Immunotherapy

Immunotherapy is a medical term defined as "treatment of disease by inducing, enhancing, or suppressing an immune response"^[1].

 

Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies.

Immunotherapies designed to reduce, suppress or more appropriately direct an existing immune response, as in cases of autoimmunity or allergy, are classified as suppression immunotherapies.

 

The active agents of immunotherapy are collectively called immunomodulators. They are a diverse array of recombinant, synthetic and natural preparations, often cytokines. Some of these substances, such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacterial microorganisms are already licensed for use in patients. Others including IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG), oligodeoxynucleotides and glucans are being currently investigated extensively in clinical and preclinical studies. Immunomodulatory regimens offer an attractive approach as they often have fewer side effects than existing drugs, including less potential for creating resistance in microbial diseases.^[2]

Cell based Immunotherapies are proven to be effective for cancers, where the immune cells such as lymphocytes, macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL), etc., work together to defend the body against cancers and attacks by "foreign" or "non-self" invaders such as bacteria and viruses.

 Examples of activation immunotherapies

 Cancer

Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. Immuno cell therapy for cancer was first introduced by 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 suggested that immuno cell therapy with specific chemotherapy is the future of cancer immunotherapy.^[3] In the beginning Immunotherapy treatments involved administration of cytokines such as Interleukin^[4] with an aim of inducing the lymphocytes to carry on their activity of destroying the tumor cells. Thereafter the adverse effects of such intravenously administered cytokines ^[5] lead to the extraction of the lymphocytes from the blood and culture-expanding them in the lab and then injecting the cells alone to enable them to destroy the cancer cells.^[6]

Though the concept of this treatment started in the US in 80s, fully 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]} and its efficacy is enhanced by 20 – 30% when cell based immunotherapy is combined with other conventional treatment methods.

BCG immunotherapy^[11] for early stage (non-invasive) bladder cancer utilizes instillation of attenuated live bacteria into the bladder, and is effective in preventing recurrence in up to two thirds of cases. Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which is an interferon producer causing the patients own killer T cells to destroy warts,^[12], actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,^[13] squamous cell cancer^[11][14], cutaneous lymphoma,^[15] and superficial malignant melanoma,^[16]. Injection immunotherapy uses mumps, candida the HPV vaccine^[17][18] or trichophytin antigen injections to treat warts (HPV induced tumors). Lung cancer has been demonstrated to potentially respond to immunotherapy^[19]

Mushrooms, clockwise from left, Enokitake, Beech mushroom, bunapi-shimeji, King Oyster mushroom and Shiitake in front.

In many parts of Asia, medicinal mushrooms are thought to be able to boost the immune system naturally. Cellular and animal research has shown that Agaricus blazei may stimulate immune system cells and the production of interferons and interleukins (reviewed by G. Hetland).^[20] Mushroom isolates like PSK also are used to increase immune system parameters (reviewed by Kobayashi).^[21] Used in conjunction with chemotherapy, PSK has increased the survival time of cancer patients in randomized, control studies, with a variety of cancer types. PSK together with extracts of Astragalus propinquus, Ganoderma lucidum and Shiitake are used in the pharmacological blend MC-S, which has been shown to promote proliferation of peripheral blood lymphocytes due to cytokine upregulation.

 Autologous Immune Enhancement Therapy (AIET)

In the multipronged approach to treat cancer, one very useful latest weapon would be AIET which is in clinical practice in Japan since 90s for more than 15 years with good effectiveness and several clinical trials and researches are reported from institutions all over the world including from the US. AIET is a treatment method in which some immune cells are taken out of a patient's body which are cultured and processed to be activated or to acquire additional functions until their resistance to cancer is strengthened, then the cells are put back in the body. Researchers have found that the thus activated immune system might also be able to determine the difference between healthy cells and cancer cells to eliminate the cancer cells from the body.　 In AIET, specific type 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 before its lifespan. This is the mechanism by which AIET is effective in Cancer therapy.

