Autologous immune enhancement therapy

Autologous immune enhancement therapy (AIET) is a treatment method in which immune cells are taken out from the patient's body which are cultured and processed to activate them until their resistance to cancer is strengthened and then the cells are put back in the body. The cells, antibodies, and organs of the immune system work to protect and defend the body against not only tumor cells but also bacteria or viruses.

Autologous immune enhancement therapy
Specialtyimmunology/oncology

Cell division in any living organism is an integral part of life, as worn out cells have to be replaced by newly generated cells. This process of generating new cells varies between organs and the mechanisms involved are highly complex which include the nature and capability of the underlying stem cells, their environment, metabolism, physical and allied biological factors the organ or tissue is subjected to etc., Aberrant cell division takes place that ends up in a cancer cell and such aberrance may be due to faulty stem cell, abnormal genetic components or any other factor such as radiation or a constant irritation. Cancer is still a leading cause of death in the world yet much is still not known about its mechanisms of establishment and destruction. While surgery and/or chemo- and radiotherapies are various treatment modalities available, still in many cases they don’t offer a permanent cure. Another major point to be addressed about this killer disease is the relapse rate which is very high.

Researchers have found that these cells mainly target the cancer cells and not the healthy cells whereas in chemotherapy and radiotherapy the healthy cells are also getting destroyed.

Mechanism of action

Cancer cells are formed in our body almost every day but we are not affected by them. This is because they are immediately destroyed by the body's immune system. The immune system is a complex network of cells and organs comprising lymphocytes, macrophages, Dendritic cells, Natural Killer cells (NK Cell), Cytotoxic T Lymphocytes (CTL), etc., that work together to defend the body against attacks by "foreign" or "non-self" invaders including cancer cells. Immediately after a cancer cell is recognized, the Lymphocytes and/or the NK cells attack the cancer cell to kill it. When the immune system is weaker then cancer evolves as a disease and starts growing.

Each type of cancer needs a specific combination of treatments aimed at that particular kind of cancer. When the extent of spread of cancer is deep, total removal of the cancer growth by surgery may not be possible. At times, after surgical removal of a part of the cancer, radiotherapy and/or chemotherapy may be necessary to treat the remnant portion of cancer. It is widely known that Chemotherapy has profound toxic side effects and has limitations in efficacy. Radiotherapy is also a very effective mode of treatment in certain types of cancer, but it has its own adverse effects as well. These two modalities affect not only the cancer affected cells, but also the normal cells

Now in AIET, specific types of cells mainly the NK cells and T lymphocytes are isolated from the peripheral blood of the cancer patients (during remission in patients who undergo chemotherapy) by proven methods, expanded to 25–30 fold and activated and then reinfused back into the patient’s body. These cells act against the cancer cells effectively and recharge the immune system. Upon encountering a tumor cell, the activated NK cell attaches to the membrane of the cancer cell and injects toxic granules which dissolve the target cell. In less than five minutes, the cancer cell dies and the NK cell moves on to its next target cancer cell. A single NK cell can destroy up to 27 cancer cells within its lifespan. This is the mechanism by which AIET is effective in cancer therapy.

History

Adoptive Immuno cell therapy of cancer was first introduced by Steven Rosenberg and his colleagues of National Institute of Health USA. In the late 80s, they published an article in which they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy (ASI), and they suggest that AIET with specific chemotherapy or radiotherapy as the future of cancer immunotherapy.[1] In the beginning Immunotherapy treatments involved administration of cytokines such as Interleukin.[2] with an aim of inducing the lymphocytes which will carry their activity of destroying the tumour cells. Thereafter the adverse effects of such intravenously administered cytokines [3] lead to the extraction of the lymphocytes from the blood and culture-expand them in the lab and then to inject the cells alone enable them destroy the cancer cells.[4] Till date different kinds of autologous and allogenic immune cells such as lymphokine-activated killer(LAK)cells, Natural killer (NK) cells, Activated Cytotoxic T lymphocytes(CTLs), Dendritic cells(DCs), Gene manipulated autologous and allogenic Immune cells have been used in clinical applications of Immunotherapy.

The present technology of AIET was developed by Japanese scientists and it is being widely practised in several Asian countries which uses autologous natural killer (NK) cells and activated T lymphocytes to treat various cancers.

This treatment modality has been in practice since early 90s and has several random clinical trials in lung cancer, gastric cancer, Ovarian cancer and Liver cancer.[3] which has been published with significant disease free survival rates. One of the largest studies in 1400 patients.[3] has proven that the cell based immunotherapy when combined with conventional treatment the efficacy improves by 20–30%. A recent finding published about a relapsed stage IV ovarian cancer [5] treated successfully with this methodology has found its place in the Global medical discovery.[6]

Status of immunotherapy worldwide

Though the concept of this treatment started in the US in 1980s, full-fledged clinical treatments on a routine basis have been in practice in Japan since 1990. Randomized controlled studies in different cancers with significant increase in survival and disease free period have been reported.[7][8][9][10] In India immunotherapy has shown positive results in patients with advanced cancer including acute myeloid leukaemia,[11] pancreatic cancer,[12] cervical cancer,[13] ovarian cancer,[5][14] Breast Cancer[15] and Philadelphia chromosome Positive Acute Lymphoblastic Leukemia.[16] [17]

Relevance to Auto-Immune Diseases

Auto-Immune diseases like the Auto-Immune Hemolytic Anemia (AIHA) have been known to be associated with malignancies. In general lower Natural Killer (NK) profile has been associated with development of cancers by earlier studies.[18] Recently an article has been published in which it has been described that the in vitro expansion of NK cells is decreased in cancer patients who have concomitant Auto-immune Diseases like the AIHA.[19] This study also throws questions on whether AIHA is a complication of malignancies, due to the lower NK cell profile in cancer which would have given rise to the AIHA due to some common antibody between NK cells and Red Blood Cells (RBCs) or whether the AIHA lowers the NK cell profile which in turn causes the cancer. This warrants further investigations into the identification of common antibodies between NK cells & RBCs and also finding new Immuno- therapeutic strategies which can tackle both cancer and auto-immunity

