Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM)
JSRM Code: 008030700137
Cancer incidence and novel therapies developed in Japan Iwasaki M*
Abstract According to the ministry of Health, Labour and welfare of Japan, Cancer has been the leading cause of death in [1] Japan since 1981. As per the data in 2010, in Japan, one [2] in every three deaths was due to cancer. The Japanese Government has introduced so far, three terms of 10 years strategies for Cancer control since 1984 till date. The budget allocated for cancer control in 2009 was 52.5 billion yen in Japan. [3] Lung is the leading site for cancer in both males and females in Japan. In males, following the lung, stomach, liver, colon and pancreas are other leading sites while in the females, stomach, colon, pancreas and breast are the other leading sites. [1] In 2006, the cancer incidence was 694,000 and the male cancer incidence was 1.4 times as large as that of females. The peak age for cancer deaths in males is their fifties while in the females it is the sixties among Japanese. In addition to the conventional treatments such as surgery, radiotherapy and chemotherapy, some of other therapies in practice in Japan are the Hyperthermia [4] that uses high temperatures to kill or damage the cancer cells, the Ion Beam therapy using proton beams [5] to damage the DNA of the cells as cancer cells have high rate of cell divisions and lesser ability to repair DNA damage, the molecular targeted therapies that interfere with a specific molecular target involved in tumour growth and progression[6] and most importantly the autologous cell based Immunotherapies. Modern Cancer Immunotherapy started in the 1970s in Japan. The immunopotentiators using compounds from Bacteria, Beta Glucans from fungi were the first forms of modern Immunotherapy. Then was the era of direct injection of cytokines such as Interleukins, Interferons etc. The adverse effects associated with the injection of cytokines led to development of cell based [7] Immuno-cell therapies Immunotherapies in the 1980s. involve isolation of immune cells which are then processed and re-injected into the body to exert their action against the cancer. There are different kinds of Immuno-cell therapies being practised in more than 25 private and public institutions in Japan using Natural Killer (NK) cells,
Cytotoxic T lymphocytes (CTLs), Tumour Infiltrating Lymphocytes (TIL), Lymphokine activated Killer (LAK) cells, [7] Dendritic cells and Gamma Delta T (γδ T) cells. Importantly most of the innovations in cell based therapies in the world have been made in Japan because immunotherapy is a part of the Japanese Health care system and routine therapies for cancer in Japan. There have been randomized clinical trials on Immuno-cell therapy for liver cancer, lung cancer, gastric cancer, ovarian cancer with the results suggesting statistically significant increase in survival rate and increase in disease free survival rate. [8, 9, 10, 11] There are more than 25 institutions in Japan performing such cell based immunotherapies. A comprehensive review by Egawa et al on 1401 patients showed that when Immuno-cell therapy was combined with the conventional therapies, the efficacy [7] increased upto 20-30%. Immuno-cell is the least toxic of all therapies and can be administered even to terminally ill cancer patients. [12] Contrast to drugs, as autologous cell based Immuno-therapies are from the patient’s own blood and as they are custom tailored to each patient, though expensive, the adverse effects are minimal. To conclude, cancer-Immunocell therapies are the future of cancer therapies and further research is needed to enhance its efficacy and validate the results. References: 1.
2.
3.
4.
Cancer Statistics in Japan 2011. http://ganjoho.jp/data/public/statistics/backnumber/2011/f iles/cancer_statistics_2011.pdf Japan Cancer Society. Statistics on dynamic trends in Population compiled by the Ministry of Health, Labour and welfare. http://www.jcancer.jp/english/cancerinjapan/ Maehara Y. Current Status of Cancer Treatment in Japan, and Future Prospects for the Japan Society of Clinical Oncology. JMAJ 54(1): 44–46, 2011 Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Critical Reviews in Oncology/Hematology 2002; 43(1):33–56.
* Department of Clinical Research, Yamanashi University- School of Medicine, Chuo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) 5. 6.
7. 8.
9.
Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer.2005; 93(8):849-54. Widakowich C, de Castro G Jr, de Azambuja E, Dinh P, Awada A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist. 2007; 12(12):1443-55. Egawa K. Immuno-cell therapy of cancer in Japan. Anticancer Res. 2004;24(5C):3321-6. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000; 356(9232):802-7. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or
radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1):42-9. 10. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumorassociated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002; 8: 1767-71. 11. Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995; 1(5):501-7. 12. Goto S, Shirotani N, Hatakeyama M, Tagami C, Arakawa H, Kuwata E, Noguchi K, Egawa K. Clinical benefit of non-toxic therapy in patients with advanced cancer (opinion). Anticancer Res. 2002; 22(4):2461-4.
