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Methodologies for battling cancer used today include radiation therapy, chemotherapy, and surgery to eliminate cancer cells. While each of these types of treatments have varying levels of effectiveness, they also destroy a large number of healthy cells in the process.
Immunotherapy has shown significant potential for a more targeted approach to treating cancer by harnessing the body's immune system to fight tumor cells. Cancer cells are common in the body and the immune system works to find and fight the them by activating the immune response. Sometimes, cancer cells can undergo changes in order to escape the body's ability to attack them, allowing the cancer to grow and spread.
There are various immunotherapy approaches to boost the immune system:
The human immune system protects against foreign pathogens and diseases, but it also plays a very important role in clearing the body’s own unhealthy and ailing cells. As such, the immune system is also capable of recognizing and eliminating cancer cells.
The T cells of the immune system have a capacity to selectively recognize and kill pathogens or unhealthy cells by orchestrating a coordinated immune response including innate and adaptive responses.
There are many checkpoints to ensure the cells of the immune system do not mistakenly destroy healthy cells during an immune response (autoimmune reaction). Cancer cells have adapted to exploit these immune checkpoints as way to evade immune detection and elimination.
Inhibition of T cells by receptors expressed by tumor cells can be targeted to induce T cell activation for tumor specific immunotherapy.
T-cell receptors (TCR) recognize the antigen/MHC complex present on the antigen presenting cell (APC) to stimulate T-cell activation. But this interaction alone is not sufficient for activation of T cells, and there are many co-stimulatory receptors present on the T cell and the APC that can augment or inhibit the T-cell response (Table 1).
Simultaneous recognition of antigen/MHC complexes and co-stimulatory ligands by T cells initiates cytokine production, cell-cycle progression, and production of anti-apoptotic factors that result in proliferation and functional differentiation of T cells. These modulatory ligands and receptors, or checkpoints, have emerged as the leading targets to facilitate an enhanced anti-tumor response from the immune system.
List of interactions between T cells and APCs that can regulate T-cell response.
|Antigen presenting cell||T cell||T-cell regulation|
(Adopted from DM Pardoll, 2012)
Using various strategies to block key checkpoint inhibitors, cancer immunotherapy research is trying to overcome the cancer’s ability to resist the immune responses and to stimulate the body's own mechanisms to remain effective in its defences against cancer.
Adoptive T-cell therapy
Adoptive T-cell therapy involves the isolation of tumor specific T cells from patients and their expansion ex vivo. This method enables greater number of tumor specific T cells to be generated than vaccination alone. The tumor specific T cells are then infused into patients in an attempt to give their immune system the ability to overwhelm remaining tumor via T cells. There are many forms of adoptive T-cell therapy used for cancer treatment:
(CH June, 2007)
T cells are engineered to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens. Researchers can prime the cells to recognize and kill tumor cells that would otherwise escape immune detection (S Grupp et.al., 2013). The process of generating CAR-T cells involves extracting a patient’s T cells, transfecting them with a gene for a chimeric antigen receptor (CAR), then reinfusing the transfected cells into the patient. The infusion of T cells is generally well tolerated. Any adverse events from T-cell infusion are infrequent and mild (SK Tey, 2014).
Recent studies of CD19-directed (CAR)-expressing T cells have shown dramatic results in the treatment of acute lymphoblastic leukemia as well as activity in B-cell lymphoma (MK Brenner, 2013). These studies have shown great potential of adoptive T-cell therapies for treatment of malignancies.
There has been recent advances in the development of peptide vaccines for cancer therapy. Malignant cells express antigens that can be harnessed to elicit anticancer immune responses. These antigens are able to stimulate the patient’s specific T-cell responses against the tumor cells.
Cancer vaccines consists of administration of tumor-associated antigens (TAAs) for e.g., melanoma-associated antigen-A3 (MAGE-A3), in the form of either peptides or recombinant proteins in the presence of adequate adjuvants. The antigen presenting cell (APC) are able to interact with the TAA to initiate T-cell driven immune response against cancer cells that expresses the antigen.
Targeting biologically relevant antigens via vaccination, in animal models, has resulted in both tumor inhibition and modulation of the biology of the tumor to make cancer more amenable to standard treatments.
Anticancer vaccines are often employed as therapeutic (rather than prophylactic) agents. Current efforts are focused on the identification of relevant tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication.