Allogenic Vγ9Vδ2 T cell as new potential immunotherapy drug for solid tumor: a case study for cholangiocarcinoma

Abstract

Background: Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA.

Case presentation: A 30-year-old male ( https://www.clinicaltrials.gov/ ID: NCT02425735) was diagnosed with recurrent mediastinal lymph node metastasis after liver transplantation because of Cholangiocarcinoma (stage IV). In the course of his therapy sessions, he only received allogenic γδ T cell immunotherapy from August, 2017 through February, 2018 (8 infusions in total). γδ T cells were expanded from peripheral blood mononuclear cells (PBMCs) of healthy donor, and ~ 4 × 108 cells were adoptive transferred to the patient.

Conclusion: In the above case report of the Cholangiocarcinoma (stage IV) patient who had received liver transplantation and afterward was diagnosed with recurrent mediastinal lymph node metastasis, we clinically proved that allogenic γδ T cell treatment had no adverse effects. We observed that allogenic γδ T cell treatments positively regulated peripheral immune functions of the patient, depleted tumor activity, improved quality of life, and prolonged his life span. After 8 γδ T cell treatments, the size of lymph nodes was remarkably reduced with activity depletion. This clinical work suggested that allogenic γδ T cell immunotherapy could be developed into a promising therapy drug for CCA.

Keywords: Cholangiocarcinoma; Clinical trial; Gamma delta (γδ) T cells; Immunotherapy.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol received ethical approval from the Regional Ethics Committee of Guangzhou Fuda Cancer Hospital, China. Written informed consent was obtained from participant in accordance with the Declaration of Helsinki, and Consent for publication

Not applicable.

Competing interests

The IND for allogenic γδ T cell application in clinical therapy is filling in both PR China and USA.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

A sketch diagram describing immunotherapy from allogenic γδ T cell expansion to infusion: check donor blood (infection diseases), draw peripheral blood (100 ml) from healthy volunteer, isolate PBMC, cell culture and amplification, quality controlling and finally adoptive transfer γδ T cell to patient. The allogenic γδ T cells expanded in vitro were quality-controlled using immunofluorescence labeling and flow cytometry analysis. Quality controlling was performed before every cycle’s intravenous infusions. In our work, patient immune cell function was also analyzed before and after γδ T cell treatments by analyzing peripheral immunophenotypes using flow cytometry

Fig. 2

a Schematic diagram on schedules of γδ T cell treatments and immunophenotypes monitoring. Patient was enrolled in on June 2017, and received cell treatments starting from August 2017. The patient received 8 treatment courses (3 infusions per treatment course infused within 2 days) of γδ T cell treatments from August, 2017 through February 2018. As (a) showing, infusion was performed every 2 weeks for first six infusions, and then 4 weeks for last two infusions. Moreover, before and after γδ T cell treatments, immunophenotyping of the patient was checked up each time. b Purity phenotype of infused allogenic Vγ9Vδ2 T cells for each treatment course. It shows > 85% Vδ2 T cells in CD3+ T lymphocytes were intravenously infused. As for phenotypes of infused Vδ2 T cells and non-Vδ2 T cells were attached in Additional file 1: Figures S1 and S2

Fig. 3

Upper abdominal MRI examinations were taken at 3 time points, a 2 weeks before treatment, b 3 month’s clinical effect post treatment and c 6 months clinical effect post treatment. In this figure, we show representative MRI images obtained before entry into the clinical trial and after the 8th treatment course

Fig. 4

The changes in immunophenotyping before (‘1’) and after (‘2’ - ‘8’) γδ T cell treatments. The results showed that γδ T cell therapy could greatly improve immunity by regulating the immunological functions of peripheral immune cells, as the administration of γδ T cells was associated with an increase of the functional CD3 + CD4 + CD28+ T cells and CD3 + CD8 + CD28+ T cells, and with a decrease of CD3 + CD4 + CD28- T cells and CD3 + CD4 + CD28-CD57+ T cells. In these graphs, checking point ‘1’ means immunophenotyping without γδ T cell treatment, while checking points ‘2’ - ‘8’ stand for immunophenotyping from the first time to the seventh γδ T cell treatments

Fig. 5

Blood biochemical examination. All biochemical markers maintained at a low lever before and after γδ T cell treatments, showing no difference in the level of a alpha-fetoprotein (AFP), b carbohydrate antigen (CA-199), c serum Creatinine, d serum direct bilirubin, e Serum total bilirubin, and f total white blood cells