|Year : 2014 | Volume
| Issue : 3 | Page : 752-754
Autologous immune enhancement therapy in a case of gall bladder cancer stage IV after surgical resection and chemotherapy yielding a stable non-progressive disease
Sulabhchandra Bhamare1, Pimparkar Prabhakar1, Aniruddha Dharmadhikari1, Vidyasagar Devaprasad Dedeepiya2, Hiroshi Terunuma3, Rajappa Senthilkumar4, Thangavelu Srinivasan4, Helen C Reena4, Senthilkumar Preethy5, Samuel J K Abraham6
1 Shree Saibaba Heart Institute and Research Centre, Nashik, Maharashtra, India
2 The Mary-Yoshio Translational Hexagon, Nichi-In Centre for Regenerative Medicine, Chennai, Tamil Nadu
3 Biotherapy Institute of Japan, Tokyo, Japan
4 The Fujio-Eiji Academic Terrain, Nichi-In Centre for Regenerative Medicine, Chennai, Tamil Nadu, India
5 The Fujio-Eiji Academic Terrain, Nichi-In Centre for Regenerative Medicine; Hope Foundation (Trust), Chennai, Tamil Nadu, India
6 The Mary-Yoshio Translational Hexagon, Nichi-In Centre for Regenerative Medicine, Chennai, Tamil Nadu, India; Yamanashi University-School of Medicine, Chuo, Japan
|Date of Web Publication||14-Oct-2014|
Dr. Samuel J K Abraham
The Mary-Yoshio Translational Hexagon, Nichi-In Centre for Regenerative Medicine, PB 1262, Nungambakkam, Chennai - 600 034, Tamil Nadu, India
Source of Support: None, Conflict of Interest: None
Advanced gall bladder cancer generally has a poor prognosis and also shows decreased response to conventional therapies like chemotherapy and radiotherapy. Though surgical resection is the most common approach followed, the 1-year survival rate is only 10%. Herein, we report the outcome of administration of autologous natural killer cell and activated T lymphocyte-based autologous immune enhancement therapy (AIET) in a case of gall bladder cancer stage IV which was progressing in spite of surgical resection and several sittings of chemotherapy. There were no adverse reactions after AIET. After three infusions of AIET, an improvement of the quality of life and general condition which is sustaining for more than 6 months and a substantial decrease in the CA 19-9 marker levels from 2938.22 U/mL before AIET to 511 U/mL, 5 months after AIET, in our experience make us recommend AIET along with other conventional treatments in similar cases.
Keywords: Activated T lymphocytes, autologous immune enhancement therapy, gall bladder cancer, immunotherapy, natural killer cells
|How to cite this article:|
Bhamare S, Prabhakar P, Dharmadhikari A, Dedeepiya VD, Terunuma H, Senthilkumar R, Srinivasan T, Reena HC, Preethy S, Abraham SJ. Autologous immune enhancement therapy in a case of gall bladder cancer stage IV after surgical resection and chemotherapy yielding a stable non-progressive disease. J Can Res Ther 2014;10:752-4
|How to cite this URL:|
Bhamare S, Prabhakar P, Dharmadhikari A, Dedeepiya VD, Terunuma H, Senthilkumar R, Srinivasan T, Reena HC, Preethy S, Abraham SJ. Autologous immune enhancement therapy in a case of gall bladder cancer stage IV after surgical resection and chemotherapy yielding a stable non-progressive disease. J Can Res Ther [serial online] 2014 [cited 2017 Dec 12];10:752-4. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/752/136048
| > Introduction|| |
The cancer of the gall bladder though rare, ranks 5 th in the incidence of gastrointestinal cancers  and carries poor prognosis with a 10% 1-year survival rate for advanced stages.  Response to chemotherapy and radiotherapy is also poor and the long-term survival after curative resection is only 5%-12%. , Cell-based immunotherapies with published randomized clinical studies , present a potential option. Herein, we report the effects of natural killer (NK) cell and activated T lymphocyte cell-based autologous immune enhancement therapy (AIET) in a stage IV gall bladder cancer patient after surgical resection and chemotherapy.
| > Case History|| |
A 62-year-old female presented with complaints of pain above the abdomen in February 2011. A computed tomography scan revealed the presence of a lesion in the gall bladder and a focal hepatic lesion. Her CA 19-9 level was 58489.20 U/mL. She underwent six cycles of chemotherapy with carboplatin and paclitaxel, followed by R-0 resection of the gall bladder tumour with the hepatic lesion. Postoperatively, she underwent nine cycles of chemotherapy with carboplatin. After the surgery and postoperative chemotherapy, her CA19-9 level was 72.58 U/mL in July 2011 and she was under continuous follow-up. There was a progressive increase in the CA 19-9 level which was 1284.80 U/mL in February 2012, 1430.41 U/mL in March 2012 and 1987.50 U/mL in April 2012. The patient was again suggested for chemotherapy which ended in July 2012. Her CA 19-9 level was high in spite of the chemotherapy administered (2938.22 U/mL) which indicated progressive disease. Then, she was recommended to undergo NK cell and activated T lymphocyte-based AIET. Exactly, 215 mL of peripheral blood was withdrawn from the patient in the month of August 2012 after proper informed consent. The study was approved by institutional review board of Shree Saibaba Heart Institute and Research Centre, Nashik, Maharashtra, India. The cell count obtained after the isolation of the peripheral blood mononuclear cells was 77 × 10 6 cells. The in vitro NK cell, T cell expansion [Figure 1] and activation were based on the earlier described protocols. , Only patient's autologous plasma was used for the expansion and no feeder layers were employed. Three infusions of the in vitro expanded NK cells and activated T lymphocytes were administered after the 11 th day with 3 days interval between each infusion. The average number of NK cells infused was 1.12 × 10 9 cells and the average activated T cell number infused was 1.47 × 10 9 cells. In September 2012, her CA 19-9 was 2876.68 U/mL. However, in October 2012, the CA 19-9 level increased to 4844.29 U/mL and in November 2012, it increased to 9089.45 U/mL. Four months after the AIET infusions, in January 2013, her CA 19-9 level decreased to 511 U/mL. The patient had other subjective improvements including improvement in appetite, decreased pain, and she even was able to accompany her family for long distance travel on a pilgrimage. The patient's condition remained stable as per the latest follow-up in March 2013. There were no adverse effects reported after AIET.