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM)
JSRM Code: 008030700138
Autologous Immune Enhancement Therapy for Cancer - Our experience since 2004 Terunuma H*
Abstract Introduction: Cancer, the major killer disease of the century requires a multi-pronged approach and among the latest modalities of treatments, Immunotherapy occupies a promising role. Immunotherapy for cancer was first started to be practised in the NIH and cell based immunotherapy for cancer is in practice for the past three decades. [1, 2] There are several literatures from various countries on the successful application of cell based Immunotherapies for various solid [3-8] Our team’s tumours and haematological malignancies. association with immune cells started when I was working on RNA transcriptome analysis to understand the immune system in HIV carriers which in turn required in vitro expansion of human Natural Killer (NK) cells. [9] This led to the customization of protocols which has resulted in successful in vitro expansion, activation of NK cells and T cells for Immunotherapy. The purpose of Biotherapy institute of Japan (BIJ) is to support research and clinical application of immune cells like NK cells, γδT cells, αβT cells, Cytotoxic T lymphocytes (CTL) and Dendritic cells (DC) for application as Autologous Immune Enhancement Therapy (AIET) to fight against cancer. AIET using NK cells, CTLs, DCs etc have been administered for more than 5000 patients since 2004 till date by BIJ. Principle of AIET: For AIET using NK cells, the process involves separation of lymphocytes from the peripheral blood of the patient followed by selective NK cell expansion using the expansion kit (BINKIT, BIJ, JAPAN) without feeder layers [10,11] and then infusion of the expanded-activated NK cells. As reports suggest that the activity of peripheral blood NK cells are lower in cancer patients compared to normal [12] and as in vitro expansion of NK cells individuals increases the cytotoxic ability 5 to 10 fold, [13] the NK cells are expanded in vivo and then infused to the patient in AIET. We are also working on combination immunotherapy using NK cells and CTLs and also NK cells and peptide pulsed DCs. The principle behind combining NK cells and CTLs is
a dual advantage approach combining the innate immune system and adaptive immune system wherein the CTLs will kill the MHC expressing cancer cells while NK cells will kill [10] In case of the MHC non-expressing cancer cells also. NK cells and DCs, DCs will in turn activate the CTLs thereby giving rise to the dual advantage mentioned above. We have recently suggested that the AIET using expanded NK cells, particularly in combination with monoclonal antibody drugs, may be very useful tool for cancer immunotherapy. [14] Our experience: In our studies in NOG SCID mice, activated NK cells were shown to reduce the size of breast cancer cells (MDAMB231) [15] and the volume of ascites also inhibiting lung [16] In metastasis of pleural effusion lymphoma (PEL) cells. a primary lung adenocarcinoma patient where AIET was administered in combination with Hyperthermia, the CEA values decreased from 4.8 ng/ml to 1.6 ng/ml, the SLX decreased from 30 U/ml to 27 U/ml, the IAP reduced from 300 μg/ml to 221 μg/ml along with resolution of the lung lesions in four months. A 55 year old woman treated for invasive ductal carcinoma of breast presented with metastasis to the lungs. She was then treated with trastuzumab in combination with multiple injections of activated natural killer (NK) cells (at two week intervals) following which the tumor markers decreased. Progression [11] Fifty-two patients with free survival was 10 months. advanced cancers in organs like lung, breast, colon, prostate, liver, kidney, ovary etc, refractory to conventional therapy when treated with a combination of hyperthermia and NK cell-and CTL-based immune cell therapy with lowdose chemotherapy, in 18 of 52 patients, objective responses was observed including one complete response (CR) and 17 partial responses (PR) evaluated according to to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Sixteen patients had stable disease (SD), whereas 18 had progressive disease (PD). Disease control rate was 66％ including CR, PR and SD. After treatment for six months, the objective responses and disease control rate were 25％ and 52％, respectively. [17] There were no adverse effects in any of these patients.
*Biotherapy Institute of Japan (BIJ), Tokyo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) Conclusion: Cancer has to be tackled with a multipronged approach and combining NK cell and CTL cell based AIET with conventional modalities of treatments such as Surgery, Chemotherapy and Radiotherapy as well as other modalities like Hyperthermia, Proton Beam therapy and low dose chemotherapy is effective even in advanced cancers which are refractory to conventional therapeutic modalities.
9.
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References: 1. 2.
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Rosenberg SA, Rapp HJ. Intralesional immunotherapy of melanoma with BCG. Med Clin North Am. 1976 May;60(3):419-30. Mazumder A, Eberlein TJ, Grimm EA, Wilson DJ, Keenan AM, Aamodt R, Rosenberg SA. Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells. Cancer. 1984 Feb 15;53(4):896-905 Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000 ;356(9232):802-7. Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F, Baynes R, Wood G. Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg Focus. 2000; 9(6):e9. Recchia F, Candeloro G, Di Staso M, Necozione S, Bisegna R, Bratta M, Tombolini V, Rea S. Maintenance immunotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck. J Immunother. 2008; 31(4):413-9. Wright SE, Rewers-Felkins KA, Quinlin IS, Phillips CA, Townsend M, Philip R, Dobrzanski MJ, Lockwood-Cooke PR, Robinson W. Cytotoxic T-lymphocyte immunotherapy for ovarian cancer: a pilot study. J Immunother. 2012 Feb-Mar;35(2):196-204. Iliopoulou EG, Kountourakis P, Karamouzis MV, Doufexis D, Ardavanis A, Baxevanis CN, Rigatos G, Papamichail M, Perez SA. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother. 2010 Dec;59(12):1781-9. Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin
