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Musculoskeletal and Neurological Complications of Check Point Inhibitors
Introduction
For decades, the standard of care for lung cancer, especially advanced disease, has been chemotherapy. However, the identification of specific genetic mutations and molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has facilitated the development of immunotherapy. Since 2015, the Food and Drug Administration (FDA) has approved using multiple immunotherapy agents to be used in combination or as monotherapy for lung cancer treatment (see Table 17.1 ). These agents are antibodies targeting “immune brakes molecules” such as programmed death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Overall, there are known as immune checkpoint inhibitors (ICIs). They work by improving tumor antigen presentation and recognition, thus amplifying antitumor response.
Table 17.1
FDA approved check point inhibitors for treatment of lung cancers.
| Immune Check Point Inhibitor (ICI) | Mechanism of Action | FDA Approved ICI for Lung Cancer |
|---|---|---|
| Atezolizumab | Antibody blocks programmed death-ligand 1 (PD-L1) | Small cell lung cancer with chemotherapy Squamous NSCLC Nonsquamous NSCLC with platinum chemotherapy |
| Nivolumab | IgG4 monoclonal antibody blocks programmed death-1 (PD-1) | Small cell lung cancer after platinum chemotherapy Squamous NSCLC |
| Pembrolizumab | IgG4k monoclonal antibody blocks PD-1 | Squamous NSCLC Monotherapy or with platinum chemotherapy Nonsquamous NSCLC with platinum chemotherapy |
NSCLC , Nonsmall Cell Lung Cancer.
This immune response potentially cause nonspecific activation of the immune system to any organ system. The mechanisms that underlie adverse immune effects (irAE) development are poorly understood but are likely due to increased systemic inflammation caused by ICI, resulting in autoimmune responses and dysregulation of T-cell self-tolerance. , Musculoskeletal and neurologic adverse effects have been reported up to 30%–40% and 9%–12%, respectively, in multiple clinical trials, where mild symptoms are likely underreported. , Immunotherapy is now the standard of care for lung cancer patients. Any clinician that takes care of these patients should have a general understanding of the potential complications of immunotherapy and provide adequate care.
This chapter will discuss the adverse effects of ICI on the musculoskeletal and neurologic system and how rehabilitation could play a role in treating the effects of these novel treatments.
Mechanism of Action of Checkpoint Inhibitors
The success of tumor cells depends on their ability to evade the immune system's surveillance and downregulate the T cell response.
The transmembrane protein PD-1 is present on the surface of B, T, and Natural Kill cells (NK) and is upregulated during the release of proinflammatory cytokines. In normal conditions, once the desired response from the interaction between the antigen-presenting cell (APC) and T cell is no longer needed, the PD-1 receptor on the T cell membrane will interact with the surface ligand on the APC, resulting in the cessation of cytotoxic products release. To escape the immune surveillance, cancer cells produce programmed cell death ligand (PD-L1) on their membrane (see Fig. 17.1 ).
When PD-1 interacts with the tumor; PD-L1 will downregulate T cells and inhibit apoptosis of the cancer cell. Similarly, the CTLA-4 transmembrane protein expression increases based on inflammatory signals on CD8 and CD4 T cells. When they bind to APC ligands, they reduce the release of cytokines and apoptosis inducing enzymes (see Fig. 17.2 ). Checkpoint inhibitor treatments are antibodies direct to the PD-1 or CTLA-4 receptors, thus enhancing identification of tumor cells and adequate immune response to eliminate cancer cells.
Musculoskeletal Complications of Immunotherapy
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