Immunotherapy

For the academic journal, see Immunotherapy (journal).
Immunotherapy
Intervention
MeSH D007167
OPS-301 code 8-03

Immunotherapy is the "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, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

Immunomodulatory regimens often have fewer side effects than existing drugs, including less potential for creating resistance in microbial disease.[2]

Cell-based immunotherapies are effective for some cancers. Immune effector cells such as lymphocytes, macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL), etc., work together to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells.

Therapies such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria are licensed for use in patients. Others including IL-2, IL-7, IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG) oligodeoxynucleotides and glucans are involved in clinical and preclinical studies.

Immunomodulators

Immunomodulators are the active agents of immunotherapy. They are a diverse array of recombinant, synthetic and natural preparations.

Agent Example
Interleukins IL-2, IL-7, IL-12
Cytokines Interferons, G-CSF, Imiquimod
Chemokines CCL3, CCL26, CXCL7
Other cytosine phosphate-guanosine, oligodeoxynucleotides, glucans

Activation immunotherapies

Cancer

Main article: Cancer immunotherapy

Cancer immunotherapy attempts to stimulate the immune system to destroy tumors. A variety of strategies are in use or are undergoing research and testing. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported[3][4][5][6] and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.

The extraction of G-CSF lymphocytes from the blood and expanding in vitro against a tumour antigen before reinjecting the cells[7] with appropriate stimulatory cytokines. The cells then destroy the tumor cells that express the antigen.

BCG immunotherapy[8] for early stage (non-invasive) bladder cancer instills 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 produces interferon, causing the patient's killer T cells to destroy warts,[9] actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,[10] squamous cell cancer,[8][11] cutaneous lymphoma,[12] and superficial malignant melanoma.[13]

Injection immunotherapy ("intralesional" or "intratumoral") uses mumps, candida, the HPV vaccine[14][15] or trichophytin antigen injections to treat warts (HPV induced tumors).

Adoptive cell transfer has been tested on lung and other cancers.[16]

Dendritic cell-based pump-priming

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, causing them to display the antigen. Upon transfusion into the patient these activated cells present the antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxic CD8+ T cells and B cells). This initiates a cytotoxic response against tumor cells expressing the antigen (against which the adaptive response has now been primed).[17] The cancer vaccine Sipuleucel-T is one example of this approach.[18]

T-cell adoptive transfer

Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.[19] The T cells may already target tumor cells. Alternatively, they may be genetically engineered to do so. These T cells, referred to as tumor-infiltrating lymphocytes (TIL), are multiplied using high concentrations of Interleukin-2, anti-CD3 and allo-reactive feeder cells. These T cells are then transferred back into the patient along with administration of IL-2 to further boost their anti-cancer activity.

Before reinfusion, lymphodepletion of the recipient is required to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines.[19][20][21][22] Lymphodepletion can be achieved by total body irradiation.[23] Transferred cells multiplied in vivo and persisted in peripheral blood in many patients, sometimes representing levels of 75% of all CD8+ T cells at 6–12 months after infusion.[24] As of 2012, clinical trials for metastatic melanoma were ongoing at multiple sites.[25]

Immune enhancement therapy

Autologous immune enhancement therapy use the patient's peripheral blood-derived natural killer cells, cytotoxic T lymphocytes and other relevant immune cells are expanded in vitro and then reinfused.[26] The therapy has been tested against Hepatitis C,[27][28][29] Chronic fatigue syndrome[30][31] and HHV6 infection.[32]

Genetically engineered T cells

Genetically engineered T cells are created by infecting a patient's cells with a retrovirus that contains a copy of a T cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus integrates the receptor into the T cells' genome. The cells are expanded non-specifically and/or stimulated. The cells are then reinfused into the patient and produce an immune response against the tumour cells.[33] The technique has been tested on refractory stage IV metastatic melanomas[19] and advanced skin cancer[34][35][36]

Immune recovery

Another potential use of immunotherapy is to restore the immune system of patients with immune deficiencies. Cytokines, Interleukin-7 and Interleukin-2 have been tested in clinical trials.

Vaccination

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

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.

Immunosuppressive drugs

Immunosuppressive drugs help manage organ transplantation and autoimmune disease. Immune responses depend on lymphocyte proliferation. Cytostatic drugs are immunosuppressive. Glucocorticoids are somewhat more specific inhibitors of lymphocyte activation, whereas inhibitors of immunophilins more specifically target T lymphocyte activation. Immunosuppressive antibodies target steps in the immune response. Other drugs modulate immune responses.

Immune tolerance

Main article: Immune tolerance

The body naturally does not launch an immune system attack on its own tissues. Immune tolerance therapies seek 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.[37] Creating immunity reduces or eliminates the need for lifelong immunosuppression and attendant side effects. It has been tested on transplantations, and type 1 diabetes or other autoimmune disorders.

Allergies

Immunotherapy is used to treat allergies. While allergy treatments (such as antihistamines or corticosteroids) treat allergic symptoms, immunotherapy can reduce sensitivity to allergens, lessening its severity.

Immunotherapy may produce long-term benefits.[38] Immunotherapy is partly effective in some patients and ineffective in others, but it offers allergy sufferers a chance to reduce or stop their symptoms.

The therapy is indicated for people who are extremely allergic or who cannot avoid specific allergens. Immunotherapy is generally not indicated for food or medicinal allergies. This therapy is particularly useful for people with allergic rhinitis or asthma.

The first dose contain tiny amounts of the allergen or antigen. Dosages increase over time, as the the patient becomes desensitized. This technique has been tested on infants to prevent peanut allergies.[39]

Helminthic therapies

Whipworm ova (Trichuris suis) and Hookworm (Necator americanus) have been tested for immunological diseases and allergies. Helminthic therapy has been investigated as a treatment for relapsing remitting multiple sclerosis[40] Crohn’s,[41][42][43] allergies and asthma.[44] The mechanism of how the helminths modulate the immune response, is unknown. Hypothesized mechanisms include re-polarisation of the Th1 / Th2 response[45] and modulation of dendritic cell function.[46][47] The helminths down regulate the pro-inflammatory Th1 cytokines, Interleukin-12 (IL-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.[45][48]

Co-evolution with helminths has shaped some of the genes associated with Interleukin expression and immunological disorders, such Crohn's, ulcerative colitis and Celiac disease. Helminth's relationship to humans as hosts should be classified as mutualistic or symbiotic.

See also

References

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  2. ↑ Masihi KN (July 2001). "Fighting infection using immunomodulatory agents". Expert Opin Biol Ther 1 (4): 641–53. doi:10.1517/14712598.1.4.641. PMID 11727500.
  3. ↑ Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K (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.
  4. ↑ 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.
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  7. ↑ Li K, Li CK, Chuen CK, Tsang KS, Fok TF, James AE, Lee SM, Shing MM, Chik KW, Yuen PM (February 2005). "Preclinical ex vivo expansion of G-CSF-mobilized peripheral blood stem cells: effects of serum-free media, cytokine combinations and chemotherapy". Eur. J. Haematol. 74 (2): 128–35. doi:10.1111/j.1600-0609.2004.00343.x. PMID 15654904.
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