References
  1. Rosenberg SA (January 1984). "Adoptive immunotherapy of cancer: accomplishments and prospects". Cancer Treat Rep. 68 (1): 233–55. PMID 6362866.
  2. Yang Q, Hokland ME, Bryant JL, et al. (July 2003). "Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases". Int. J. Cancer. 105 (4): 512–9. doi:10.1002/ijc.11119. PMID 12712443. S2CID 25325594.
  3. Egawa K (2004). "Immuno-cell therapy of cancer in Japan". Anticancer Res. 24 (5C): 3321–6. PMID 15515427.
  4. Kunishima S, Matsushita T, Shiratsuchi M, et al. (January 2005). "Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness". Eur. J. Haematol. 74 (1): 1–5. doi:10.1111/j.1600-0609.2004.00328.x. PMID 15613099. S2CID 20398097.
  5. Manjunath, Sadananda Rao; Ramanan, Ganapathi; Dedeepiya, Vidyasagar Devaprasad; Terunuma, Hiroshi; Deng, Xuewen; Baskar, Subramani; Senthilkumar, Rajappa; Thamaraikannan, Paramasivam; Srinivasan, Thangavelu; Preethy, Senthilkumar; Abraham, Samuel J.K. (2012). "Autologous immune enhancement therapy in recurrent ovarian cancer with metastases; 18 months follow-up- A case report". Case Reports in Oncology. 5 (1): 114–118. doi:10.1159/000337319. PMC 3364094. PMID 22666198.
  6. "Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report-Global Medical Discovery key scientific article". Archived from the original on 16 November 2012. Retrieved 30 August 2012.
  7. Fujita K, Ikarashi H, Takakuwa K, et al. (May 1995). "Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes". Clin. Cancer Res. 1 (5): 501–7. PMID 9816009.
  8. Kimura H, Yamaguchi Y (July 1997). "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. 80 (1): 42–9. doi:10.1002/(SICI)1097-0142(19970701)80:1<42::AID-CNCR6>3.0.CO;2-H. PMID 9210707.
  9. Takayama T, Sekine T, Makuuchi M, et al. (September 2000). "Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial". Lancet. 356 (9232): 802–7. doi:10.1016/S0140-6736(00)02654-4. PMID 11022927. S2CID 19241915.
  10. Kono K, Takahashi A, Ichihara F, et al. (June 2002). "Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial". Clin. Cancer Res. 8 (6): 1767–71. PMID 12060615.
  11. Sharat Damodar; Terunuma H; Sheriff AK; Farzana L; Manjunath S; Senthil KR; Shastikumar G; Abraham S (November 2006). "Autologous Immune Enhancement Therapy (AIET) for a Case of Acute Myeloid Leukemia (AML) — Our Experience". 1 (1): 40–41. {{cite journal}}: Cite journal requires |journal= (help)
  12. Baskar S, Dedeepiya V D, Terunuma H, Manjunath S R, Senthilkumar R, Sivaraman G, Pandian A, Abraham S. Prolonged survival of a patient with inoperable, locally advanced adenocarcinoma of pancreas after autologous immune enhancement therapy with chemotherapy. Indian J Cancer 2015;52:395-6.
  13. Sumana Premkumar; Vidyasagar Devaprasad Dedeepiya; Hiroshi Terunuma; Rajappa Senthilkumar; Thangavelu Srinivasan; Helen C. Reena; Senthilkumar Preethy; Samuel JK Abraham (2013). "Cell based Autologous Immune Enhancement Therapy (AIET) after radiotherapy in a locally advanced carcinoma of the cervix". Case Reports in Oncological Medicine. 2013: 1–3. doi:10.1155/2013/903094. PMC 3638504. PMID 23653878.
  14. Press release on Advanced Ovarian Cancer treated with AIET
  15. Chidambaram R, Terunuma H, Balamurugan M, Dedeepiya VD, Sumana P, Senthilkumar R, Rajmohan M, Karthick R, Preethy S, Abraham SJK. Cell-based immunotherapy in stage IIIA inflammatory breast cancer with declining innate immunity following successive chemotherapies: A case report. Mol Clin Oncol. 2017 Sep;7(3):493-497.
  16. Revathi Raj; M. Deenadayalan; G. Vimal Kumar; Vipin Khandelwal; Karuna Sri; Rajappa Senthilkumar; Samuel J. K. Abraham; Terunuma Hiroshi (2014). "Autologous Immune Enhancement Therapy in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia". Journal of Hematology and Blood Transfusion. 30 (Suppl 1): 202–204. doi:10.1007/s12288-013-0327-3. PMC 4192214. PMID 25332578.
  17. Explore 'Killer Cell' Treatment to Cure rare Cancers
  18. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K (November 2000). "Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population". Lancet. 356 (9244): 1795–9. doi:10.1016/S0140-6736(00)03231-1. PMID 11117911. S2CID 22918838.
  19. Vidyasagar Devaprasad Dedeepiya; Hiroshi Terunuma; Xuewen Deng; Subramani Baskar; Sadananda Rao Manjunath; Rajappa Senthilkumar; Palanisamy Murugan; Paramasivam Thamaraikannan; Thangavelu Srinivasan; Senthilkumar Preethy; Samuel J.K. Abraham (February 2012). "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. 3 (2): 435–440. doi:10.3892/ol.2011.498. PMC 3362377. PMID 22740927.
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