Medical discoveries are aimed at putting an end to the sufferings of the people affected by a never-ending list of diseases and disorders. Even as this never -ending battle between diseases and medical discoveries continues, what we see is that the more solutions we come up with, more and more is the emergence of new diseases. In this battle, cancer, the “Killer Disease” of the century deserves a special mention, being multifactorial in origin, development and progress requiring a multi-pronged approach.
There is a lot to be understood about the processes that lead to cancer development at the cellular and molecular level. Cancer continues to be a disease that cannot always be diagnosed with precision at an early stage even after the advent of sophisticated equipment and technologies. Ignorance of symptoms indicative of development of cancer at an early stage especially in developing countries due to lack of periodic health check-ups and awareness leads to a situation in which a majority of cancers are discovered only in the stage of advanced malignancy, when the prognosis is poor with limited treatment options.
In an array of treatments for cancer, conventional approaches include chemotherapy, radiotherapy and surgery. Though these treatments are effective, their side effects jeopardize the life of the patients. Recurrence of cancer is another major concern. In this multipronged approach to cancer, patients own immune-cell based Immunotherapy is an effective mode of therapy with least side effects when compared to conventional modalities of treatment for cancer. Though it is relatively new in developing nations like India, it has been in clinical practice in countries like Japan for more than two decades with proven safety and efficacy.
Immune system against cancer
The Immune system is a boon by the nature as it is consistently involved in tackling the budding cancer cells that are formed everyday and the viruses, bacteria etc that enter the body. The immune system is a complex network of cells and organs comprising the Lymphocytes, Macrophages, Dendritic cells, Natural Killer Cells (NK cell), Cytotoxic T Lymphocytes (CTL) and lymph nodes etc. that work together to defend the body against attacks by these “foreign or non-self" invaders including cancer cells. Cells divide everyday normally and 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. The immune system acts through various mechanisms, majority of them sense the abnormal or cancer cells by their "antigen" which is a specific marker or code of identity, expressed on the surface of these cells.
The Immune System functions through various mechanisms. The Dendritic Cells (DC) facilitate the antigen presentation which evokes the next step of cells called Cytotoxic T-Lymphocytes (CTL) which destroys the cancer cells. Independent of this mechanism, the Natural Killer cells (NK) destroys the cancer cells by injecting a cytolytic material called Perforin .
Immunotherapy and its components
Immunotherapy is a broad term encompassing approaches that modulate the immune system to fight against diseases by inducing, enhancing or suppressing it either directly or indirectly. Immunotherapy against cancer involves a diverse range of approaches involving natural and synthetic substances including cytokines, granulocyte colony-stimulating factor (G-CSF), interferons, IL-12, various chemokines etc which are continuously explores for the abilities to fight against cancer at a molecular and cellular level and these agents act mainly indirectly. The most advantageous and the direct cancer tackling mechanism using immune system is to take the immune cells from patients own blood, multiply the CTLs and NK Cells and then re-inject to the patient enable them directly attack and destroy the cancer cells.
Autologous Immune Enhancement Therapy
Autologous Immune Enhancement Therapy (AIET) is a cell- based Immunotherapy process which enhances and empowers the innate immunity of the patient by employing in vitro multiplied, patient`s own immune cells. Lymphocytes are the most important functioning components of this innate immunity, in which a part of them are Natural Killer (NK) cells and Cytotoxic T-Lymphocytes. In AIET these cells are taken from the patient’s own blood and then in the laboratory (in vitro) they are multiplied, activated and transfused intravenously to the patient and being one own cells doesn’t cause any adverse reaction as these immune cells target only the non-self cancer cells doing no-harm to the normal cells.
How does AIET work?
To explain in simple terms,a body can be compared to a house in which cells and organs are nested. Like a thief who enters the house, cancer enters the human body by stealth and destroys the human body cells and tissues. A thief will plant bombs at various places in the house as his sole aim is destruction of the house. Similarly cancer spreads via lymphatic and blood vessels to other organs of the body.
Conventional therapies for cancer Surgery
Just like a thief is located using radar, cancer is diagnosed with the help of diagnostic equipment and if his position (cancer location) is clear, he is removed by physically for which an entry is necessary into the house. Surgical approach is possible when the tumour is located in one region without spread. Diagnosis like CT, MRI, and PET scan are used to locate the extent of the disease and the tumour is removed. The scar will take time to heal and post-operative care is necessary.
Chemotherapy
If in order to drive out thieves , poisonous gas is sent through the chimney, it will not only kill the thieves but also the guard dogs and even the pet animals. Chemotherapy not only destroys the cancer cells, but also the normal cells depending upon the dosage and type of cancer treated. Chemotherapy also brings down the peripheral blood count in which the immune cells are also affected. Since chemotherapy has many side effects, immunotherapy can be considered as a viable alternative.
Radiotherapy
Laser guns also could be used to target the thief when locations are clearly known. But again, some damage to surrounding structures could be there especially at the entry point. Radiotherapy is given for specific tumours which are amenable to radiotherapy depending on the type of organ or tissue. There could be some minor to major scarring of skin and surrounding tissues depending upon the dosage and tissue, tumour location.
Immunotherapy
In contrast to conventional treatments, Immunotherapy brings out the guard dogs (immune cells) which have been restrained by the thief.
The guard dogs are released from restraints, rejuvenated, bred and multiplied and then sent into the house. The immune cells not only destroy the cancer cells but also are capable of destroying the cancer stem cells that are the major factors behind metastasis and recurrence, which gives an added advantage. Moreover being the guard dogs of the same house, they know the thief to be destroyed and accomplish the same while leaving the belongings of the house undamaged which is why this is considered the least toxic therapy.
