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

Allogenic Vγ9Vδ2 T cell as new potential immunotherapy drug for solid tumor: a case study for... 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 × 10 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: Gamma delta (γδ) T cells, Immunotherapy, Cholangiocarcinoma, Clinical trial Introduction duct stones, parasitic infections, hepatitis B virus infection, Cholangiocarcinoma (CCA) is the most common malig- chemical carcinogen exposure, diabetes, and smoking nancy of the biliary tree; it may cause fatal consequences were reported to be probably related to CCA incidences in a short period of time [1–3]. Currently, the pathogen- [4, 5]. CCA is highly aggressive and metastatic; statistics esis of this disease has not yet been clearly defined, al- have shown an approximate median survival of 24 months though high-risk factors, such as Primary Sclerosing [6, 7]. Cholangitis (PSC), fibrous polycystic liver, intrahepatic bile For recurrent CCA, however, the median survival is only 9 months, and the five-year survival is less than 5% [8]. * Correspondence: xukc@vip.163.com; tyzwu@jnu.edu.cn; zhinan.yin@yale.edu Because of poor efficacy results and prognoses of exist- Kecheng Xu, Yangzhe Wu and Zhinan Yin contributed equally to this work. ing treatments for malignant cancer, the most up-to-date Mohammed Alnaggar and Yan Xu share the first authorship. treatments are continually being researched, or under clin- Department of Oncology, Fuda Cancer Hospital, School of Medicine, Jinan University, Guangzhou 510665, Guangdong, People’s Republic of China ical trials. Among new developing therapeutics, immune Biomedical Translational Research Institute and The First Affiliated Hospital, cell therapy is emerging as an important alterative for ma- Jinan University, 601 W Ave Huangpu, Guangzhou 510632, Guangdong, lignant cancer treatment, particularly after the success of People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 2 of 7 CD19 CAR-T [9, 10]. However, for all existing adoptive In addition, for the first time via this clinical trial study immune cell therapy, autologous T cells were applied for CCA, we discovered evidence that allogenic γδ T because of MHC restriction. Until present, there have been cells in immunotherapy are clinically safe and risk-free. no reports concerning allogenic T cell applications regard- In this case, the patient only received allogenic γδ Tcell ing clinical safety or efficacy. As for γδ T cells, all previous treatments. We did not observe any side effects after cell reported works only focused on autologous cells (in vitro infusions, and more strikingly, peritoneal lymph node or in vivo expansion strategy) as well [11–20]. metastasis was depleted. Currently, the patient’s condi- In this report, we applied allogenic γδ Tcells (Vγ9Vδ2 tion is completely released and stable. The Regional Eth- subsets) as a new type of immune cell therapy to treat ics Committee of Guangzhou Fuda Cancer Hospital CCA. To our knowledge, our work provided the first approved the study protocol (Approval ID 2017–02). paradigm on using allogenic γδ T cells to treat cancer. Written informed consent was obtained from the par- Previously, literatures have demonstrated that γδ Tcells ticipant, in accordance with the Declaration of Helsinki. are the “first line of defense” as an antitumor effector cell And ClinicalTrials.gov ID: NCT02425735. [21, 22], for instance, γδ T cells provide an early source of IFN-γ in the tumor microenvironment [23]. Unlike αβ T Case report and methods cells, γδ T cells recognize antigens in a non-MHC restric- A 30-year-old man was diagnosed as Cholangiocarci- tion manner. Molecules like LFA, NKG2D, CD16, and noma with mediastinal lymph node metastasis stage others play key roles in γδ T cell recognition and killing of IV. In July 2013, he received treatment at a local hos- cancer cells. Altogether, γδ T cells could be a promising pital for Crohn’s disease. In Nov. 2014, he received a candidate for cancer immunotherapy [24–26]. liver transplantation; a huge tumor at hepatic portal 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 3 of 7 was intraoperatively resected. The postoperative path- for infectious diseases. Following this procedure, a ology report revealed a liver and hepatic portal poorly- cell culture