Activation immunotherapies

Cancer

Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. Dr William Coley used Coley's Toxins in the late 1800s as crude immunotherapy with some success. Immuno cell therapy for cancer was first introduced by Rosenberg and his colleagues ofNational 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 along with specific chemotherapy is the future of cancer immunotherapy. Initially Immunotherapy treatments involved administration of cytokines such as Interleukin. Thereafter the adverse effects of such intravenously administered cytokines lead to the extraction of the lymphocytes from the blood and expanding in vitro against tumour antigen before injecting the cells with appropriate stimulatory cytokines. The cells will then specifically target and destroy the tumor expressing antigen against which they have been raised.

The concept of this treatment started in the US in 80s and fully fledged clinical treatments on a routine basis have been in practice in Japan since 1990. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with other conventional treatment methods.

BCG immunotherapy 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, actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia, squamous cell cancer, cutaneous lymphoma, and superficial malignant melanoma. Injection immunotherapy uses mumps, candida the HPV vaccine or trichophytin antigen injections to treat warts (HPV induced tumors). Lung cancer has been demonstrated to potentially respond to immunotherapy

Dendritic cell-based immunotherapy

Dendritic cells can be stimulated 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. Upon transfusion back into the patient these activated cells present tumour antigen to effector lymphocytes (CD4+ T cells, CD8+ T cells, and B cells). This initiates a cytotoxic response to occur against cells expressing tumour antigens (against which the adaptive response has now been primed).The cancer vaccineSipuleucel-T is one example of this approach.

T-cell adoptive transfer

Adoptive cell transfer uses T cell-based cytotoxic responses to attack cancer cells. T cells that have a natural or genetically engineered reactivity to a patient's cancer are generated in vitro and then transferred back into the cancer patient. One study using autologous tumor-infiltrating lymphocytes was an effective treatment for patients with metastatic melanoma;. This can be achieved by taking T cells that are found with the tumor of the patient, which are trained to attack the cancerous cells. These T cells are referred to as tumor-infiltrating lymphocytes (TIL) are then encouraged to multiply in vitro using high concentrations of IL-2, anti-CD3 and allo-reactive feeder cells. These T cells are then transferred back into the patient along with exogenous administration of IL-2 to further boost their anti-cancer activity.

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

The initial studies of adoptive cell transfer using TIL, however, revealed that persistence of the transferred cells in vivo was too short. 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. Lymphodepletion was made by total body irradiation prior to transfer of the expanded TIL.The trend for increasing survival as a function of increasing lymphodepletion was highly significant (P=0.007). 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. Clinical trials based on adoptive cell transfer of TILs for patients with metastatic melanoma are currently ongoing at the National Cancer Institute (Bethesda,MD,USA), Moffitt Cancer Center (Tampa,FL,USA), MD Anderson Cancer Center (Houston,TX,USA), Sheba Medical Center (Tel Hashomer,Israel), Herlev University Hospital (Herlev,Denmark) and NKI Antonie van Leeuwenhoek (Amsterdam, Netherlands).

Autologous Immune Enhancement Therapy

The Autologous immune enhancement therapy (AIET) is an autologous immune cell based therapy wherein the patient's own peripheral blood-derived NK cells Cytotoxic T Lymphocytes and other relevant immune cells are expanded in vitro and then reinfused to tackle cancer. There are also studies proving their efficacy against Hepatitis C Viral infection, Chronic fatigue Syndrome and HHV6 infection.

Genetically engineered T cells

Genetically engineered T cells are created by infecting patient's cells with a virus that contain a copy of a T cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus is not able to reproduce within the cell however integrates into the human genome. This is beneficial as new TCR gene remains stable in the T-cell. A patient's own T cells are exposed to these viruses and then expanded non-specifically or stimulated using the genetically engineered TCR. The cells are then transferred back into the patient and ready to have an immune response against the tumour. Morgan et al. (2006) demonstrated that the adoptive cell transfer of lymphocytes transduced with retrovirus encoding TCRs that recognize a cancer antigen are able to mediate anti-tumour responses in patients with metastatic melanomas. 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. The use of adoptive cell transfer with genetically engineered T cells is a promising new approach to the treatment of a variety of cancers.

In one case study, United States 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. 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. Responses, however, were not seen in other patients in this clinical trial. Larger trials are now under way.

Immune recovery

The potential use of immunotherapy to restore the immune system of patients with immune deficiencies as result of infection or chemotherapy. For example cytokines have been tested in clinical trials interleukin-7 has been in clinical trials for HIV and cancer patients. In addition, interleukin-2has also been tested in HIV patients.

Vaccination

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