Clinical evidences of AIET
AIET is a cell based immunotherapy which is being practiced in Japan and several developed nations since late 1990s. There are several randomized clinical trials which have proven the advantage of this treatment with significant increase in survival rates as well disease- free duration in patients treated with immunotherapy compared with those who have not been treated
Results of clinical trials
In a trial by Fujita et al in 1995, about 13 patients with ovarian cancer were given AIET along with surgical resection and chemotherapy and these patients had increased survival rate and increased disease free survival rate (P<0.01; P<0.05) .In a phase III randomised clinical trial by Kimura et al in 1997, about 82 patients with Stage III and IV advanced lung cancer were given AIET along with resection and chemotherapy and (or) radiotherapy. About 88 patients treated with only surgical resection and chemotherapy and (or) radiotherapy were kept as controls and it was identified with evidence that patients who were treated with AIET had increased survival rate (P<0.001). The increased survival rate of patients with cancer who were given AIET along with conventional treatments were further confirmed by Clinical trials by Takayama et al , Kono et al and many others in a variety of cancers including liver and stomach cancer.
AIET can be administered with or without the combination of conventional treatments to all cancers in general including renal cell cancer (kidney), malignant melanoma (skin), advanced pancreatic tumours, lymphomas, breast cancer, ovarian cancer, liver cancer, lung cancer, colon cancer, cancer of oesophagus and some types of leukemias (blood cancers). terminally ill patients with metastases in the lungs, Liver and bone have also been treated with AIET. The number of transfusions ranged between 12-24.
Efficacy of AIET combined with other therapies
Egawa et al presented a comprehensive review of nearly 1401 patients who were administered immunotherapy for various solid cancers including cancer of ovary, lung cancer, stomach cancer, liver cancer. It has become evident that the efficacy of cell based immunotherapy when combined with conventional treatment improves by 20-30% and less than 1% of the patients experienced fever or a rash thus proving that this treatment is free of significant side effects when compared with other standard cancer therapies.
Efficacy of AIET sans other therapies
The AIET alone without other treatments has been administered to 11 patients with advanced stage of cancers which resulted in prolonged stable disease. Breast cancer patients with bone and liver metastases could survive beyond 15 months. Uterus cancer patients with lymph node and colon metastases could live beyond 15 months. Stomach, uterus and oesophagus cancer patients, all with lymph node metastases could live beyond 14 months. Ovarian cancer patients could live beyond 26 months and lung cancer patients beyond 22 months. Liver cancer patients could live beyond 12 months. An inoperable pancreatic cancer patient after four transfusions of AIET alone could survive upto two years . Around 13 out of 46 patients with advanced pancreatic tumour were administered Immunocell treatment alone. These patients had a 50% survival time of 14.5 months.
The role of NCRM in spreading awareness on AIET
NCRM is the first institute in India to provide AIET involving NK cells and CTLs for patients with cancer. The Biotherapy Institute in Japan, the technology providers to NCRM treats almost 10-20 patients every day with an overall efficacy of this treatment when added to the conventional treatment more than 20-30 %.
Till date 23 patients with different types of cancers at various stages have been administered AIET by NCRM . For example, a male patient aged 40 years with Stage III (advanced) adenocarcinoma of the pancreas was given three transfusions of expanded NK and Cytotoxic T Lymphocytes along with surgery and adjuvant chemotherapy by NCRM. There was considerable improvement in the quality of life of the patient after the first transfusion which made the patient to take two more cycles of the AIET. The patient showed steady improvement with a significant tumour response proven by a steady decrease in tumour marker CA 19-9 values from 3800 -750 and a tumour progression-free survival of 18 months. Similarly a 54 years old female diagnosed with papillary serous cystedenocarcinoma of Ovary stage III-C was given four cycles of AIET along with chemotherapy. The CA-125 cancer marker came down from 243 U/Ml to 6.68 U/mL and the patient reported improvement in appetite and quality of life with no adverse reactions following the NK cell transfusions.
Other benefits of AIET
The AIET, apart from victims of cancer is considered to be useful in improving the immunity of healthy people in terms of NK cell profile and fighting viral infection. Imai et al have found after an 11 year follow-up of 3625 volunteers that the NK cell profile of cancer victims is significantly lower than their peers without cancer. This finding could be the basis for a study of long-term effects of intermittent AIET in people with cancer history in their family and also with people who undergo stress related decrease of NK cell profile. As the antigenic sensing of the tumour cells and viruses are almost the same , the AIET could be tried in victims of HIV and HCV in bringing down the viral load.
What the future holds?
The future will see further advances in Immunotherapy and other alternative approaches to cancer. One of the latest modalities is Monoclonal Antibody based approach in which antibodies designed against cancer antigens specific to each type of cancer are employed in the form of antibody based drugs. This is now administered in combination with AIET as a more effective weapon in the fight against cancer in Biotherapy Institute, Japan.
Thus AIET is an effective modality against various cancers and this can be given in combination with conventional therapies or alone as per the need. This least toxic therapy will continuously be explored to its fullest potential so that one day it can be used effectively in combination with other approaches to win the battle against cancer..
Acknowledgement: The author acknowledges Dr John Sudhakar and Dr SP. Preethy for their assistance provided in the preparation of the article.
- The author is Director, NCRM, Chennai and also Faculty of Medicine,Yamanashi University,Japan