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Immunotherapy has shown significant potential as a more targeted approach to treating cancer by harnessing the body's immune system to fight tumor cells. There are various cancer immunotherapy approaches to boost the response of the immune system to cancer cells:
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.
Many checkpoints 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.
By blocking checkpoint inhibitors including PD-1, PD-L1 and CTLA-4 with monoclonal antibodies, the immune system can overcome the cancer’s ability to resist the immune responses and stimulate the body's own mechanisms to remain effective in its defenses against cancer.
Figure 1. T cells can be inhibited by receptors expressed by tumor cells. Using monoclonal antibodies against immune checkpoint receptors induces T cell anti-tumor activity.
The efficiency of the immune checkpoint blockade with monoclonal antibodies in cancer treatment is remarkable and has durable effects; however, it is limited to a subset of patients. To enhance and broaden the anti-tumor activity of immune checkpoint inhibition the next step is combining agents with synergistic mechanisms of action. Examples are the success of the combination of PD-1/PD-L1 inhibition blockage with complementary checkpoint inhibitor CTLA-4 1.
Another example is IDO (indoleamine-pyrrole 2,3-dioxygenase), this enzyme is constitutively expressed in the tumor microenvironment either by tumor cells or host immune cells and is stimulated by inflammatory cytokines as IFN-γ, leading to host immune inhibition through increased Treg and effector T cell proliferation blockage. Combination of IDO inhibition and immune checkpoint blockage are currently under clinical investigation, with promising initial results1.
Novel treatments like agonistic co-stimulatory antibodies costimulatory molecules such as CD137 (4-1BB), CD134 (OX40), glucocorticoid-induced TNFR (GITR; CD357), and CD40 are expressed by activated T cells, activated natural killer (NK) cells, natural killer T (NKT) cells, Tregs, and other immune cells are emerging new therapeutics1.
Adoptive T cell therapy involves isolation of tumor-specific T cells from patients and their expansion ex vivo. This method enables greater a 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 cells. There are many forms of adoptive T cell therapy used for cancer treatment:
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 detection2 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 mild3 .
CAR-T cells and T cells with engineered tumor-specific TCRs show anti-tumor activity in some solid tumors and hematological malignances1.
There have been recent advances in the development of peptide vaccines for cancer therapy. Malignant cells express antigens that can be harnessed to elicit anti-cancer immune responses. These antigens are able to stimulate the patient’s specific T-cell responses against the tumor cells. This strategy can be particularly important and efficient for low mutational burden tumors, where anti-PD1 monotherapy efficiency is limited by low levels of T cell clones primed for tumor antigens1.
Cancer vaccines consists of administration of tumor-associated antigens – for example melanoma-associated antigen-A3 (MAGE-A3) – in the form of either peptides or recombinant proteins in the presence of adequate adjuvants. The antigen-presenting cells interact with the tumor-associated antigens 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 1.
Anti-cancer vaccines are often employed as therapeutic (rather than prophylactic) agents. Current efforts are focused on identifying relevant tumor rejection antigens, ie tumor-associated antigens that can elicit an immune response leading to disease eradication.
2. Grupp, S., Kalos, M., Barrett, D., Aplenc, R., Porter, D., Rheingold, S., Teachey, D., Chew, A., Hauck, B., Wright, J., Milone, M., Levine, B. and June, C. (2013). Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. New England Journal of Medicine, 368(16), pp.1509-1518.