|Figure 1: Flow cytometry images of (a) isolated peripheral blood mononuclear cells, (b) cells in the natural killer cell culture flask after in vitro culture expansion, (c) cells in the T cell culture flask after in vitro culture expansion|
Click here to view
| > Discussion|| |
Cell-based immunotherapy has already been applied for stage IV cancers refractory to other modalities of treatment. , Advanced gall bladder cancers are generally refractive to conventional modalities of treatment and administration of cell-based immunotherapy has been already been reported for advanced gall bladder cancer.  Hence in this present case, as the disease continued to progress in spite of surgical resection and chemotherapy, she was recommended for AIET. After the AIET, there was a transient increase in the CA 19-9 levels. A transient increase in CA 19-9 during chemotherapy has been hypothesized to be due to the tumorolytic effect  and it has been suggested that this transient increase should not be considered as disease progression.  Recent reports have also suggested NK cell-based immunotherapy may, in fact, act as a cellular vaccine as it activates the endogenous adaptive tumor response,  thereby having a prolonged beneficial effect. Therefore, the transient increase of the CA 19-9 level in this patient in the acute phase after the AIET may also be hypothesized due to the tumourolytic effect of the injected NK cells and activated T cells. The CA 19-9 level, which is a significant biomarker indicating the status of gall bladder, biliary, and pancreatic cancers,  has significantly decreased following AIET. In addition, the improvement of the general condition and the quality of life which is sustaining in this stage IV gall bladder cancer patient for more than 6 months after immunotherapy suggests that AIET can be beneficial in patients with gall bladder cancer, especially in advanced stages refractory to conventional modalities of treatment and this approach can be tried in similar cases in the future.
| > Conclusion|| |
Autologous NK cells and T lymphocytes-based AIET is found to be safe and considered to have helped, as evident from the decrease of cancer marker CA 19-9 levels and an improvement of the quality of life and general condition which is sustaining for more than 6 months in a case of stage IV gall bladder cancer. As conventional therapies have not been significantly effective in this case and that the administration of AIET having been found helpful, we recommend the same be considered as an option in similar cases along with the conventional treatments such as surgery and chemotherapy.
| > Acknowledgments|| |
The authors thank the following:
- M/S Hope Foundation, Loyola ICAM College of Engineering Technology (LICET) and Loyola Institute of Frontier Energy (LIFE) for their support to our research work
- M/s Department of Clinical Research, Yamanashi University, Japan for their assistance with the publication of the manuscript.
| > References|| |
Mekeel KL, Hemming AW. Surgical management of gallbladder carcinoma: A review. J Gastrointest Surg 2007;11:1188-93.
Lazcano-Ponce EC, Miquel JF, Muñoz N, Herrero R, Ferrecio C, Wistuba II, et al
. Epidemiology and molecular pathology of gallbladder cancer. CA qCancer J Clin 2001;51:349-64.
Qu K, Chang HL, Liu SN, Liu C, Xu XS, Wang RT, et al
. Prognosis and management for gallbladder cancer with hepatic invasion: Long-term results of 139 patients from a single center in China. Asian Pac J Cancer Prev 2012;13:1015-8.
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al
. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet 2000;356:802-7.
Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, et al
. Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: A randomized trial. Clin Cancer Res 2002;8:1767-71.
Takada M, Terunuma H, Deng X, Dewan MZ, Saji S, Kuroi K, et al
. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer 2011;18:64-7.
Dedeepiya VD, Terunuma H, Deng X, Baskar S, Manjunath SR, Senthilkumar R, et al
. A comparative analysis of in vitro
expansion of natural killer cells of a patient with autoimmune haemolytic anaemia and ovarian cancer with patients with other solid tumours. Oncol Lett 2012;3:435-40.
Nakamura M, Wada J, Suzuki H, Tanaka M, Katano M, Morisaki T. Long-term outcome of immunotherapy for patients with refractory pancreatic cancer. Anticancer Res 2009;29:831-6.
Murakami K, Tanimura H, Yamaue H, Mizobata S, Noguchi K, Nakamori M, et al
. Clinical effect of immunochemotherapy for a patient with advanced gallbladder cancer: Report of a case. Surg Today 1998;28:923-8.
Yau T, Wong H, Chan P, Chan T, Mak J, Epstein RJ. Transient carcinoembryonic antigen elevations during adjuvant chemotherapy for colorectal cancer reflect the burden of residual micrometastatic disease. Clin Colorectal Cancer 2010;9:108-12.
Kim HJ, Lee KW, Kim YJ, Oh DY, Kim JH, Im SA, et al
. Chemotherapy-induced transient CEA and CA19-9 surges in patients with metastatic or recurrent gastric cancer. Acta Oncol 2009;48:385-90.
Salagianni M, Baxevanis CN, Papamichail M, Perez SA. New insights into the role of NK cells in cancer immunotherapy. Oncoimmunology 2012;1:205-7.
Malati T. Tumour markers: An overview. Indian J Clin Biochem 2007;22:17-31.