipiracil. Because γδ T cells recognize stressed tumor cells independent of the major histocompatibility complex, they may retain antitumor activity even when immune checkpoint blockade fails. This case is hypothesis-generating and supports further investigation of γδ T-cell-based immunotherapy in gastric cancer.

INTRODUCTION

Systemic therapy is the cornerstone of treatment for unresectable or metastatic gastric cancer; however, durable complete responses remain rare. In patients with human epidermal growth factor receptor 2-negative advanced gastric or gastroesophageal junction adenocarcinoma, nivolumab combined with chemotherapy has demonstrated improved overall survival compared with chemotherapy alone in a phase III trial[1].

After progression on first-line immunochemotherapy, recommended options include antiangiogenic agents and later-line cytotoxic chemotherapy, but responses are often modest and short-lived[2]. Gamma delta (γδ) T cells are innate-like lymphocytes capable of recognizing and killing tumor cells in a major histocompatibility complex (MHC)-independent manner. Here, we describe a patient with Stage IV gastric adenocarcinoma who achieved long-term remission after the addition of autologous γδ T-cell infusion to ramucirumab and trifluridine/tipiracil following progression on capecitabine/oxaliplatin plus nivolumab.

CASE PRESENTATION

Chief complaints

A 58-year-old male was admitted to our hospital with progressively worsening upper abdominal pain for 3 days.

History of present illness

The patient reported several weeks of chronic upper abdominal discomfort and nausea, with progressive worsening of pain over the preceding 3 days. There was no associated fever or bloody stool.

History of past illness

The patient had a prior history of Helicobacter pylori infection and underwent eradication therapy nine years earlier.

Personal and family history

The patient was a current smoker. There was no family history of malignancy.

Physical examination

Body temperature was 36.6 °C, blood pressure 125/86 mmHg, heart rate 75 beats/minute, and respiratory rate 18 breaths/minute. Mild upper abdominal tenderness was noted without peritoneal signs.

Laboratory examinations

Laboratory testing revealed anemia (hemoglobin at 10.1 g/dL) and hypoalbuminemia (serum albumin at 3.1 g/dL). Tumor markers were elevated: Carcinoembryonic antigen 9 ng/mL (reference range: 0-5 ng/mL) and carbohydrate antigen 19-9 42 mg/L (reference range: 0-35 mg/L).

Imaging examinations

Upper gastrointestinal endoscopy identified a 33 mm × 32 mm ulcerative mass in the gastric antrum (Figure 1A). Biopsy demonstrated moderately differentiated adenocarcinoma with poorly differentiated components (Figure 1B). Contrast-enhanced computed tomography (CT) demonstrated gastric wall thickening, a 2.1 cm hepatic metastatic lesion, and enlarged para-aortic lymph nodes, corresponding to a clinical stage of cT4aN2M0. During exploratory laparotomy, multiple peritoneal nodules were identified, confirming peritoneal metastasis and stage IV disease.

Figure 1 Endoscopic and histopathological findings. A: Esophagogastroduodenoscopy reveals an ulcerative lesion in the gastric antrum; B: Hematoxylin and eosin staining of the biopsy specimen shows moderately differentiated adenocarcinoma with poorly differentiated components (original magnification × 200).

A timeline of key clinical events and treatments is summarized in Table 1.

Table 1 Timeline of the clinical course.

Time	Key events and treatments	Response/outcome
At diagnosis	Diagnosis of gastric adenocarcinoma; palliative subtotal gastrectomy with Roux-en-Y gastrojejunostomy; peritoneal metastasis found intraoperatively	Stage IV disease confirmed
0-6 months after surgery	Capecitabine/oxaliplatin plus nivolumab (first-line)	Progressive disease with new liver metastasis and lymphadenopathy
After progression	Ramucirumab plus paclitaxel (second-line, 2 cycles)	Stopped due to peripheral neuropathy
Next 4 months	Ramucirumab plus trifluridine/tipiracil combined with autologous γδ T-cell infusions (7 cycles)	Radiologic complete response on computed tomography
After the response	Liver wedge resection of the treated lesion	No viable tumor cells (pathologic response)
Additional 3 months	Continuation of ramucirumab, trifluridine/tipiracil, and γδ T-cell infusion	No evidence of disease progression
Follow-up (≥ 24 months after completion)	Routine surveillance	No recurrence

γδ: Gamma delta.

MULTIDISCIPLINARY EXPERT CONSULTATION

Given the complexity of stage IV gastric adenocarcinoma with peritoneal and subsequent hepatic metastases, a multidisciplinary expert consultation comprising specialists in hematology, oncology, surgery, pathology, and cell therapy convened to review the case and develop an integrated treatment strategy.

FINAL DIAGNOSIS

Stage IV gastric adenocarcinoma with peritoneal metastasis and subsequent hepatic metastasis, classified as clinical stage T4aN2M0.

TREATMENT

The patient underwent palliative subtotal gastrectomy and Roux-en-Y gastrojejunostomy for symptom relief. First-line treatment with capecitabine/oxaliplatin plus nivolumab was administered for approximately 6 months, after which radiologic progression was observed, including a new 2.1-cm hepatic lesion and enlarged para-aortic lymph nodes. Second-line ramucirumab plus paclitaxel was initiated; however, paclitaxel was discontinued after two cycles because of peripheral neuropathy. Given limited therapeutic options and intolerance to paclitaxel, treatment was modified to ramucirumab plus trifluridine/tipiracil, and autologous γδ T-cell infusion was added as adoptive cellular immunotherapy.

Autologous γδ T cells were manufactured at the Cell Therapy Center of China Medical University Hospital using a standardized ex vivo expansion protocol. Release criteria included sterility, mycoplasma, and endotoxin testing, along with assessment of cell viability and γδ T-cell enrichment as confirmed by flow cytometry. The patient received seven intravenous γδ T-cell infusions at approximately 2-4 weeks intervals during systemic therapy.

We hypothesized that combining chemotherapy and anti-angiogenic therapy might reduce tumor burden and modulate the tumor microenvironment, thereby enhancing the cytotoxic activity of infused γδ T cells; however, this mechanism was not directly evaluated.

OUTCOME AND FOLLOW-UP

After 4 months of combination therapy, contrast-enhanced CT demonstrated disappearance of the hepatic lesion, resolution of peritoneal metastases, and marked regression of lymphadenopathy (Figure 2). Radiologic complete response was defined as disappearance of all measurable lesions without new lesions on imaging.

Figure 2 Radiologic response to combination therapy. A and B: Contrast-enhanced abdominal computed tomography (CT) performed before initiation of ramucirumab plus trifluridine/tipiracil combined with gamma delta T-cell infusion demonstrates a 2.1 cm hepatic metastatic lesion and enlarged para-aortic lymph nodes; C and D: Follow-up CT obtained after four months of therapy demonstrates disappearance of the hepatic lesion and marked regression of lymphadenopathy (A and C: Transverse plane; B and D: Coronal plane).

To confirm hepatic response, liver wedge resection was performed and revealed no viable tumor cells, consistent with a pathologic complete response. The patient continued ramucirumab, trifluridine/tipiracil, and γδ T-cell infusions for an additional 3 months. More than 24 months after completion of combination therapy, he remains free of disease recurrence.

DISCUSSION

Durable remission refers to a sustained clinical response marked by the absence of disease progression or recurrence for an extended period following therapy. In this case, a durable complete response was achieved in stage IV gastric cancer following disease progression on capecitabine/oxaliplatin combined with nivolumab. Although immune checkpoint inhibitors have improved survival outcomes in advanced gastric cancer, both primary and acquired resistance remain frequent, and many patients ultimately experience disease progression[1].

Potential explanations

Loss or downregulation of MHC class I antigen presentation is a well-recognized mechanism of tumor immune evasion and may limit the effectiveness of CD8 T cell-dependent checkpoint blockade[3]. In contrast, γδ T cells are capable of recognizing stressed tumor cells in an MHC-independent manner. Therefore, adoptive γδ T-cell transfer may retain cytotoxic activity even when antigen presentation pathways are impaired.

Rationale for combination therapy

The clinical response observed in this case occurred during treatment with ramucirumab plus trifluridine/tipiracil in combination with γδ T-cell infusions. Chemotherapy may have enhanced tumor cell stress and antigen release, while anti-angiogenic therapy could have improved immune cell trafficking. However, these proposed mechanisms require further mechanistic validation.

Clinical context

In gastric cancer, higher densities of tumor-infiltrating γδ T cells have been associated with improved prognosis and enhanced response to chemotherapy, suggesting that γδ T cells can participate in antitumor immunity[4]. Emerging evidence also suggests interactions between γδ T cells and immune checkpoint pathways, supporting continued exploration of γδ T-cell-based immunotherapeutic strategies[5].

Limitations

This report has several limitations. As a single-patient case, it is not possible to distinguish the relative contributions of ramucirumab, trifluridine/tipiracil, and γδ T-cell infusion to the observed clinical response. In addition, key biomarker data-including programmed death ligand 1 expression, microsatellite instability status, and longitudinal immune monitoring-was unavailable. Mechanistic correlates, such as the persistence of infused γδ T-cells, were also not assessed. Therefore, the findings should be interpreted as hypothesis-generating.

CONCLUSION

This case suggests that autologous γδ T-cell infusion combined with chemotherapy may contribute to a favorable response and durable complete remission in refractory stage IV gastric cancer. Prospective clinical studies are needed to determine efficacy, optimal integration with systemic therapy, and appropriate patient selection.

ACKNOWLEDGEMENTS

The authors would like to thank the patient and his family for providing consent to share his clinical course for educational and scientific purposes. We also acknowledge the staff of the Cell Therapy Center at China Medical University Hospital for their technical support in the preparation and quality control of the autologous γδ T-cell products.