Cancer immunotherapy

Overview
Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease. This can be either through immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies.

Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result of the onset of cancer are more or less tolerated by the patient's own immune system since the tumor cells are essentially the patient's own cells that are growing, dividing and spreading without proper regulatory control.

In spite of this fact, however, many kinds of tumor cells display unusual antigens that are either inappropriate for the cell type and/or its environment, or are only normally present during the organisms' development (e.g. fetal antigens). Examples of such antigens include the glycosphingolipid GD2, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuronal cells, where its exposure to the immune system is limited by the blood-brain barrier. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. GD2 is thus a convenient tumor-specific target for immunotherapies.

Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer tumor cells.

Monoclonal antibody therapy
Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.

A number of therapeutic monoclonal antibodies have been approved for use in humans; approvals mentioned here are by the FDA.

Alemtuzumab
Alemtuzumab is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of Chronic lymphocytic leukemia(CLL), the most frequent form of leukaemia in Western countries. The function of CD52 is unknown, but it is found on >95% of peripheral blood lymphocytes and monocytes. Upon binding to CD52, alemtuzumab initiates its cytotoxic effect by complement fixation and antibody-dependent cell-mediated cytotoxicity mechanisms. Alemtuzumab therapy is also indicated for T-prolymphocytic leukaemia (TPPL), for which no standard treatment exists. This is a highly aggressive tumour, with a median survival of 7.5 months.

Bevacizumab
Bevacizumab is a humanized IgG1 monoclonal antibody which binds to and sterically interferes with the vascular endothelial growth factor-A (VEGF-A), preventing receptor activation. A marked increase in VEGF expression is thought to play a role in tumor angiogenesis. Bevacizumab is indicated for colon cancer; but has been applied to numerous other cancers in small scale studies, especially renal cell carcinoma. Results obtained showed that bevacizumab increased the duration of survival, progression-free survival, the rate of response and the duration of response in a statistically relevant manner.

Cetuximab
Cetuximab is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of the epidermal growth factor receptor (EGFR). It functions by competitively inhibiting ligand binding, thereby preventing EGFR activation, and is indicated for the treatment of colorectal cancer. Studies have also been carried out on numerous other malignancies, especially non-small cell lung cancer and head and neck cancer. As a single agent, cetuximab showed a response rate of 10.8% in patients with EGFR overexpressed metastatic colon cancer. Other anti-EGFR monoclonal antibodies in development include: ABX-EGF, hR3, and EMD 72000. Although they hold significant promise for the future, as of yet none of the agents are currently beyond phase I clinical trials.

Gemtuzumab ozogamicin
Gemtuzumab ozogamicin is an “immuno-conjugate” of an anti-CD33 antibody chemically linked to calicheamicin, a cytotoxic agent. It is indicated for the treatment of acute myeloid leukaemia (AML). The patient group most likely to benefit from gemtuzumab is young adults, and trials have reported high complete responses (85%), when combined with intensive chemotherapy. There are minimal side-effects associated with Gemtuzumab therapy.

Rituximab
Rituximab is a chimeric monoclonal antibody specific for CD20. CD20 is widely expressed on B-cells. Although the function of CD20 is relatively unknown it has been suggested that CD20 could play a role in calcium influx across plasma membrane, maintaining intracellular calcium concentration and allowing for the activation of B cells. The exact mode of action of rituximab is also unclear, but it has been found to have a general regulatory effect on the cell cycle and on immune-receptor expression. Experiments involving primates showed that treatment with anti-CD20 reduced peripheral B-cells by 98%, and peripheral lymph node and bone marrow B-cells by up to 95%.

Trastuzumab
Trastuzumab is a monoclonal IgG1 humanized antibody specific for the epidermal growth factor receptor 2 protein (HER2). It received FDA-approval in 1998, and is clinically used for the treatment of breast cancer. The use of Trastuzumab is restricted to patients whose tumours over-express HER-2, as assessed by immunohistochemistry (IHC) and either chromogenic or Fluorescent in situ hybridisation (FISH), as well as numerous PCR-based methodologies.

HER-2 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases, and is normally involved in regulation of cell proliferation and differentiation. Amplification or overexpression of HER-2 is present in 25-30% of breast carcinomas and has been associated with aggressive tumour phenotype, poor prognosis, non-responsiveness to hormonal therapy and reduced sensitivity to conventional chemotherapeutic agents.

Radioimmunotherapy
Radioimmunotherapy involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body.

Ibritumomab tiuxetan
Ibritumomab is a murine antibody chemically linked to tiuxetan, which chelates Yttrium-90. 90Y is a beta radiator, has a half-life of 64 h and a tissue penetration of 1-5 millimetres. Its use has been investigated, primarily in the treatment of follicular lymphoma.

Tositumomab
Tositumomab is a murine IgG2a anti-CD20 antibody and is covalently bound to Iodine 131. 131I emits both beta and gamma radiation, and is broken down rapidly in the body. Clinical trials have established the efficacy of tositumomab in patients with relapsed follicular lymphoma.

Advances in immunotherapy
The development and testing of second generation immunotherapies are already under way. While antibodies targeted to disease-causing antigens can be effective under certain circumstances, in many cases, their efficacy may be limited by other factors. In the case of cancer tumors, the microenvironment is immunosuppressive, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient, against his or her own tumor tissue. Certain members of a group of molecules known as cytokines, such as Interleukin-2 also play a key role in modulating the immune response, and have been tried in conjunction with antibodies in order to generate an even more devastating immune response against the tumor. While the therapeutic administration of such cytokines may cause systemic inflammation, resulting in serious side effects and toxicity, a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets the cytokine's activity to a specific environment such as a tumor, are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side-effects. A different type of chimeric molecule is an artificial T cell receptor.

The targeted delivery of cytokines by anti-tumor antibodies is one example of using antibodies to delivery payloads rather than simply relying on the antibody to trigger an immune response against the target cell. Another strategy is to deliver a lethal radioactive dose directly to the target cell, which has been utilized in the case of the Zevalin® therapeutic. A third strategy is to deliver a lethal chemical dose to the target, as used in the Mylotarg® therapeutic. Engineering the antibody-payload pair in such a way that they separate after entry into a cell by endocytosis can potentially increase the efficacy of the payload. One strategy to accomplish this is the use of a disulfide linkage which could be severed by the reducing conditions in the cellular interior. However, recent evidence suggests that the actual intracellular trafficking of the antibody-payload after endocytosis is such to make this strategy not generally applicable. Other potentially useful linkage types include hydrazone and peptide linkages.

Topical immunotherapy
Dermatologists use new creams and injections in the management of benign and malignant skin tumors. Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which is an interferon producer causing the patient's own killer T cells to destroy warts, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, cutaneous T cell lymphoma, and Superficial spreading melanoma. Injection immunotherapy uses mumps, candida or trichophytin antigen injections to treat warts (HPV induced tumors).