formula, which we developed (patent differentiated adenocarcinoma with unresectable Cholan- pending) that included zoledronic acid and a variety giocarcinoma metastasized to lymph nodes. of interleukin was applied specifically to expand The MRI scan performed on Feb. 24th, 2015 showed a Vγ9Vδ2 T cells in vitro (culture media components lesion in patient’s liver, therefore, he received lymph and mechanism will be discussed in detail in our pre- node resection on Apr. 13th, 2015. From Jun. 13th, 2015 paring article). With this formula, we can generally to Aug. 14th, 2015, the patient received radiotherapy for obtain 300–400 million of Vδ2 T cells at ~ 12 days. hepatic portal and the area adjacent to inferior vena Figure 1 shows a brief illustration on cell expansion cava, with a total dosage of 45Gy. Afterward, the patient and cell quality control as well as cell reinfusion, and did not receive any further anti-cancer treatments, ex- Fig. 2 indicates schedules of γδ T cell treatments and cept follow-up visits. The PET/CT collected on Apr. immunophenotypes monitoring (Additional file 1: 15th, 2016, showed lesions in mediastinum and liver. On Figure S1 and S2). Jun. 29th, 2016, the patient came to the Fuda Cancer Hospital. Firstly, aspiration biopsy was conducted and 10 Immunophenotype evaluation I was seeded into the mediastinal tumor. On June 5 mL of peripheral blood was extracted from the patient 2017, when the patient came back the Fuda Cancer Hos- each time, 1–3 days before receiving Vδ2 T cell treat- pital for follow-up check-up, biopsy result showed recur- ment. Peripheral blood monocyte cells (PBMC) were rent abdominal lymph node metastasis by experts’ isolated using the Ficoll recipe. Then immunofluores- consultation, therefore starting from June 2017, the pa- cence labeled cells were analyzed using flow cytometry tient only received γδ T cell immunotherapy to control (FACSanto™ II; BD Biosciences, San Jose, CA, USA). The his lesions, and the first γδ T cell infusion was scheduled analyzed immune cells mainly included T lymphocytes, on August 2017. NK cells, and γδ T cells. Immunotherapy Tumor monitoring by MRI imaging and follow-up 100 ml of blood was donated by a donor who had During Vδ2 T cell treatment, tumor was routinely evalu- passed a health examination that included a check ated by using MRI imaging to monitor tumor size/area 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 4 of 7 AB C 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 changes by the largest transverse diameter, particularly Results before and after treatment. The patient received plain Firstly, from the MRI images (Fig. 3), we can see that and enhanced MRI 2 weeks before treatment, and then the size of the lymph nodes is markedly reduced, visual- scanned periodically at the 3rd and 6th months after izing that lymph nodes metastases of the patient were treatment. gradually eliminated with increasing infusion times of 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 5 of 7 Vδ2 T cells. Such visual images indicated that the patient Discussion greatly benefited from allogenic Vγ9Vδ2 T cell treatment Because γδ T cells can bridge the gap between innate in this case. Then, the immunophenotypes of the patient and adaptive immune systems and are critical in surveil- before and after γδ T cell treatment were analyzed lance and defense of tumorigenesis and infection, γδ T (Fig. 4). We evaluated immunophenotype variations of cell-based immunotherapy could be developed into a CD4+, CD8+, NK, and γδ T cells using immunofluores- promising treatment for tumor control or elimination cence labeling and flow cytometry. The results showed [24–30], particularly for diseases refractory to traditional that γδ T cell therapy could greatly improve immunity by treatments (surgery, chemotherapy and radiotherapy). regulating the immunological functions of these immune It’s known that γδ T cells can recognize target cells cells, as the administration of γδ T cells was associated with (cancer cells or pathogen-infected cells) in a MHC inde- an increase of the functional CD3 + CD4 + CD28+ T cells pendent way, which implicates with the immunological and CD3 + CD8 + CD28+ T cells, and decrease of CD3 + mechanism of high allogeneic safety of γδ T cells [31]. CD4 + CD28- T cells and CD3 + CD4 + CD28-CD57+ T This clinical trial study also