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Autologous Immune Enhancement Therapy (AIET) in Oncology

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INTRODUCTION

Despite numerous advances in medicine, cancer remains a major health problem. It is the second leading cause of death in the world yet much is still not known about its mechanisms of establishment and definitive modalities of complete cure. Globally it is estimated that there are 7.6 million new cancer cases, of which 52% occur in developing countries every year. The magnitude of the problem of cancer in the Indian Sub-Continent in terms of sheer number is most alarming. The estimated new cases of cancer in India per year is nearly 6.5  lakhs (1999) and at the start of the millennium it was estimated to be 806,000. The crude incidence of cancer in India is approximately 100 per 100,000 population. The Cancer in women in the Indian Sub-continent constitutes more than 50% of the total cancer. Recent epidemiological studies done at National Cancer Registry programme in India report that Cancer burden in the country is 2.5 to 3 million and estimated number of new cases diagnosed every year found to be 700,000 - 900,000.

Fig. 1; Delhi Cancer Registry data as of 2001

 Although the common treatment modalities such as surgery and/or chemo and radiotherapies have played major roles in bringing down the mortality and morbidity to a significant extent, complete cure is still uncertain and the prognosis varies depending upon the stage and the type of the disease. Even when patients experience tumor regression immediately after therapy, recurrence or metastasis (spreading to other parts of the body) can occur later.

Almost everyday several cancer cells are formed in our body. This is because thousands of cell divisions take place in the body every day and a few of such divisions resulting in mutated cells result in the birth of cancer cells. But this is immediately tackled by the body's immune system. The immune system is a complex network of cells and organs comprising of lymphocytes, macrophages, Dentritic cells, Natural Killer cells (NK Cell), Cytotoxic T Lymphocytes (CTL), lymph nodes etc., that work together to defend the body against attacks by "foreign" or "non-self" invaders including cancer cells. Immediately upon a cancer cell is recognized, the Lymphocytes get activated and engulf the same and/or  the NK cells attack the cancer cell to kill it (Fig. 2). When the immune systems efficacy is overwhelmed by the cancer formation abundantly or when the immune system is weaker, then cancer evolves as a disease and starts growing.

Given the variable nature of cancerous cells, each cancer behaves somewhat unique. In general, a multipronged approach to cancer is vital as cancer grows at different rates and respond to different treatments and people with each specific cancer need specific combination of treatment aimed at their particular kind of cancer. When the spread of cancer is very deep, total removal of the cancer growth by surgery may not be possible. At times, after removing a portion of the cancer growth, radiotherapy and/or chemotherapy may be necessary to treat the remnant portion of cancer. It has been widely recognized that Chemotherapy of cancer has profound toxic side effects and has limitations in efficacy. Radiotherapy is also a very effective mode of treatment in certain types of cancer, with its own adverse effects as well. These two modalities affect not only the cancer affected cells, but also the normal cells (Fig.3).

    In the multipronged approach to treat cancer, the latest scientific advancement has yielded Immune therapy and cancer vaccines as well. Consequently many patients with advanced cancer opt for less toxic therapies like immuno cell therapy and cancer vaccine which are collectively known as Biological therapy.

Fig. 2; The formation of cancer cells is immediately tackled by NK cells and Lymphocytes under normal circumstances.

Fig. 3; Ill effects of chemotherapy and radiotherapy are their cytotoxic effect on normal cells also.

Immuno Cell therapy is a promising new addition to the family of cancer treatments that includes surgery, chemotherapy, radiotherapy and cancer vaccines. This mode of treatment uses the body's immune system, either directly or indirectly, to fight cancer by enhancing the immune mechanisms of the body. As this therapy uses only the patients own cells for treatment, it is very safe and doesn't result in any allergy and combining this (Fig. 4) with the conventional therapy(ies) appropriately as per the patients condition, type of cancer and regimen of chemo/radio therapies, improves the outcome. As the immune cells of the patient upon transfusion doesn't affect the normal functioning cells of the body, it is furthermore safe.

Fig. 4; Combining AIET to conventional therapies improves the outcome..

