Understanding Immune checkpoint inhibitors and the potential
synergistic role of interventional radiology procedures
Raya AlHalawani, MD, Anil Pillai, MD, HongyuWang, PhD
Cancerimmunotherapy is one of the new strategies to fight cancer. It acts by triggering patient’s innate immune antitumor response. In cancer state, the interaction of PD-L1 on the tumor cells with PD-1 on a T-cell generates an immunosuppressive effect and allows the tumor to evade immune destruction. Recently the developments of immune checkpoint inhibitors that inhibit the interaction between PD-L1 and PD-1 have demonstrated clinical activities across a variety of tumor types (1-3). What is more impressive is that these immune checkpoint inhibitors can be augmented with interventional ablation or embolization treatments, creating synergistic effect and very promising results in patients with solid tumors.
- Review the Cancer-Immunity cycle.
- Immune checkpoint inhibitors (ICI) definition and mechanism of action.
- Describe the different classes of ICI along with their different targets.
- Describe the effect of interventional radiological procedures on expression of immune checkpoint proteins with a review of literature.
- Discuss the prospects of ICI and its implications on the management of IR patients.
Checkpoint proteins in the immune system:
Immune checkpoints are regulators of the immunity system. They are majorly divided into stimulatory and inhibitory.
Stimulatory checkpoint proteins are members of the tumor necrosis factor (TNF) receptor superfamily and B7-CD28 superfamily. They have a crucial role in the direct and indirect generation, expansion and activation of T-cells.
Inhibitory checkpoint proteins are molecules that keep the body’s immune system from recognizing its cells as foreign or abnormal. It is vital for self-tolerance and prevents the immune system from attacking the body’s own cells. Some of the most prominent ICP’s are the PD-1, CTLA-4, TIM-3 and LAG3.
PD-1 is the Programmed Cell Death 1 (PD-1) protein (found T cells), has two ligands, PD-L1 and PD-L2 (found on monocytes and tumor cells). When the T-cells’ PD-1binds the PD-L1/PD-L2 receptor, the cell is marked as safe and no cell death is initiated. Monoclonal antibodies have been developed to block PD-1 and PD-L1 interaction, thus aiding the immune system to recognize these cancer cells and initiate cell death.
Some examples of PD-1 inhibitors include pembrolizumab(Keytruda) andnivolumab(Opdivo). Some example of PD-L1 blockers include, atezolizumab(Tecentriq), avelumab(Bavencio) anddurvalumab(Imfinzi).
CTLA-4 is the Cytotoxic T-Lymphocyte-Associated protein 4 (CD152), is expressed on regulatory T (Treg) cells to control T-cell proliferation. The monoclonal antibody against CTLA-4 that has been FDA for the treatment of melanoma is the Ipilimumab(Yervoy). However, this particular drug has been associated with severe side effects.
Interventional radiology oncologic procedures including RF ablation, embolization, chemoembolization and radiation therapy have been shown to cause the release of numerous tumor antigens that provoke an immune response (including the proliferation of tumor-specific T-cells and antigen presenting cells). However, tumors blunt this immune response by upregulatingthe expression of inhibitory immune checkpoint proteins. Thus, at least theoretically, using immune checkpoint inhibitors in conjunction with these IR procedures, would optimize the attack on cancer cells and ultimately cure cancer.
Summary and Implications:
NationalCancer Institute predicts that 39% of the American population will develop cancer at some point in their lifetime. Novel treatment options for cancers are being explored actively. Interventional radiologists with the ability to target treatments with image guidance are playing a greater role in cancer treatments. Understanding immunotherapy and the effect of interventional procedures on the immune system will enhance the field of interventional oncology. The reader will get a clear understanding of immunotherapy pertaining to check point inhibitors and the potential synergistic effect for interventional radiology procedures.4,5
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