clearly evidenced that there cells. It should be mentioned that, the patient was oraling were no observed complications related to γδ Tcell Rapamune 2mg, Ursofalk 500mg once a day, these two infusion. drugs serve as anti-transplanet rejection since the patient In this report, we evaluated the safety and efficacy of received liver transplantation. allogenic Vγ9Vδ2 T cells for the first time as a new type Biochemical examination results clearly demonstrated of immunotherapy to treat a patient (stage IV Cholan- that allogenic Vγ9Vδ2 T cells were safe for immunother- giocarcinoma and liver transplanted) with recurrent me- apeutic application (Fig. 5). We noticed that the expres- diastinal lymph node metastasis. The patient received γδ sion of tumor marker molecule was maintained at a low T cell treatment every 2 weeks for the first six treat- level during γδ T cell treatment, and there was no liver ments, and every 4 weeks for the last two treatments function impairment. This was consistent with the stable (between August, 2017 and February, 2018) (Fig. 2). physical condition and sound prognosis of the patient. Clinical results clearly demonstrated that allogenic Altogether, this clinical trial study clearly evidenced that Vγ9Vδ2 T cells were safe for immunotherapeutic appli- there were no observed complications related to γδ T cation, and that allogenic Vγ9Vδ2 T cell treatment elimi- cell infusion. nated tumor metastases in this case (Fig. 3). Firstly, from 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 6 of 7 the MRI images (Fig. 3), we can see that the size of the Acknowledgements We thank Mrs. Pipoly Zsofia, a patient’s friend who donated blood four times lymph nodes is markedly reduced, visualizing that lymph for PBMC isolation and cell culture, and as translator between researchers nodes metastases of the patient were gradually elimi- and the patient. nated with increased infusion times of Vδ2 T cells. Then, Funding the immunophenotypes of the patient before and after The present study was partially supported by: Guangzhou Science and γδ T cell treatment were analyzed (Fig. 4). We evaluated Technology Key Project (201604020006), Scientific and Technological Plan of immunophenotypes of CD4+, CD8+, NK, and γδ T cells Guangdong Province (201704KW010), the Key Program of the National Natural Science Foundation of China (31830021), the Major International using immunofluorescence labeling and flow cytometry. Joint Research Program of China (31420103901), the ‘111 project’ We found that γδ T cell therapy could greatly improve (B16021), and International Foundation for Sciences of Guangzhou, Fuda immunity by regulating αβ T cells and NK cells. For in- Cancer Hospital (Y2016-ZD-007). stance, it could elevate ratio of naïve, functional CD4+, Availability of data and materials and CD8+ T cells, and reduce exhausted and aged CD4 No data sets were generated or analyzed for inclusion in this report. +, CD8+ T cells, and so on (Fig. 4). Previous literatures [21, 26, 32, 33] proposed that γδ T cells can regulate Authors’ contributions Protocol design: ZNY, YZW, KCX, MA, and JBC. Clinical therapy of the patient: other immune cells including potentiating functions of KCX, MA, and JBC. Immuno-function testing and statistics analysis: YX, JXL, CD4+, CD8+ T cells, maturing dendritic cells and acti- JYH, QLW, LL, ML, JWL, YC, and YH. Cell culture and quality control: YQL and vate neutrophils. As a further step, our work here re- XHW. Manuscript drafting: MA. Manuscript writing, revision and proof- reading: YZW, ZNY. All authors contributed to results discussion and confirm- vealed that Vδ2 subpopulation transfer therapy can ation of clinical protocol, and approved manuscript submission. affect αβ T cell differentiation and NK maturation, par- ticularly, for example, by reducing exhausted and aged Ethics approval and consent to participate The study protocol received ethical approval from the Regional Ethics αβ T cells and elevating functional αβ T cells. Addition- Committee of Guangzhou Fuda Cancer Hospital, China. Written informed ally, according to Fig. 5, we noticed that the expression consent was obtained from participant in accordance with the Declaration of tumor marker molecules AFP and CA-199 was main- of Helsinki, and ClinicalTrials.gov ID: NCT02425735. tained at a low lever during γδ T cell