For most of the 20th century there was no concrete evidence that human cancer antigens existed or that there were any measurable immune responses against growing cancers in patients. A major development in this field was the identification of the antitumor properties of interleukin-2 (IL-2), a secreted cytokine produced by helper T lymphocytes that is a major regulator of immune reactions. The interaction of antigens with T lymphocytes activates lymphoid cells to express receptors for IL-2, and the simultaneous stimulation of IL-2 secretion leads to the expansion of immune cells and effective immunity. Animal studies done by Dudley and colleagues from National Institute of Health USA, demonstrated that antitumor impact of IL-2 administration is a result of stimulating immune reactions in vivo.

Immunocell therapy is a treatment method in which some immune cells are taken out of a patient's own (Autologous) peripheral blood or bone marrow which are cultured and processed to be activated or to acquire additional functions until their resistance to cancer is strengthened and the cells are put back in the body.

There are three requirements for an effective immunotherapy for cancer.

1. A sufficient number of appropriate tumor reactive lymphocytes (cancer fighting cells) must be present in the peripheral blood of the patient or donor.

2. Lymphocytes must be capable of reaching and extravasating at the site of the cancer.

3. Lymphocytes at the tumor site must have appropriate effector mechanisms to destroy cancer cells.

Blood or bone marrow from a donor (allogenic) are also used. Since patients own cells have less chance of rejection compared with allogeneic donor, it is widely accepted that Autologous cells are much safer than allogeneic donor.

Autologous Immune Enhancement Therapy (AIET) has a successful clinical history in Japan, Europe and USA for the past two decades. Immuno cell therapy of cancer using autologous lymphocytes activated in the laboratory was first introduced by Rosenberg and his colleagues of National Institute of Health USA. In the late 80s, they published a turning-point article in which they reported a low tumor regression rate (2.6–3.3%) in patients (n = 1,205) with metastatic cancer who underwent different types of active specific immunotherapy (ASI), and suggest AIET with specific chemotherapy as the future of cancer immunotherapy.

In 1999, the first private clinic Seta in Japan with a cell processing facility and specializing in immuno-cell therapy was established. Dr.Terunuma et al established the Biotherapy Institute of Japan who apart from offering AIET, have been exploring in depth the finer components of innate immunity against cancer in the form of Cyto toxic T lymphocytes. Since then, the number of such institutes has increased, many cancer patients are opting for this kind of less toxic treatment. Several clinical trials and researches are reported from institutions all over the world, though there have not been any publications in this field from Indian Institutes or hospitals.

Development of this new line of therapy in India would be a major boost for treating cancer as well as HIV because both are encountered by body’s cell mediated immune mechanism. A currently practiced treatment method in cancer-specific immuno-cell therapy uses Activated Lymphocytes (AL), Natural Killer cells (NK) and Dendritic Cells (DC), the major immune cells which play key role in destroying cancer cells. Natural Killer cell is an important component of the innate immune system and plays a central role in host defense against tumor and virus infected cells. NK cells release perforin, which punches large holes through the cancer cell membrane and then injects large quantities of granzymes, which degrade the DNA and other cellular components through these holes, leading to death of the cancer cell. A single NK cell can destroy up to 27 cancer cells before it dies.

LIMITATIONS IN AIET

A major limitation to the development of effective lymphocyte transfer therapies for patients with cancer has been the inability to mediate the prolonged persistence of the transferred cells. A pilot clinical trial in 13 patients with metastatic melanoma studied by Dudley and colleagues suggested that conditioning with nonmyeloablative chemotherapy before adoptive transfer of activated tumor-reactive T cells enhances tumor regression and increases the overall rates of objective clinical responses. The study demonstrated that there was a significant correlation between tumor regression and the degree of persistence in peripheral blood of adoptively transferred T cell clones, suggesting that inadequate T cell persistence may represent a major factor limiting responses to AIET.

The Chennai Centre of NCRM is well equipped with

state-of-the-art Japanese clean room equipments

and it stringently adheres to all cGMP SOP norms.

WHAT IS DONE AT NCRM?

Nichi In Centre for Regenerative Medicine (NCRM) is an institute carrying out research, training of young scientists and physicians and exploring the possible clinical applications in regenerative medicine based on cell therapeutics, with emphasis on stem cells, Progenitor cells and Autologous cells with regenerative capability and to take them to clinical application, while maintaining the highest ethical and scientific values of international standards. The first Indo Japan research collaboration of NCRM started with Vision Research Foundation-Sankara Nethralaya, Chennai on corneal limbal stem cells. The research collaboration then expanded to Acute Liver failure treatment with the Centre for Liver Research and Diagnostics, Owaisi Hospital, Hyderabad and continued to expand further to Orthopedics, Dermatology, Hemato-Oncology, solid tumors, HIV, Corneal endothelial and Retina related disorders etc with reputed scientists and research institutes in India.