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RS. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2005 Mar;11(3):181-7. Abraham S. Academic Serendipity to clinical, commercial success. Trade Secrets - Nature Biotech Blog. 2011 Sep. http://blogs.nature.com/tradesecrets/2011/09/12/academ ic-serendipity-to-clinical-commercial-success Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N. Potential role of NK cells in the induction of immune responses: Implications for NK cell-based immunotherapy for cancers and viral infections. Int Rev Immunol 2008; 27: 93-110 Takada M, Terunuma H, Deng X, Dewan MZ, Saji S, Kuroi K, Yamamoto N, Toi M. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer 18:64-7, 2011. Dewan MZ, Takada M, Terunuma H, Deng X, Ahmed S, Yamamoto N, Toi M. Natural killer activity of peripheralblood mononuclear cells in breast cancer patients. Biomed Pharmacother 63:703-6, 2009. Dedeepiya V, Terunuma H, Deng X, Baskar S, Manjunath S, Senthilkumar R, Murugan P, Thamaraikannan P, Srinivasan T, Preethy S, Abraham S. 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.Oncology Letters. 2011;3(2). Doi: 10.3892/ol.2011.498; Deng X, Terunuma H, Nieda M, Xiao W, Nicol A. Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells. International Immunopharmacology (in press) Dewan MZ, Terunuma H, Takada M, Tanaka Y, Abe H, Sata T, Toi M, Yamamoto N. Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo. Breast Cancer Res Treat. 2007 Sep;104(3):267-75. Dewan MZ, Terunuma H, Toi M, Tanaka Y, Katano H, Deng X, Abe H, Nakasone T, Mori N, Sata T, Yamamoto N. Potential role of natural killer cells in controlling growth and infiltration of AIDS-associated primary effusion lymphoma cells. Cancer Sci. 2006 Dec;97(12):1381-7. Terunuma H, Deng X , Toki A, Yoshimura A, Nishino N, Takano Y, Nieda M, Sasanuma J, Teranishi Y, Watanabe K. Effects of Hyperthermia on the Host Immune System : From NK Cell-based Science to Clinical Application.Thermal Medicine 2012; 28 (1): 1-9
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM)
JSRM Code: 008030700139
Hurdles overcome in technology transfer for AIET and Positive outcome in Indian patients Dedeepiya V1, Ramanan G2, Munirathnam D3, Sumana P4,Terunuma H5, Senthilkumar R1, Srinivasan T1, 1 1,6 1,7 Reena H , Preethy S , Abraham S
Abstract Introduction Cell based immunotherapies have been in practice in Japan for the past two decades with established clinical trials on its efficacy in both solid tumours and hematological malignancies including gastric cancer, ovarian cancer , [1,2,3,4] In India, NCRM has lung cancer and liver cancer. been providing Autologous Immune Enhancement Therapy (AIET) using autologous Natural Killer (NK) cells and activated T Lymphocytes for Cancer since 2005 following the established protocols practiced by the Biotherapy Institute of Japan. Significant outcome achieved after AIET in advanced pancreatic cancer, Acute Myeloid leukemia (AML) in Indian patients have already been reported.[5, 6] Here we report our experience in few more patients and present the hurdles overcome and lessons learned in translating the technology from Japan to India Case Details: Case 1: A 54 year-old female presented with Stage IV recurrent ovarian malignancy in 2010 with a history of previous surgery and chemotherapy for ovarian malignancy in June 2009. The CA-125 level of 243 U/ml. CT scan revealed lesions in the liver, spleen, along the greater curvature of body of stomach and in the perisplenic region, between the medial aspect of liver and stomach and in the right inguinal region. She was suggested six cycles of chemotherapy with Doxorubicin (50 mg) and Carboplatin (450 mg) along with AIET. After proper informed consent, the peripheral blood was withdrawn and the in vitro expansion of the NK cells, activated T Lymphocytes from the peripheral blood [7] was performed using the protocol reported earlier. Average cell count after the in vitro expansion was 1.2 X 108 cells. Six transfusions of the in vitro expanded NK cells and activated T lymphocytes were administered following which the CA-125 decreased to 4.7 U/mL. CT scan taken in
December 2010 showed a regression of the lesions in the spleen and perisplenic peritoneal deposits, stable hepatic lesions and resolution of perigastric peritoneal deposits with a marked decrease in the size of the inguinal lymph nodes from and no recurrence in the pelvic region. There was also improvement in appetite and quality of life of the patient. There were no adverse reactions following the [8] AIET infusions. The latest follow-up in May 2012 revealed static non progressive disease with all the parameters including tumor markers within normal range. Case 2: A 15 year old girl presented with complaints of diffuse bone pain for 3 months, intermittent fever for 1 month and increasing pallor in October 2004. On examination, she was found to have pallor with hepatosplenomegaly. A low haemoglobin level (9.3 mg/dl), low platelets (21000) and a WBC count of 13600 with 83% lymphoblasts was revealed in her blood picture. Bone marrow examination and flow cytometry were suggestive of Acute Lymphoblastic Leukemia – CD 10+ CD 19+. Cytogenetics revealed Philadelphia chromosome and BCR-ABL positivity. Qualitative BCR-ABL was done serially to assess disease status. She was started on chemotherapy as per UK MRC protocol – Regimen B along with Imatinib Mesylate (in view of her BCR-ABL positivity) and prophylactic cranial radiotherapy of 12 Gy at the end of delayed intensification. She had persistent disease with low positive BCR-ABL at 0.04% at the end of delayed intensification. As there were no matched HLA donors as she had high risk disease she was suggested for AIET using autologous natural killer 6 in (NK) cells (CD3-CD56+) in January 2007. 562 x 10 vitro expanded NK cells were infused to the patient intravenously and four weeks later, the BCR-ABL in the PB turned negative. She completed her treatment in October 2007. She has been on regular follow up for the last five years and she continues to be in remission.
1. Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India, 2. Cancer Research and Relief Trust, Chennai, India. 3. Apollo Speciality Hospital, Chennai, India, 4. Kamakshi Memorial Hospital, Chennai, India, 5. Biotherapy Institute of Japan, Tokyo, Japan, 6. Hope Foundation (Trust), Chennai, India, 7. Yamanashi University- School of Medicine, Chuo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) Case 3: A female patient aged 64 years with advanced serous papillary Adenocarcinoma of both ovaries with liver metastasis underwent omentectomy and resection of the liver nodule in the month of January 2011 and completed 6 cycles of chemotherapy with Paclitaxel and Carboplatin, completed in April 2011. In April 2011, non-enhancing lesions in the Left lobe of the liver and a left gastric node were revealed in the CT scan of the whole abdomen. The patient was suggested for radiofrequency ablation and maintenance chemotherapy along with AIET. The patient was administered five transfusions of AIET using autologous NK cells and activated T lymphocytes. 140 ml of peripheral blood (PB) was withdrawn in May 2011 from which two transfusions of AIET with the average NK cell count being 618 million and T cell count being 331 million were administered. However when 140 ml of PB was withdrawn for the second time in June 2011 for two more transfusions, the peripheral blood mononuclear cells (PBMNCs) count were alarmingly lower though she had a WBC count of 4600 cells, and the expansion of NK cells, T lymphocytes was not marked following which her report which was received from a Hospital in Thailand revealed that she had Auto-immune Hemolytic anemia (AIHA) for which she was prescribed steroids. It has already been reported that the functional profile of NK cell is lower in [9] Also the limiting factor of steroid AIHA patients. administration is also to be considered. The average NK cell count of the third and fourth was 3.9 million while activated T cell count was 4.2 million. When the PB was withdrawn for the fifth transfusion, the NK, T lymphocytes expansions were higher leading to transfusion of a cell count of 103 million and activated T lymphocytes of 329 million. On the whole, the immune cells expansion in this patient was lesser compared to other patients and this can [10] Nevertheless be attributed to the association of AIHA. there were no adverse effects after the AIET and the patient continues to be stable as per the latest follow-up in August 2012.
protocols to suit the Indian conditions. With these lessons learned in translating the technology of AIET from Japan to India and following the significant outcomes in the various patients mentioned above and more than 60 others, future studies are underway to analyze the methods by which the in vivo efficacy of NK cells can be enhanced and analyzing the synergistic effects when AIET is combined with Monoclonal antibodies. Conclusion: AIET technology was successfully translated from Japan to India overcoming various hurdles and since 2005 several patients in India have been administered AIET with no adverse reactions of any kind, which falls in line with the earlier reports from the literature. Significant increase in disease free survival or static non-progressive disease could be accomplished in patients with ovarian cancer, Acute Lymphoblastic leukemia, Acute Myeloid Leukemia, advanced in-operable pancreatic cancer, prostate cancer with multiple metastasis and breast cancer with metastasis, we have experienced. An increase in awareness about this least toxic method of Cancer treatment among physicians and the public for an early referral is necessary. Further studies on prevention of cancer using in vitro expanded autologous immune cells are underway. References: 1.
2.
3.
Hurdles overcome and lessons learned: As with translation of any therapy, there were hurdles during the initial translation of the AIET technology from the Biotherapy Institute of Japan to India. As AIET was new to our team of scientists, they were trained initially for two years by the Japanese experts and there is a constant interaction with frequent information exchange among the Indian technical team and the Japanese team till date. The hurdle faced in the use of Laboratory reagents is that their efficacy might vary according to the manufacturer and to put aside the doubt and to ensure that the same results obtained in Japan are reproduced in India, all the laboratory reagents used in India are the same used in Biotherapy institute obtained from Japan. Biotherapy Institute constantly monitors quality of the reagents by assessing their effects on primary cell cultures and cell lines which are maintained in that Institute. The hurdle in infrastructure requirements were overcome by establishing a laboratory in India with similar specifications and equipments as that in Japan with even more stringent
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Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000 ;356(9232):802-7. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1):42-9. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumorassociated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002; 8 : 1767-71. Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995;1(5):501-7. Sivaraman G, Pandian A, Baskar S, Senthil KR, Senthilnagarajan R, Dedeepiya V, Abraham S. Autologous Immune Enhancement therapy for advanced carcinoma of pancreas a case report. PASRM 2008-004. J Stem Cells Regen Med. 2008; 4(1):13 Damodar S, Terunuma H , Sheriff AK , Farzana L , Manjunath S , Senthilkumar R , Shastikumar G , Abraham S , Wang FS. Autologous Immune Enhancement Therapy (AIET) for a Case of Acute Myeloid Leukemia (AML) - Our Experience. PASRM 2006-001. J Stem Cells Regen Med. 2006, 1(1): 40-41
P208 Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved
Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) 7.
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Takada M, Terunuma H, Deng X, Dewan MZ, Saji S, Kuroi K, Yamamoto N, Toi M. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer 18:64-7, 2011. Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, Senthilkumar R, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ. Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report. Case Rep Oncol. 2012 Jan;5(1):114-8.
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Conte R, Dinota A, Tazzari PL, Belletti D, Sermasi G. Analysis of natural killer cells in patients with idiopathic autoimmune hemolytic anemia. Vox Sang 56:270-3, 1989 10. Dedeepiya VD, Terunuma H, Deng X, Baskar S, Manjunath SR, Senthilkumar R, Murugan P, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ. 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 Feb;3(2):435440.