treatment, with no Consent for publication observed impaired liver functions. This is consistent Not applicable. with the stable physical condition and sound prognosis of the patient. Competing interests The IND for allogenic γδ T cell application in clinical therapy is filling in both In conclusion, in this case report, we conducted allo- PR China and USA. genic γδ T cell immunotherapy of Cholangiocarcinoma for the first time. The clinical outcome evidenced that Publisher’sNote allogenic γδ T cell therapy was very safe and displayed Springer Nature remains neutral with regard to jurisdictional claims in reliable efficacy in liver cancer treatment. This exciting published maps and institutional affiliations. trial opened a new window for cancer immunotherapy Author details and could inspire more clinical trial studies, based upon Biomedical Translational Research Institute and The First Affiliated Hospital, allogenic γδ T cell. Allogenic γδ T cells could be devel- Jinan University, 601 W Ave Huangpu, Guangzhou 510632, Guangdong, People’s Republic of China. Department of Oncology, Fuda Cancer Hospital, oped into a very promising ‘immune drug’ for malignant School of Medicine, Jinan University, Guangzhou 510665, Guangdong, tumor therapy. Our report will undoubtedly represent People’s Republic of China. Department of Biological Treatment Center, the next frontier for immunotherapeutic innovations in Fuda Cancer Hospital, School of Medicine, Jinan University, Guangzhou 510665, Guangdong, People’s Republic of China. cancer research and treatment. Received: 3 October 2018 Accepted: 9 January 2019 Additional file References 1. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Additional file 1: Figure S1. Purity of infused allogenic Vγ9Vδ2 T cells Gores GJ. Guidelines for the diagnosis and management of intrahepatic of all 8 treatment courses is > 85%. According to flow cytometry data, cholangiocarcinoma. J Hepatol. 2014;60:1268–89. rest non Vδ2 T cells including Vδ1 T cells, NK cells, B cells, NKT cells, + + + + - - 2. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, CD8 T cells, CD4 T cells, CD4 CD8 T cells, and CD4 CD8 T cells. Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Figure S2. Molecular phenotypes of allogenic Vγ9Vδ2 T cells Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RI, Raggi C, Perugorria cultured using our developed specific culture formula, showing MJ, Gaudio E, Boberg KM, Marin JJ, Alvaro D. 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Allogenic Vγ9Vδ2 T cell as new potential immunotherapy drug for solid tumor: a case study for cholangiocarcinoma

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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 × 10 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: Gamma delta (γδ) T cells, Immunotherapy, Cholangiocarcinoma, Clinical trial Introduction duct stones, parasitic infections, hepatitis B virus infection, Cholangiocarcinoma (CCA) is the most common malig- chemical carcinogen exposure, diabetes, and smoking nancy of the biliary tree; it may cause fatal consequences were reported to be probably related to CCA incidences in a short period of time [1–3]. Currently, the pathogen- [4, 5]. CCA is highly aggressive and metastatic; statistics esis of this disease has not yet been clearly defined, al- have shown an approximate median survival of 24 months though high-risk factors, such as Primary Sclerosing [6, 7]. Cholangitis (PSC), fibrous polycystic liver, intrahepatic bile For recurrent CCA, however, the median survival is only 9 months, and the five-year survival is less than 5% [8]. * Correspondence: xukc@vip.163.com; tyzwu@jnu.edu.cn; zhinan.yin@yale.edu Because of poor efficacy results and prognoses of exist- Kecheng Xu, Yangzhe Wu and Zhinan Yin contributed equally to this work. ing treatments for malignant cancer, the most up-to-date Mohammed Alnaggar and Yan Xu share the first authorship. treatments are continually being researched, or under clin- Department of Oncology, Fuda Cancer Hospital, School of Medicine, Jinan University, Guangzhou 510665, Guangdong, People’s Republic of China ical trials. Among new developing therapeutics, immune Biomedical Translational Research Institute and The First Affiliated Hospital, cell therapy is emerging as an important alterative for ma- Jinan University, 601 W Ave