NCRM, having signed a collaborative agreement with Biotherapy Institute of Japan (BIJ) headed by Dr. Hiroshi Terunuma, a clinical immunologist and cell biologist, has brought Autologous Immune Enhancement Therapy (AIET) to India that would benefit patients suffering from above cancers. M/S BIJ have been practicing this treatment for more than a decade in Japan for patients with Cancer of Liver, Lungs, Pancreas, Breast, Renal Cell Carcinoma, Malignant Melanoma, Lymphomas and blood cancers with relatively good results and above all since this treatment uses the patients own cells taken from the peripheral blood, doesn’t have any rejection problem.

References (for a full list of publications of AIET click here) :

1. Vinod R, Tyagi BB, Manoharan N., Cancer incidence and mortality in Delhi UT urban - 2001 (Publication by Delhi Cancer Registry, Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences)

2. Dewan MZ, Terunuma H et al. Potential role of NK cells in growth and infiltration of AIDS – associated primary effusion lymphoma cells: Implication of Immune therapy. Submitted to Blood.

3. Dewan MZ, Terunuma H et al. Natural killer cells in breast cancer cell growth and metastasis in SCID mice. Biomedicine and Pharmacotherapy. 2005; 59: S373-S377.

4. Hiroshi Terunuma, Xuewen Deng et al. Adoptive immunotherapy of cancer with ex vivo expanded, Autologous NK cells. The Society for Natural Immunity 2005; 9^th Meeting, NK Hawaii B070.

5. Shigenori Goto, Toru Kaneko et al. Combined Immunocell therapy using Acitvated Lymphocytes and Monocyte-derived Dendritic cells for Malignant Melanoma. Anticancer Res 2005; 25: 3741-3746.

6. Steven A. Rosenberg. Shedding light on Cancer. N engl j med 2004; 14: 1461-1463.

7. Rosenberg, S.A., Yang, J.C. & Restifo. Cancer Immuno therapy: moving beyond current vaccines.  N.P. Nat. Med. 2004; 10, 909–915.

8. Steven A Rosenberg. Development of Effective Immunotherapy for the Treatment of Patients with Cancer. J Am Coll Surg. 2004; 198:685-696

9. Mark E.Dudley and Steven A. Rosenberg. Adoptive cell transfer therapy for the treatment of patients with cancer. Nature 2003; 3: 666-675.

10. Kohji Egawa. Immuno-cell therapy of Cancer in Japan. Anti Cancer Res 24:3321-3326

11. Shigenori Goto, Noriko Shirotani et al. Clinical Benefit of Nontoxic Therapy in patients with advanced cancer. Anti cancer Res 2002; 22: 2461-2464.

12. Steven A. Rosenberg. Progress in human tumor immunology and immunotherapy. Nature 2001; 411(6835): 380-384.

13. Michael Schleuning. Adoptive allogeneic immunotherapy – history and future perspectives. Transfusion science 2000; 23: 135-150.

14. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immuno-logic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4:321-7.

Glossary

§         Metastasis

Spread of cancer from its primary site to other places in the Body; Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body.

§         Lymphocytes

Lymphocyte is a type of white blood cell involved in the human body's immune system and commonly seen in the lymphatic system. The blood has three types of lymphocytes: B cells, T cells and natural killer cells. B cells make antibodies that bind to pathogens to enable their destruction. CD4+ (helper) T cells co-ordinate the immune response. CD8+ (cytotoxic) T cells and natural killer cells are able to kill tumor cells as well as virus infected cells.

§         Macrophages

These are big eater cells involved in engulfing invading pathogens.

§         Mono Nuclear cells

These are lymphocytes, monocytes and immature cells of their lineage including stem cells other than polymorphonuclear cells involved in defence mechanism.

§         Natural killer cells

Natural NK cells are cytotoxic cells that causes lysis of tumor cell's plasma membrane by inserting proteins called perforins and they also induce programmed cell death of tumor cells.

§         Dendritic cells

They are present in small quantities in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines. Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the immune response.

§         Lymph Node

These are bean shaped components of the lymphatic system having internal connective tissue filled with lymphocytes that collect and destroy bacteria and viruses. They become enlarged due to a tumor or infection.