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Cancer incidence and novel therapies developed in Japan Iwasaki M*
Abstract According to the ministry of Health, Labour and welfare of Japan, Cancer has been the leading cause of death in [1] Japan since 1981. As per the data in 2010, in Japan, one [2] in every three deaths was due to cancer. The Japanese Government has introduced so far, three terms of 10 years strategies for Cancer control since 1984 till date. The budget allocated for cancer control in 2009 was 52.5 billion yen in Japan. [3] Lung is the leading site for cancer in both males and females in Japan. In males, following the lung, stomach, liver, colon and pancreas are other leading sites while in the females, stomach, colon, pancreas and breast are the other leading sites. [1] In 2006, the cancer incidence was 694,000 and the male cancer incidence was 1.4 times as large as that of females. The peak age for cancer deaths in males is their fifties while in the females it is the sixties among Japanese. In addition to the conventional treatments such as surgery, radiotherapy and chemotherapy, some of other therapies in practice in Japan are the Hyperthermia [4] that uses high temperatures to kill or damage the cancer cells, the Ion Beam therapy using proton beams [5] to damage the DNA of the cells as cancer cells have high rate of cell divisions and lesser ability to repair DNA damage, the molecular targeted therapies that interfere with a specific molecular target involved in tumour growth and progression[6] and most importantly the autologous cell based Immunotherapies. Modern Cancer Immunotherapy started in the 1970s in Japan. The immunopotentiators using compounds from Bacteria, Beta Glucans from fungi were the first forms of modern Immunotherapy. Then was the era of direct injection of cytokines such as Interleukins, Interferons etc. The adverse effects associated with the injection of cytokines led to development of cell based [7] Immuno-cell therapies Immunotherapies in the 1980s. involve isolation of immune cells which are then processed and re-injected into the body to exert their action against the cancer. There are different kinds of Immuno-cell therapies being practised in more than 25 private and public institutions in Japan using Natural Killer (NK) cells,
Cytotoxic T lymphocytes (CTLs), Tumour Infiltrating Lymphocytes (TIL), Lymphokine activated Killer (LAK) cells, [7] Dendritic cells and Gamma Delta T (γδ T) cells. Importantly most of the innovations in cell based therapies in the world have been made in Japan because immunotherapy is a part of the Japanese Health care system and routine therapies for cancer in Japan. There have been randomized clinical trials on Immuno-cell therapy for liver cancer, lung cancer, gastric cancer, ovarian cancer with the results suggesting statistically significant increase in survival rate and increase in disease free survival rate. [8, 9, 10, 11] There are more than 25 institutions in Japan performing such cell based immunotherapies. A comprehensive review by Egawa et al on 1401 patients showed that when Immuno-cell therapy was combined with the conventional therapies, the efficacy [7] increased upto 20-30%. Immuno-cell is the least toxic of all therapies and can be administered even to terminally ill cancer patients. [12] Contrast to drugs, as autologous cell based Immuno-therapies are from the patient’s own blood and as they are custom tailored to each patient, though expensive, the adverse effects are minimal. To conclude, cancer-Immunocell therapies are the future of cancer therapies and further research is needed to enhance its efficacy and validate the results. References: 1.
2.
3.
4.
Cancer Statistics in Japan 2011. http://ganjoho.jp/data/public/statistics/backnumber/2011/f iles/cancer_statistics_2011.pdf Japan Cancer Society. Statistics on dynamic trends in Population compiled by the Ministry of Health, Labour and welfare. http://www.jcancer.jp/english/cancerinjapan/ Maehara Y. Current Status of Cancer Treatment in Japan, and Future Prospects for the Japan Society of Clinical Oncology. JMAJ 54(1): 44–46, 2011 Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Critical Reviews in Oncology/Hematology 2002; 43(1):33–56.
* Department of Clinical Research, Yamanashi University- School of Medicine, Chuo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved
JSRM/Vol8 No.3, 2012; P203
Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) 5. 6.
7. 8.
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Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer.2005; 93(8):849-54. Widakowich C, de Castro G Jr, de Azambuja E, Dinh P, Awada A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist. 2007; 12(12):1443-55. Egawa K. Immuno-cell therapy of cancer in Japan. Anticancer Res. 2004;24(5C):3321-6. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000; 356(9232):802-7. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or
radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1):42-9. 10. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumorassociated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002; 8: 1767-71. 11. Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995; 1(5):501-7. 12. Goto S, Shirotani N, Hatakeyama M, Tagami C, Arakawa H, Kuwata E, Noguchi K, Egawa K. Clinical benefit of non-toxic therapy in patients with advanced cancer (opinion). Anticancer Res. 2002; 22(4):2461-4.