 Dendritic cell based immunotherapy

This utilizes dendritic cells to activate a cytotoxic response towards an antigen. Dendritic cells, a type of antigen presenting cell, are harvested from a patient. These cells are then either pulsed with an antigen or transfected with a viral vector. The activated dendritic cells are then placed back into the patient; these cells then present the antigens to effector lymphocytes (CD4+ T cells, CD8+ T cells, and in specialized dendritic cells, B cells also). This initiates a cytotoxic response to occur against these antigens and anything that may present these antigens. one use for this therapy is in cancer immunotherapy. Tumor Antigens are presented to dendritic cells, which cause the immune system to target these antigens, which are often expressed on cancerous cells^[22]. The Dendreon drug Provenge is one example of this approach.

 T cell based adoptive immunotherapy

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes is an effective treatment for patients with metastatic melanoma;^[23] this is based on adoptive immunity.

Adoptive cell transfer, or "ACT," uses T cell-based cytotoxic responses to attack cancer. T cells that have a natural or genetically engineered reactivity to a patient's cancer are expanded, made more effective, in vitro using a variety of means and then adoptively transferred into a cancer patient.

For example, T cells with a naturally occurring reactivity to a patient’s cancer can be found infiltrated in the patient's own tumors. The tumor can be harvested, and these tumor-infiltrating lymphocytes (TIL) can then be expanded, or made more effective, in vitro using high concentrations of interluekin-2 (IL-2), anti-CD3 and allo-reactive feeders. These T cells can then be transferred back into the patient along with exogenous administration of IL-2 to further boost their activity.

Thus far, a 51% objective response rate has been observed; and in some patients, tumors shrank to undetectable size^[24][25].

The initial studies of adoptive cell transfer using TIL, however, revealed that persistence of the transferred cells in vivo was too short.^[26] Before reinfusion, lymphodepletion of the recipient is required to eliminate regulatory T cells as well as normal endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines.^{[23][27][28][29]} Prior lymphodepletion to transfer of the expanded TIL was made by total body irradiation.^[30] The trend for increasing survival as a function of increasing lymphodepletion was highly significant (P=0.007).^[30] Transferred cells expanded in vivo and persisted in the peripheral blood in many patients, sometimes achieving levels of 75% of all CD8⁺ T cells at 6-12 months after infusion.^[31]

Morgan et al. (2006)^[32] demonstrated that the adoptive cell transfer of lymphocytes transduced with retrovirus encoding T cell receptors (TCRs) that recognize a cancer antigen can mediate anti-tumor responses in patients with metastatic melanomas.

In such T cell genetic engineering, TCRs that have been identified to have reactivity against tumor-associated antigens are cloned into a replication-incompetent virus that is capable of genomic integration. A patient's own lymphocytes are exposed to these viruses and then expanded non-specifically or stimulated using the engineered TCR. The cells are then transferred back into the patient. This therapy has been demonstrated to result in objective clinical responses in patients with refractory stage IV cancer. The Surgery Branch of the National Cancer Institute (Bethesda, Maryland) is actively investigating this form of cancer treatment for patients suffering aggressive melanomas.

Combination of ACT with such genetic engineering of T cells has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment.^[23]

In June 2008, it was announced that US doctors from the Clinical Research Division led by Dr. Cassian Yee at Fred Hutchinson Cancer Research Center in Seattle had successfully treated a patient with advanced skin cancer by injecting the patient with immune cells cloned from his own immune system.^[33] The patient was free from tumours within eight weeks of treatment. Dr. Cassian Yee described the research findings at The Cancer Research Institute International 2008 Symposia Series. [1]. Responses, however, were not seen in other patients in this clinical trial.

Larger trials are now under way. [2] [3]

 Vaccination

Anti-microbial immunotherapy, which includes vaccination, involves activating the immune system to respond to an infectious agent.

 Examples of suppression immunotherapies

Immune suppression dampens an abnormal immune response in autoimmune diseases or reduces a normal immune response to prevent rejection of transplanted organs or cells.

