ells.
Typically, antibodies directed towards PD-1 are not preferred as they prevent its binding to both ligands which results in higher toxicity. PD-L1 inhibition as opposed to PD-1 inhibition blocks only PD-1:PD-L1 interactions while preserving PD-1:PD-L2 interactions. This provides more target specific signaling. PD-L1 also binds to CD80 to deliver inhibitory signals to T-cells so its inhibition prevents reverse signaling and resulting T-cell downregulation.
MAbs can significantly reduce toxicity while shrinking solid tumors, suppressing metastasis, and improving overall patient survival. Current FDA approved PD-1/PD-L1 inhibitors include Nivolumab and Pembrolizumab which are PD-1 inhibitors and Atezolizumab which is a PD-L1 inhibitor. These are currently the frontline treatments for metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial cancer.
Immune mediated adverse reactions describe the side effects of immunotherapy. PD-1/PD-L1 inhibitors can have adverse reactions that lead to immune system dysregulation which can cause autoimmune disease-like symptoms. Classic chemotherapy toxicities (fatigue, anorexia, nausea, diarrhea), are also seen in patients treated with PD-1/PD-L1 inhibitors. These adverse effects are likely due to off-target interactions.
PD-1/PD-L1 inhibitors are closely related to CTLA-4 inhibitors as both PD-1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are expressed on activated T cells. The difference between the two inhibitors is the phase of the immune response in which they are active. While PD-1 inhibitors target T-cell activation in the tumor environment, anti-CTLA-4 antibodies centrally affect T-cell priming.
CTLA-4 is an immune checkpoint that stops and inactivates autoreactive T-cells that are unable to differentiate self from non-self, at the initial stage of activation in the lymph nodes. Activation of the CTLA-4 receptor downregulates any immunogenic response by binding to its ligands CD80 and CD86. The CTLA-4 receptor is expressed by both CD4+ (helper) and CD8+ (cytotoxic) T-cells while its ligands are present on the surface of APCs. CTLA‐4 is also expressed on regulatory T cells which suppress the immune response in the tumor microenvironment. Due to a variety of targets, a CTLA‐4 blockade results in a broad, nonspecific activation of an immune response.
CTLA-4 inhibitors are mAbs that attach and block CTLA-4 from binding to its ligands, which boosts the immune response against cancer cells. Blocking CTLA-4 induces an antitumor immune response by promoting the activation and proliferation of tumor specific T-cells. This blockade is also thought to promote the generation of memory T-cells which provides a long term antitumor response.
The mechanism of action behind this effect is explained by the fact that CTLA-4 is a CD28 homolog that binds with higher affinity to CD80 (B7.1) and CD86 (B7.2). The relative amount of CD28:B7 binding versus CTLA-4:B7 binding determines whether a T-cell will undergo activation. When CTLA-4 and its ligands bind, no stimulatory signal is produced. This competitive binding can prevent the stimulatory signal normally provided by CD28/B7 binding. Some evidence suggests that CTLA-4 binding to B7 may also produce inhibitory signals that counteracts the stimulatory signals from CD28:B7 binding.
Ipilimumab is an FDA approved CTLA-4 inhibitor which is a selective human IgG1 mAB used for the treatment of melanoma. It is currently undergoing clinical trials for the treatment of non-small cell lung carcinoma, small cell lung cancer, bladder cancer and metastatic prostate cancer. Like all immune checkpoint inhibitors, CTLA-4 inhibitors are associated with immune mediated toxicities, most of whic