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM)
JSRM Code: 008030700138
Autologous Immune Enhancement Therapy for Cancer - Our experience since 2004 Terunuma H*
Abstract Introduction: Cancer, the major killer disease of the century requires a multi-pronged approach and among the latest modalities of treatments, Immunotherapy occupies a promising role. Immunotherapy for cancer was first started to be practised in the NIH and cell based immunotherapy for cancer is in practice for the past three decades. [1, 2] There are several literatures from various countries on the successful application of cell based Immunotherapies for various solid [3-8] Our team’s tumours and haematological malignancies. association with immune cells started when I was working on RNA transcriptome analysis to understand the immune system in HIV carriers which in turn required in vitro expansion of human Natural Killer (NK) cells. [9] This led to the customization of protocols which has resulted in successful in vitro expansion, activation of NK cells and T cells for Immunotherapy. The purpose of Biotherapy institute of Japan (BIJ) is to support research and clinical application of immune cells like NK cells, γδT cells, αβT cells, Cytotoxic T lymphocytes (CTL) and Dendritic cells (DC) for application as Autologous Immune Enhancement Therapy (AIET) to fight against cancer. AIET using NK cells, CTLs, DCs etc have been administered for more than 5000 patients since 2004 till date by BIJ. Principle of AIET: For AIET using NK cells, the process involves separation of lymphocytes from the peripheral blood of the patient followed by selective NK cell expansion using the expansion kit (BINKIT, BIJ, JAPAN) without feeder layers [10,11] and then infusion of the expanded-activated NK cells. As reports suggest that the activity of peripheral blood NK cells are lower in cancer patients compared to normal [12] and as in vitro expansion of NK cells individuals increases the cytotoxic ability 5 to 10 fold, [13] the NK cells are expanded in vivo and then infused to the patient in AIET. We are also working on combination immunotherapy using NK cells and CTLs and also NK cells and peptide pulsed DCs. The principle behind combining NK cells and CTLs is
a dual advantage approach combining the innate immune system and adaptive immune system wherein the CTLs will kill the MHC expressing cancer cells while NK cells will kill [10] In case of the MHC non-expressing cancer cells also. NK cells and DCs, DCs will in turn activate the CTLs thereby giving rise to the dual advantage mentioned above. We have recently suggested that the AIET using expanded NK cells, particularly in combination with monoclonal antibody drugs, may be very useful tool for cancer immunotherapy. [14] Our experience: In our studies in NOG SCID mice, activated NK cells were shown to reduce the size of breast cancer cells (MDAMB231) [15] and the volume of ascites also inhibiting lung [16] In metastasis of pleural effusion lymphoma (PEL) cells. a primary lung adenocarcinoma patient where AIET was administered in combination with Hyperthermia, the CEA values decreased from 4.8 ng/ml to 1.6 ng/ml, the SLX decreased from 30 U/ml to 27 U/ml, the IAP reduced from 300 μg/ml to 221 μg/ml along with resolution of the lung lesions in four months. A 55 year old woman treated for invasive ductal carcinoma of breast presented with metastasis to the lungs. She was then treated with trastuzumab in combination with multiple injections of activated natural killer (NK) cells (at two week intervals) following which the tumor markers decreased. Progression [11] Fifty-two patients with free survival was 10 months. advanced cancers in organs like lung, breast, colon, prostate, liver, kidney, ovary etc, refractory to conventional therapy when treated with a combination of hyperthermia and NK cell-and CTL-based immune cell therapy with lowdose chemotherapy, in 18 of 52 patients, objective responses was observed including one complete response (CR) and 17 partial responses (PR) evaluated according to to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Sixteen patients had stable disease (SD), whereas 18 had progressive disease (PD). Disease control rate was 66％ including CR, PR and SD. After treatment for six months, the objective responses and disease control rate were 25％ and 52％, respectively. [17] There were no adverse effects in any of these patients.
*Biotherapy Institute of Japan (BIJ), Tokyo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) Conclusion: Cancer has to be tackled with a multipronged approach and combining NK cell and CTL cell based AIET with conventional modalities of treatments such as Surgery, Chemotherapy and Radiotherapy as well as other modalities like Hyperthermia, Proton Beam therapy and low dose chemotherapy is effective even in advanced cancers which are refractory to conventional therapeutic modalities.
9.
10.
References: 1. 2.
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Rosenberg SA, Rapp HJ. Intralesional immunotherapy of melanoma with BCG. Med Clin North Am. 1976 May;60(3):419-30. Mazumder A, Eberlein TJ, Grimm EA, Wilson DJ, Keenan AM, Aamodt R, Rosenberg SA. Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells. Cancer. 1984 Feb 15;53(4):896-905 Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000 ;356(9232):802-7. Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F, Baynes R, Wood G. Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg Focus. 2000; 9(6):e9. Recchia F, Candeloro G, Di Staso M, Necozione S, Bisegna R, Bratta M, Tombolini V, Rea S. Maintenance immunotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck. J Immunother. 2008; 31(4):413-9. Wright SE, Rewers-Felkins KA, Quinlin IS, Phillips CA, Townsend M, Philip R, Dobrzanski MJ, Lockwood-Cooke PR, Robinson W. Cytotoxic T-lymphocyte immunotherapy for ovarian cancer: a pilot study. J Immunother. 2012 Feb-Mar;35(2):196-204. Iliopoulou EG, Kountourakis P, Karamouzis MV, Doufexis D, Ardavanis A, Baxevanis CN, Rigatos G, Papamichail M, Perez SA. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother. 2010 Dec;59(12):1781-9. Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin
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RS. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2005 Mar;11(3):181-7. Abraham S. Academic Serendipity to clinical, commercial success. Trade Secrets - Nature Biotech Blog. 2011 Sep. http://blogs.nature.com/tradesecrets/2011/09/12/academ ic-serendipity-to-clinical-commercial-success Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N. Potential role of NK cells in the induction of immune responses: Implications for NK cell-based immunotherapy for cancers and viral infections. Int Rev Immunol 2008; 27: 93-110 Takada M, Terunuma H, Deng X, Dewan MZ, Saji S, Kuroi K, Yamamoto N, Toi M. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer 18:64-7, 2011. Dewan MZ, Takada M, Terunuma H, Deng X, Ahmed S, Yamamoto N, Toi M. Natural killer activity of peripheralblood mononuclear cells in breast cancer patients. Biomed Pharmacother 63:703-6, 2009. Dedeepiya V, Terunuma H, Deng X, Baskar S, Manjunath S, Senthilkumar R, Murugan P, Thamaraikannan P, Srinivasan T, Preethy S, Abraham S. 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.Oncology Letters. 2011;3(2). Doi: 10.3892/ol.2011.498; Deng X, Terunuma H, Nieda M, Xiao W, Nicol A. Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells. International Immunopharmacology (in press) Dewan MZ, Terunuma H, Takada M, Tanaka Y, Abe H, Sata T, Toi M, Yamamoto N. Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo. Breast Cancer Res Treat. 2007 Sep;104(3):267-75. Dewan MZ, Terunuma H, Toi M, Tanaka Y, Katano H, Deng X, Abe H, Nakasone T, Mori N, Sata T, Yamamoto N. Potential role of natural killer cells in controlling growth and infiltration of AIDS-associated primary effusion lymphoma cells. Cancer Sci. 2006 Dec;97(12):1381-7. Terunuma H, Deng X , Toki A, Yoshimura A, Nishino N, Takano Y, Nieda M, Sasanuma J, Teranishi Y, Watanabe K. Effects of Hyperthermia on the Host Immune System : From NK Cell-based Science to Clinical Application.Thermal Medicine 2012; 28 (1): 1-9
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM)
JSRM Code: 008030700139
Hurdles overcome in technology transfer for AIET and Positive outcome in Indian patients Dedeepiya V1, Ramanan G2, Munirathnam D3, Sumana P4,Terunuma H5, Senthilkumar R1, Srinivasan T1, 1 1,6 1,7 Reena H , Preethy S , Abraham S
Abstract Introduction Cell based immunotherapies have been in practice in Japan for the past two decades with established clinical trials on its efficacy in both solid tumours and hematological malignancies including gastric cancer, ovarian cancer , [1,2,3,4] In India, NCRM has lung cancer and liver cancer. been providing Autologous Immune Enhancement Therapy (AIET) using autologous Natural Killer (NK) cells and activated T Lymphocytes for Cancer since 2005 following the established protocols practiced by the Biotherapy Institute of Japan. Significant outcome achieved after AIET in advanced pancreatic cancer, Acute Myeloid leukemia (AML) in Indian patients have already been reported.[5, 6] Here we report our experience in few more patients and present the hurdles overcome and lessons learned in translating the technology from Japan to India Case Details: Case 1: A 54 year-old female presented with Stage IV recurrent ovarian malignancy in 2010 with a history of previous surgery and chemotherapy for ovarian malignancy in June 2009. The CA-125 level of 243 U/ml. CT scan revealed lesions in the liver, spleen, along the greater curvature of body of stomach and in the perisplenic region, between the medial aspect of liver and stomach and in the right inguinal region. She was suggested six cycles of chemotherapy with Doxorubicin (50 mg) and Carboplatin (450 mg) along with AIET. After proper informed consent, the peripheral blood was withdrawn and the in vitro expansion of the NK cells, activated T Lymphocytes from the peripheral blood [7] was performed using the protocol reported earlier. Average cell count after the in vitro expansion was 1.2 X 108 cells. Six transfusions of the in vitro expanded NK cells and activated T lymphocytes were administered following which the CA-125 decreased to 4.7 U/mL. CT scan taken in
December 2010 showed a regression of the lesions in the spleen and perisplenic peritoneal deposits, stable hepatic lesions and resolution of perigastric peritoneal deposits with a marked decrease in the size of the inguinal lymph nodes from and no recurrence in the pelvic region. There was also improvement in appetite and quality of life of the patient. There were no adverse reactions following the [8] AIET infusions. The latest follow-up in May 2012 revealed static non progressive disease with all the parameters including tumor markers within normal range. Case 2: A 15 year old girl presented with complaints of diffuse bone pain for 3 months, intermittent fever for 1 month and increasing pallor in October 2004. On examination, she was found to have pallor with hepatosplenomegaly. A low haemoglobin level (9.3 mg/dl), low platelets (21000) and a WBC count of 13600 with 83% lymphoblasts was revealed in her blood picture. Bone marrow examination and flow cytometry were suggestive of Acute Lymphoblastic Leukemia – CD 10+ CD 19+. Cytogenetics revealed Philadelphia chromosome and BCR-ABL positivity. Qualitative BCR-ABL was done serially to assess disease status. She was started on chemotherapy as per UK MRC protocol – Regimen B along with Imatinib Mesylate (in view of her BCR-ABL positivity) and prophylactic cranial radiotherapy of 12 Gy at the end of delayed intensification. She had persistent disease with low positive BCR-ABL at 0.04% at the end of delayed intensification. As there were no matched HLA donors as she had high risk disease she was suggested for AIET using autologous natural killer 6 in (NK) cells (CD3-CD56+) in January 2007. 562 x 10 vitro expanded NK cells were infused to the patient intravenously and four weeks later, the BCR-ABL in the PB turned negative. She completed her treatment in October 2007. She has been on regular follow up for the last five years and she continues to be in remission.
1. Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India, 2. Cancer Research and Relief Trust, Chennai, India. 3. Apollo Speciality Hospital, Chennai, India, 4. Kamakshi Memorial Hospital, Chennai, India, 5. Biotherapy Institute of Japan, Tokyo, Japan, 6. Hope Foundation (Trust), Chennai, India, 7. Yamanashi University- School of Medicine, Chuo, Japan Proceedings of Annual Symposium & Plenary Session on Regenerative Medicine (PASRM); Published online 26 Nov 2012
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) Case 3: A female patient aged 64 years with advanced serous papillary Adenocarcinoma of both ovaries with liver metastasis underwent omentectomy and resection of the liver nodule in the month of January 2011 and completed 6 cycles of chemotherapy with Paclitaxel and Carboplatin, completed in April 2011. In April 2011, non-enhancing lesions in the Left lobe of the liver and a left gastric node were revealed in the CT scan of the whole abdomen. The patient was suggested for radiofrequency ablation and maintenance chemotherapy along with AIET. The patient was administered five transfusions of AIET using autologous NK cells and activated T lymphocytes. 140 ml of peripheral blood (PB) was withdrawn in May 2011 from which two transfusions of AIET with the average NK cell count being 618 million and T cell count being 331 million were administered. However when 140 ml of PB was withdrawn for the second time in June 2011 for two more transfusions, the peripheral blood mononuclear cells (PBMNCs) count were alarmingly lower though she had a WBC count of 4600 cells, and the expansion of NK cells, T lymphocytes was not marked following which her report which was received from a Hospital in Thailand revealed that she had Auto-immune Hemolytic anemia (AIHA) for which she was prescribed steroids. It has already been reported that the functional profile of NK cell is lower in [9] Also the limiting factor of steroid AIHA patients. administration is also to be considered. The average NK cell count of the third and fourth was 3.9 million while activated T cell count was 4.2 million. When the PB was withdrawn for the fifth transfusion, the NK, T lymphocytes expansions were higher leading to transfusion of a cell count of 103 million and activated T lymphocytes of 329 million. On the whole, the immune cells expansion in this patient was lesser compared to other patients and this can [10] Nevertheless be attributed to the association of AIHA. there were no adverse effects after the AIET and the patient continues to be stable as per the latest follow-up in August 2012.
protocols to suit the Indian conditions. With these lessons learned in translating the technology of AIET from Japan to India and following the significant outcomes in the various patients mentioned above and more than 60 others, future studies are underway to analyze the methods by which the in vivo efficacy of NK cells can be enhanced and analyzing the synergistic effects when AIET is combined with Monoclonal antibodies. Conclusion: AIET technology was successfully translated from Japan to India overcoming various hurdles and since 2005 several patients in India have been administered AIET with no adverse reactions of any kind, which falls in line with the earlier reports from the literature. Significant increase in disease free survival or static non-progressive disease could be accomplished in patients with ovarian cancer, Acute Lymphoblastic leukemia, Acute Myeloid Leukemia, advanced in-operable pancreatic cancer, prostate cancer with multiple metastasis and breast cancer with metastasis, we have experienced. An increase in awareness about this least toxic method of Cancer treatment among physicians and the public for an early referral is necessary. Further studies on prevention of cancer using in vitro expanded autologous immune cells are underway. References: 1.
2.
3.
Hurdles overcome and lessons learned: As with translation of any therapy, there were hurdles during the initial translation of the AIET technology from the Biotherapy Institute of Japan to India. As AIET was new to our team of scientists, they were trained initially for two years by the Japanese experts and there is a constant interaction with frequent information exchange among the Indian technical team and the Japanese team till date. The hurdle faced in the use of Laboratory reagents is that their efficacy might vary according to the manufacturer and to put aside the doubt and to ensure that the same results obtained in Japan are reproduced in India, all the laboratory reagents used in India are the same used in Biotherapy institute obtained from Japan. Biotherapy Institute constantly monitors quality of the reagents by assessing their effects on primary cell cultures and cell lines which are maintained in that Institute. The hurdle in infrastructure requirements were overcome by establishing a laboratory in India with similar specifications and equipments as that in Japan with even more stringent
4.
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Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000 ;356(9232):802-7. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1):42-9. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumorassociated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002; 8 : 1767-71. Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995;1(5):501-7. Sivaraman G, Pandian A, Baskar S, Senthil KR, Senthilnagarajan R, Dedeepiya V, Abraham S. Autologous Immune Enhancement therapy for advanced carcinoma of pancreas a case report. PASRM 2008-004. J Stem Cells Regen Med. 2008; 4(1):13 Damodar S, Terunuma H , Sheriff AK , Farzana L , Manjunath S , Senthilkumar R , Shastikumar G , Abraham S , Wang FS. Autologous Immune Enhancement Therapy (AIET) for a Case of Acute Myeloid Leukemia (AML) - Our Experience. PASRM 2006-001. J Stem Cells Regen Med. 2006, 1(1): 40-41
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Proceedings of the Annual Symposium & Plenary Session on Regenerative Medicine (PASRM) 7.
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Takada M, Terunuma H, Deng X, Dewan MZ, Saji S, Kuroi K, Yamamoto N, Toi M. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach. Breast Cancer 18:64-7, 2011. Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, Senthilkumar R, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ. Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report. Case Rep Oncol. 2012 Jan;5(1):114-8.
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Conte R, Dinota A, Tazzari PL, Belletti D, Sermasi G. Analysis of natural killer cells in patients with idiopathic autoimmune hemolytic anemia. Vox Sang 56:270-3, 1989 10. Dedeepiya VD, Terunuma H, Deng X, Baskar S, Manjunath SR, Senthilkumar R, Murugan P, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ. 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 Feb;3(2):435440.
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