Checkpoint
Inhibitors
Checkpoint Inhibitors
IMMUNE CHECKPOINTS
The immune system is our body’s defence mechanism against diseases, including cancer. Within this system, T-cells are like soldiers that locate and destroy cancer cells.
To protect our tissues from being mistakenly attacked by these T-cells, the body uses ‘checkpoints’-molecules on immune cells that need to be activated or blocked to start an immune response.
Cancer cells cleverly manipulate these checkpoints to avoid being attacked by the immune system. They often overexpress checkpoint proteins like PD-L1, which bind to the PD-1 receptor on T-cells, effectively turning them off. This allows cancer cells to grow and spread unchecked.
CHECKPOINT INHIBITORS
Checkpoint inhibitors are a type of immunotherapy that block these checkpoint proteins. For instance
- CTLA-4 Inhibitors: CTLA-4 is another checkpoint protein on T-cells that acts as an ‘off switch’ when bound to B7 molecules on other immune cells. Inhibitors that block CTLA-4 prevent it from binding to B7, allowing the T-cells to remain active and attack cancer cells.
- CTLA-4 Inhibitors: CTLA-4 is another checkpoint protein on T-cells that acts as an ‘off switch’ when bound to B7 molecules on other immune cells. Inhibitors that block CTLA-4 prevent it from binding to B7, allowing the T-cells to remain active and attack cancer cells.
Various Genes involved in immune checkpoints
When we talk about immune checkpoints, we’re really talking about the genes that control them. These genes are like instructions for making the proteins that either put the brakes on or speed up our immune system’s T-cells. Here’s a quick look at some of these key genes:
- PDL1 (CD274): This gene encodes for a protein called programmed death-ligand 1, which can bind to the PD-1 receptor on T-cells, leading to the inhibition of T-cell function and allowing cancer cells to evade immune detection.
- PDL2 (PDCD1LG2): Similar to PDL1, PDL2 binds to the PD-1 receptor on T-cells and modulates immune responses, playing a role in tumor immune evasion.
- PD1 (PDCD1): This gene encodes the programmed cell death protein 1 found on T-cells. When engaged by PDL1 or PDL2, it can inhibit the cytotoxic response of T-cells within the tumor microenvironment, down-regulating the immune response against cancer cells.
- TIGIT: T cell immunoreceptor with Ig and ITIM domains acts as an inhibitory checkpoint and can suppress T-cell activation and promote regulatory T-cell function.
- HAVCR2/TIM3: Hepatitis A virus cellular receptor 2, also known as T-cell immunoglobulin and mucin-domain containing-3, regulates immune responses by inhibiting T-cell proliferation and cytokine production.
- CTLA4: Cytotoxic T-lymphocyte-associated protein 4 competes with CD28 for binding to B7 costimulatory molecules on antigen-presenting cells, transmitting an inhibitory signal to T-cells, which reduces their ability to attack cancer cells.
- IDO1: Indoleamine 2,3-dioxygenase 1 is an enzyme that depletes tryptophan in the tumor microenvironment, leading to suppression of T-cell responses and contributing to immune tolerance of cancer.
- LAG3: Lymphocyte-activation gene 3 negatively regulates T-cell expansion and function and is often exploited by tumors to protect themselves from immune attack.
- CD40: While not directly a checkpoint inhibitor, CD40 is a costimulatory molecule that can influence T-cell responses. Its role in cancer is complex, as it can activate both tumor-fighting immune responses and regulatory pathways that may limit the immune response.
Mechanism
By blocking these checkpoint proteins, namely CTLA-4 and PD-1/PD-L1, checkpoint inhibitors release the immune system’s brakes, allowing T-cells to aggressively target and destroy cancer cells. This approach has led to significant advancements in treating various cancers, offering new hope for prolonged survival and, in some cases, durable remissions.
AVAILABLE INHIBITORS
There are several types of checkpoint inhibitors that target different proteins:
CTLA-4 Inhibitors
Ipilimumab (Yervoy) blocks CTLA-4 and is used for advanced melanoma and advanced renal cell cancer.
PD-1 Inhibitors
Nivolumab and pembrolizumab target PD-1, treating melanoma, Hodgkin lymphoma, lung, kidney, and head and neck cancers. Pembrolizumab also treats urinary tract cancers.
PD-L1 Inhibitors
Atezolizumab, avelumab, and durvalumab block PD-L1, used for lung, certain liver and breast cancers, urothelial cancer, and merkel cell carcinoma.
LAG3
Relatlimab is a recently approved inhibitor for LAG-3.
These drugs are usually administered through a drip into the bloodstream. The use of these drugs is determined by factors such as the type and stage of cancer, as well as previous treatments.
Additionally, our organization embraces a comprehensive approach to cancer treatment when specific FDA-approved inhibitors are not available. We utilize an array of nutraceuticals, natural supplements, and off-label medications backed by scientific research to modulate the immune system’s pathways. This holistic method targets the intricate network regulating immune checkpoints, aiming to bolster the body’s natural defenses against cancer.
Our strategy ensures we address the multifaceted interactions within cancer’s biology, not just isolated molecules. We continuously incorporate the latest scientific findings into our protocols, ensuring our treatments reflect cutting-edge research for optimal patient care.
BENEFITS OF IMMUNOTHERAPY
They may significantly increase lifespan for advanced cancer patients, particularly noted in advanced melanoma.
Patients often experience tumor shrinkage or halted growth, with effects that can persist for extended periods.
Some patients achieve a complete response, with no cancer detected post-treatment, potentially leading to sustained remission.
Effective against a wide array of cancers, including traditionally challenging ones like lung and bladder cancers.
When combined with other treatments such as chemotherapy, they can enhance overall effectiveness.
Administered less frequently than chemotherapy, offering a more manageable treatment schedule.
Side effects are often less severe than those from chemotherapy and can be effectively managed.
Biomarker testing allows for tailored treatments, especially for tumors with specific protein markers.
They may train the immune system to continuously recognize and combat cancer cells, even after treatment ends.
Research suggests they could improve long-term outcomes if used in early-stage cancers.
TREATMENT PROCESS
- Activate the Immune System: Checkpoint inhibitors block proteins that act as “off switches” on immune cells, effectively waking them up to recognize and fight cancer cells.
- Target Hidden Cancer: Cancer cells often hide from the immune system. Checkpoint inhibitors help reveal these cells so the immune system can detect and attack them.
- Administered via Infusion: These drugs are usually given through an IV infusion, allowing them to circulate throughout the body and activate immune cells.
- Regular Treatment Schedule: Treatment typically follows a schedule, with infusions every few weeks, depending on the specific drug and cancer type.
- Monitoring Response: Doctors monitor the patient’s response to treatment through scans and tests, adjusting the approach as needed.
- Managing Side Effects: Side effects, which can range from mild to serious, are managed with medications or by adjusting the treatment.
- Continued Research: Ongoing research is improving how checkpoint inhibitors are used, including which cancers they can treat and how they are combined with other therapies.