 Immune tolerance

Immune tolerance is the process by which the body naturally does not launch an immune system attack on its own tissues. Immune tolerance therapies seeks to reset the immune system so that the body stops mistakenly attacking its own organs or cells in autoimmune disease or accepts foreign tissue in organ transplantation.^[34] A brief treatment should then reduce or eliminate the need for life-long immunosuppression and the chances of attendant side effects, in the case of transplantation, or preserve the body's own function, at least in part, in cases of type 1 diabetes or other autoimmune disorders.

 Allergies

Main article: Allergy immunotherapy

Immunotherapy is also used to treat allergies. While other allergy treatments (such as antihistamines or corticosteroids) treat only the symptoms of allergic disease, immunotherapy is the only available treatment that can modify the natural course of the allergic disease, by reducing sensitivity to allergens.

A three-to-five-year individually tailored regimen of injections may result in long-term benefits. Recent research suggests that patients who complete immunotherapy may continue to see benefits for years to come.^[35] Immunotherapy does not work for everyone and is only partly effective in some people, but it offers allergy sufferers the chance to eventually reduce or stop symptomatic/rescue medication.

The therapy is indicated for people who are extremely allergic or who cannot avoid specific allergens. For example, they may not be able to live a normal life and completely avoid pollen, dust mites, mold spores, pet dander, insect venom, and certain other common triggers of allergic reactions. Immunotherapy is generally not indicated for food or medicinal allergies. Immunotherapy is typically individually tailored and administered by an allergist (allergologist). Injection schedules are available in some healthcare systems and can be prescribed by family physicians. This therapy is particularly useful for people with allergic rhinitis or asthma.

The therapy is particularly likely to be successful if it begins early in life or soon after the allergy develops for the first time. Immunotherapy involves a series of injections (shots) given regularly for several years by a specialist in a hospital clinic. In the past, this was called a serum, but this is an incorrect name. Most allergists now call this mixture an allergy extract. The first shots contain very tiny amounts of the allergen or antigen to which you are allergic. With progressively increasing dosages over time, your body will adjust to the allergen and become less sensitive to it. This process is called desensitization. A recently approved sublingual tablet (Grazax), containing a grass pollen extract, is similarly effective, with few side effects, and can be self-administered at home, including by those patients who also suffer from allergic asthma, a condition which precludes the use of injection-based desensitization. To read more about this topic, see: allergy and hyposensitization.

 Other approaches to immunotherapy

Recent research into the clinical effectiveness of Whipworm ova (Trichuris suis) and Hookworm (Necator americanus) for the treatment of certain immunological diseases and allergies means that these organisms must be classified as immuno-therapeutic agents. Helminthic therapy is being investigated as a potentially highly effective treatment for the symptoms and or disease process in disorders such as relapsing remitting multiple sclerosis^[36] Crohn’s,^[37][38][39] allergies and asthma.^[40]

The precise mechanism of how the helminths modulate the immune response, ensuring their survival in the host and incidentally effectively modulating autoimmune disease processes, is currently unknown. However, several broad mechanisms have been postulated, such as a re-polarisation of the Th1 / Th2 response,^[41] and modulation of dendritic cell function by Fujiwara^[42] and Carvalho^[43]. That helminths modulate host immune response is proven, as the core assertion of the hygiene hypothesis appears to have been, with the recent publication of a study demonstrating that co-evolution with helminths has shaped at least some of the genes associated with Interleukin ｅxpression and immunological disorders, like Crohn's, ulcerative colitis and Celiac Disease. Much of the research that has been published now indicates a key role, for what have been traditionally regarded as disease causing organisms, the helminths, in down regulating the pro-inflammatory Th1 cytokines, IL-12 (Interleukin-12), Interferon-Gamma (IFN-γ) and Tumour Necrosis Factor-Alpha (TNF-ά), while promoting the production of regulatory Th2 cytokines such as IL-10 IL-4, IL-5 and IL-13.^[41][44]