Huangpu, Guangzhou 510632, Guangdong, lignant cancer treatment, particularly after the success of People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 2 of 7 CD19 CAR-T [9, 10]. However, for all existing adoptive In addition, for the first time via this clinical trial study immune cell therapy, autologous T cells were applied for CCA, we discovered evidence that allogenic γδ T because of MHC restriction. Until present, there have been cells in immunotherapy are clinically safe and risk-free. no reports concerning allogenic T cell applications regard- In this case, the patient only received allogenic γδ Tcell ing clinical safety or efficacy. As for γδ T cells, all previous treatments. We did not observe any side effects after cell reported works only focused on autologous cells (in vitro infusions, and more strikingly, peritoneal lymph node or in vivo expansion strategy) as well [11–20]. metastasis was depleted. Currently, the patient’s condi- In this report, we applied allogenic γδ Tcells (Vγ9Vδ2 tion is completely released and stable. The Regional Eth- subsets) as a new type of immune cell therapy to treat ics Committee of Guangzhou Fuda Cancer Hospital CCA. To our knowledge, our work provided the first approved the study protocol (Approval ID 2017–02). paradigm on using allogenic γδ T cells to treat cancer. Written informed consent was obtained from the par- Previously, literatures have demonstrated that γδ Tcells ticipant, in accordance with the Declaration of Helsinki. are the “first line of defense” as an antitumor effector cell And ClinicalTrials.gov ID: NCT02425735. [21, 22], for instance, γδ T cells provide an early source of IFN-γ in the tumor microenvironment [23]. Unlike αβ T Case report and methods cells, γδ T cells recognize antigens in a non-MHC restric- A 30-year-old man was diagnosed as Cholangiocarci- tion manner. Molecules like LFA, NKG2D, CD16, and noma with mediastinal lymph node metastasis stage others play key roles in γδ T cell recognition and killing of IV. In July 2013, he received treatment at a local hos- cancer cells. Altogether, γδ T cells could be a promising pital for Crohn’s disease. In Nov. 2014, he received a candidate for cancer immunotherapy [24–26]. liver transplantation; a huge tumor at hepatic portal 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 3 of 7 was intraoperatively resected. The postoperative path- for infectious diseases. Following this procedure, a ology report revealed a liver and hepatic portal poorly- cell culture formula, which we developed (patent differentiated adenocarcinoma with unresectable Cholan- pending) that included zoledronic acid and a variety giocarcinoma metastasized to lymph nodes. of interleukin was applied specifically to expand The MRI scan performed on Feb. 24th, 2015 showed a Vγ9Vδ2 T cells in vitro (culture media components lesion in patient’s liver, therefore, he received lymph and mechanism will be discussed in detail in our pre- node resection on Apr. 13th, 2015. From Jun. 13th, 2015 paring article). With this formula, we can generally to Aug. 14th, 2015, the patient received radiotherapy for obtain 300–400 million of Vδ2 T cells at ~ 12 days. hepatic portal and the area adjacent to inferior vena Figure 1 shows a brief illustration on cell expansion cava, with a total dosage of 45Gy. Afterward, the patient and cell quality control as well as cell reinfusion, and did not receive any further anti-cancer treatments, ex- Fig. 2 indicates schedules of γδ T cell treatments and cept follow-up visits. The PET/CT collected on Apr. immunophenotypes monitoring (Additional file 1: 15th, 2016, showed lesions in mediastinum and liver. On Figure S1 and S2). Jun. 29th, 2016, the patient came to the Fuda Cancer Hospital. Firstly, aspiration biopsy was conducted and 10 Immunophenotype evaluation I was seeded into the mediastinal tumor. On June 5 mL of peripheral blood was extracted from the patient 2017, when the patient came back the Fuda Cancer Hos- each time, 1–3 days before receiving Vδ2 T cell treat- pital for follow-up check-up, biopsy result showed recur- ment. Peripheral blood monocyte cells (PBMC) were rent abdominal lymph node metastasis by experts’ isolated using the Ficoll recipe. Then immunofluores- consultation, therefore starting from June 2017, the pa- cence labeled cells were analyzed using flow cytometry