Understanding Immune Checkpoint Proteins
Immune checkpoints are regulatory pathways in the immune system that maintain self-tolerance and modulate the duration and amplitude of physiological immune responses. They are crucial for preventing autoimmunity but can be co-opted by cancer cells to evade immune detection. Several immune checkpoint proteins have been identified, including:
IDO
TDO
PD-1
PD-L1
CTLA-4
KIR
4-1BB (CD137)
OX40 (CD134)
LAG3
B7-H3 (CD276)
TIM3
TIGIT
BTLA
VISTA
ICOS
CD39
CD27
CD30 (TNFRSF8)
CD28
B7-H4 (B7-S1, B7x, VCTN1)
HHLA2
Galectins
CD155
These proteins are found on T cells or cancer cells and play diverse roles in immune regulation. The focus of this article is on the major checkpoint inhibitors and their mechanisms of action (MOA), as well as the trends in current and future research.
Anti-CTLA-4 Antibody Therapy
The Role of CTLA-4 in Immune Regulation
CTLA-4, or CD152, is a protein expressed on activated T cells that competes with the costimulatory receptor CD28 for binding to ligands CD80 and CD86 on antigen-presenting cells (APCs). CTLA-4 acts as an “off” switch for T cells, dampening immune responses and promoting self-tolerance. It achieves this by outcompeting CD28 for ligand binding, recruiting phosphatases to its intracellular domain to diminish T cell receptor (TCR) signaling, and by removing CD80 and CD86 from APCs through transendocytosis.
Ipilimumab: A Pioneer in CTLA-4 Inhibition
The first and currently only approved CTLA-4 inhibitor is Ipilimumab (Yervoy), developed by Bristol Myers Squibb (BMS) and approved by the FDA in 2011 for melanoma treatment. Ipilimumab works by binding to CTLA-4, blocking its interaction with CD80/CD86, and thereby potentiating T cell activation and proliferation. Despite its success, another CTLA-4 inhibitor, Tremelimumab, has not been approved due to unsatisfactory clinical performance.
Anti-PD-1/PD-L1 Therapy
Targeting the PD-1/PD-L1 Axis
PD-1 is a protein on the surface of T cells that, upon binding to its ligands PD-L1 or PD-L2, inhibits TCR signaling and T cell activation. This pathway is often exploited by tumors to suppress the immune response. Inhibitors of PD-1 or PD-L1 can restore T cell activity and promote anti-tumor immunity.
Success Stories in PD-1/PD-L1 Inhibition
The FDA has approved several PD-1 inhibitors, including Merck’s Pembrolizumab (Keytruda) and BMS’s Nivolumab (Opdivo), which have shown impressive sales and a range of indications such as melanoma, non-small cell lung cancer (NSCLC), and more. Atezolizumab (Tecentriq) by Roche/Genentech is the sole marketed PD-L1 inhibitor, approved for bladder and non-small cell lung cancer treatment. Other PD-L1 inhibitors in clinical trials include BMS 936559, Durvalumab by AstraZeneca, and Avelumab in collaboration with Pfizer.
Anti-LAG-3 Therapy
LAG-3: A Complementary Immune Checkpoint
LAG-3, or CD223, is structurally similar to CD4 but binds with higher affinity to MHC class II molecules. It is expressed on activated T cells, B cells, NK cells, and dendritic cells, and negatively regulates T cell function. Inhibiting LAG-3 can enhance T cell responses, particularly when combined with PD-1 inhibitors.
Clinical Trials Targeting LAG-3
Several companies are investigating LAG-3 inhibitors, including BMS9861 by BMS, REGN3767 by Regeneron and Sanofi, and LAG525 by Novartis. These trials are exploring the potential of LAG-3 inhibitors as monotherapies or in combination with other immune checkpoint inhibitors.
The Future of Immune Checkpoint Inhibition
The field of immune checkpoint inhibition is rapidly evolving, with numerous clinical trials underway to explore the full potential of these therapies. The combination of different checkpoint inhibitors, as well as their use with other treatment modalities, offers promising avenues for enhancing anti-tumor immunity and improving patient outcomes.
For more detailed information on immune checkpoint inhibitors, readers can refer to authoritative sources such as the National Cancer Institute and FDA announcements on drug approvals.
Interesting statistics and trends in the development and sales of immune checkpoint inhibitors are often discussed in industry reports and scientific publications, providing insights into the growing impact of these therapies on cancer treatment.