Immune checkpoint inhibitors
The immune system plays an important role in protecting us from disease, and clearing the body’s own unhealthy and ailing cells. The T cells of the immune system have a capacity to selectively recognize and kill pathogens or unhealthy cells, including cancer 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 (known as an autoimmune reaction). Cancer cells can exploit these immune checkpoints as a way to evade immune detection and elimination.
By blocking immune checkpoint proteins, including PD-1, PD-L1 and CTLA-4, with monoclonal antibodies, the immune system can overcome cancer’s ability to resist the immune responses and stimulate the body's own mechanisms to remain effective in its defenses against cancer.
What is the PD-1/PD-L1 pathway?
The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligands, PD-L1 and PD-L2, are commonly expressed on the surface of dendritic cells or macrophages. PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T cell response. The PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.
The role of PD-1/PD-L1 in cancer
Under normal conditions, the immune system performs a series of steps which lead to an anticancer immune response and cancer cell death, known as the cancer immunity cycle1:
1. Tumor cells produce mutated antigens that are captured by dendritic cells
2. The dendritic cells prime T cell with tumor antigen and stimulate the activation of cytotoxic T cells
3. Activated T cells then travel to the tumor and infiltrate the tumor environment
4. The activated T cells recognize and bind to the cancer cells
5. The bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cells
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous immune anti-tumor activity. PD-L1 is commonly over expressed on tumor cells or on non-transformed cells in the tumor microenvironment2. PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Using PD-1/PD-L1 and immunotherapy
Monoclonal antibody therapies against PD-1 and PD-L1 are being routinely used including:
- Nivolumab; an anti-PD-1 drug developed by Bristol-Myers Squibb, which is approved for previously treated metastatic melanoma and squamous non-small cell lung cancer.
- Pembrolizumab, developed by Merck is approved for previously treated metastatic melanoma.
There are several other immunotherapy options being used or in development.
The efficiency of the immune checkpoint blockade with monoclonal antibodies in cancer treatment is remarkable, but not all pateints respond to a single therapy.To enhance and broaden the anti-tumor activity of immune checkpoint inhibition the next step is combining agents with synergistic mechanisms of action. An example of this is the success of the combination of PD-1/PD-L1 inhibition blockage with complementary checkpoint inhibitor CTLA-4 in melanoma and non-small cell lung cancer3.
Adoptive T cell therapy
Adoptive T cell therapy involves first isolating tumor-specific T cells from patients and then expanding these ex vivo. The tumor-specific T cells can then infused into patients to give their immune system the ability to overwhelm remaining tumor cells.
T cells can be harvested either from the patient's tumor (tumor-infiltrating lymphocytes, TILs) or peripheral blood (peripheral blood lymphocytes, PBLs). Tumor specificity must be induced in PBLs either through antigen-specific expansion or genetic engineering4 . After expansion in culture, tumo-specific T cells can be reinfused into the cancer patient.
Another type of adoptive cell therapy is CAR T cell therapy, where T cells are engineered to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens. This means researchers can prime the cells to recognize and kill tumor cells that would otherwise escape immune detection5 .
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 advances in the development of peptide vaccines for cancer therapy. Malignant cells express antigens to stimulate the patient’s specific T cell responses that can be harnessed to elicit an anti-cancer immune response. 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 antigens3.
1. Chen D and Mellman I, Oncology Meets Immunology: The Cancer-Immunity Cycle, Immunity 39, 2013.
2. Pardoll D, The Blockade Of Immune Checkpoints In Cancer Immunotherapy Nature Reviews Cancer, 12, 2012.
3. Ott, P. et al. (2017). Combination immunotherapy: a road map. Journal for ImmunoTherapy of Cancer (2017) 5:16
4. Perica, K. et al. (2015). Adoptive T Cell Immunotherapy for Cancer. Rambam Maimonides Medical Journal (2015) 6(1)
5. 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.
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