tient only received γδ T cell immunotherapy to control (FACSanto™ II; BD Biosciences, San Jose, CA, USA). The his lesions, and the first γδ T cell infusion was scheduled analyzed immune cells mainly included T lymphocytes, on August 2017. NK cells, and γδ T cells. Immunotherapy Tumor monitoring by MRI imaging and follow-up 100 ml of blood was donated by a donor who had During Vδ2 T cell treatment, tumor was routinely evalu- passed a health examination that included a check ated by using MRI imaging to monitor tumor size/area 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 4 of 7 AB C 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 changes by the largest transverse diameter, particularly Results before and after treatment. The patient received plain Firstly, from the MRI images (Fig. 3), we can see that and enhanced MRI 2 weeks before treatment, and then the size of the lymph nodes is markedly reduced, visual- scanned periodically at the 3rd and 6th months after izing that lymph nodes metastases of the patient were treatment. gradually eliminated with increasing infusion times of 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 5 of 7 Vδ2 T cells. Such visual images indicated that the patient Discussion greatly benefited from allogenic Vγ9Vδ2 T cell treatment Because γδ T cells can bridge the gap between innate in this case. Then, the immunophenotypes of the patient and adaptive immune systems and are critical in surveil- before and after γδ T cell treatment were analyzed lance and defense of tumorigenesis and infection, γδ T (Fig. 4). We evaluated immunophenotype variations of cell-based immunotherapy could be developed into a CD4+, CD8+, NK, and γδ T cells using immunofluores- promising treatment for tumor control or elimination cence labeling and flow cytometry. The results showed [24–30], particularly for diseases refractory to traditional that γδ T cell therapy could greatly improve immunity by treatments (surgery, chemotherapy and radiotherapy). regulating the immunological functions of these immune It’s known that γδ T cells can recognize target cells cells, as the administration of γδ T cells was associated with (cancer cells or pathogen-infected cells) in a MHC inde- an increase of the functional CD3 + CD4 + CD28+ T cells pendent way, which implicates with the immunological and CD3 + CD8 + CD28+ T cells, and decrease of CD3 + mechanism of high allogeneic safety of γδ T cells [31]. CD4 + CD28- T cells and CD3 + CD4 + CD28-CD57+ T This clinical trial study also clearly evidenced that there cells. It should be mentioned that, the patient was oraling were no observed complications related to γδ Tcell Rapamune 2mg, Ursofalk 500mg once a day, these two infusion. drugs serve as anti-transplanet rejection since the patient In this report, we evaluated the safety and efficacy of received liver transplantation. allogenic Vγ9Vδ2 T cells for the first time as a new type Biochemical examination results clearly demonstrated of immunotherapy to treat a patient (stage IV Cholan- that allogenic Vγ9Vδ2 T cells were safe for immunother- giocarcinoma and liver transplanted) with recurrent me- apeutic application (Fig. 5). We noticed that the expres- diastinal lymph node metastasis. The patient received γδ sion of tumor marker molecule was maintained at a low T cell treatment every 2 weeks for the first six treat- level during γδ T cell treatment, and there was no liver ments, and every 4 weeks for the last two treatments function impairment. This was consistent with the stable (between August, 2017 and February, 2018) (Fig. 2). physical condition and sound prognosis of the patient. Clinical results clearly demonstrated that allogenic Altogether, this clinical trial study clearly evidenced that Vγ9Vδ2 T cells were safe for immunotherapeutic appli- there were no observed complications related to γδ T cation, and that allogenic Vγ9Vδ2 T cell treatment elimi- cell infusion. nated tumor metastases in this case (Fig. 3). Firstly, from 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 Alnaggar et al. Journal for ImmunoTherapy of Cancer (2019) 7:36 Page 6 of 7 the MRI images (Fig. 3), we can see that the size of the Acknowledgements We thank Mrs. Pipoly Zsofia, a patient’s friend who donated blood four times lymph nodes is markedly reduced, visualizing that lymph for PBMC isolation and cell culture, and as translator between researchers nodes metastases of the patient were gradually elimi- and the patient. nated with increased infusion times of Vδ2 T cells. Then, Funding the immunophenotypes of the patient before and after The present study was partially supported by: Guangzhou Science and γδ T cell treatment were analyzed (Fig. 4). We evaluated Technology Key Project (201604020006), Scientific and Technological Plan of immunophenotypes of CD4+, CD8+, NK, and γδ T cells Guangdong Province (201704KW010), the Key Program of the National Natural Science Foundation of China (31830021), the Major International using immunofluorescence labeling and flow cytometry. Joint Research Program of China (31420103901), the ‘111 project’ We found that γδ T cell therapy could greatly improve (B16021), and International Foundation for Sciences of Guangzhou, Fuda immunity by regulating αβ T cells and NK cells. For in- Cancer Hospital (Y2016-ZD-007). stance, it could elevate ratio of naïve, functional CD4+, Availability of data and materials and CD8+ T cells, and reduce exhausted and aged CD4 No data sets were generated or analyzed for inclusion in this report. +, CD8+ T cells, and so on (Fig. 4). Previous literatures [21, 26, 32, 33] proposed that γδ T cells can regulate Authors’ contributions Protocol design: ZNY, YZW, KCX, MA, and JBC. Clinical therapy of the patient: other immune cells including potentiating functions of KCX, MA, and JBC. Immuno-function testing and statistics analysis: YX, JXL, CD4+, CD8+ T cells, maturing dendritic cells and acti- JYH, QLW, LL, ML, JWL, YC, and YH. Cell culture and quality control: YQL and vate neutrophils. As a further step, our work here re- XHW. Manuscript drafting: MA. Manuscript writing, revision and proof- reading: YZW, ZNY. All authors contributed to results discussion and confirm- vealed that Vδ2 subpopulation transfer therapy can ation of clinical protocol, and approved manuscript submission. affect αβ T cell differentiation and NK maturation, par- ticularly, for example, by reducing exhausted and aged Ethics approval and consent to participate The study protocol received ethical approval from the Regional Ethics αβ T cells and elevating functional αβ T cells. Addition- Committee of Guangzhou Fuda Cancer Hospital, China. Written informed ally, according to Fig. 5, we noticed that the expression consent was obtained from participant in accordance with the Declaration of tumor marker molecules AFP and CA-199 was main- of Helsinki, and ClinicalTrials.gov ID: NCT02425735. tained at a low lever during γδ T cell treatment, with no Consent for publication observed impaired liver functions. This is consistent Not applicable. with the stable physical condition and sound prognosis of the patient. Competing interests The IND for allogenic γδ T cell application in clinical therapy is filling in both In conclusion, in this case report, we conducted allo- PR China and USA. genic γδ T cell immunotherapy of Cholangiocarcinoma for the first time. The clinical outcome evidenced that Publisher’sNote allogenic γδ T cell therapy was very safe and displayed Springer Nature remains neutral with regard to jurisdictional claims in reliable efficacy in liver cancer treatment. This exciting published maps and institutional affiliations. trial opened a new window for cancer immunotherapy Author details and could inspire more clinical trial studies, based upon Biomedical Translational Research Institute and The First Affiliated Hospital, allogenic γδ T cell. Allogenic γδ T cells could be devel- Jinan University, 601 W Ave Huangpu, Guangzhou 510632, Guangdong, People’s Republic of China. Department of Oncology, Fuda Cancer Hospital, oped into a very promising ‘immune drug’ for malignant School of Medicine, Jinan University, Guangzhou 510665, Guangdong, tumor therapy. Our report will undoubtedly represent People’s Republic of China. Department of Biological Treatment Center, the next frontier for immunotherapeutic innovations in Fuda Cancer Hospital, School of Medicine, Jinan University, Guangzhou 510665, Guangdong, People’s Republic of China. cancer research and treatment. Received: 3 October 2018 Accepted: 9 January 2019 Additional file References 1. 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Published: Feb 8, 2019

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