Immuno-oncology treatments are designed to modulate immune system activity and may influence immune responses against cancer cells. Immune checkpoint inhibitors, which are among the established treatments for cancer using immuno-oncology, block specific checkpoints that cancer cells use to suppress the actions of T cells. Of the immune checkpoint inhibitors, PD-1 inhibitor is the most established class of drugs.
pd-1 inhibitors: Understanding the PD-1 pathway and how drugs work to interfere with tumor cells’ use of the pathway to downregulate T-cell activity. The good and the bad.
What Is PD-1?
PD-1 (Programmed cell death protein 1) is a receptor found on the surface of activated T cells. As part of the immune system’s checkpoint, PD-1 prevents the immune system from becoming overactivated and causing excessive damage to healthy cells.
The typical result of PD-1 signaling is decreased activity of T cells that have recently become activated. This type of signaling serves to limit the duration of an immune response to prevent immune-mediated damage to normal tissues.
Cancer cells, however, can use the same pathway to their advantage. In particular, many tumor types express high levels of PD-L1 in the tumor microenvironment, leading to interaction with PD-1 on T cells. This results in decreased T cell function and, in general, contributes to immune suppression or evasion by the tumor.
How PD-1 Signaling Affects T Cells
Cancer and the cells of the tumor microenvironment can interact with PD-1 on T cells in a manner that is inhibitory to T cell function. These interactions can result in a state of persistent immune activation and result in the T cells becoming less effective at recognizing and attacking tumor cells.
Additional signals for T-cell activation are provided by co-stimulatory molecules that interact with co-stimulatory receptors on T cells. Therefore, in addition to the decrease in T-cell proliferation and in cytokine production, such as IL-2, signaling through PD-1 also results in a decrease in T-cell function.
Tumor-antigens are presented to T cells within the tumor microenvironment by host tumor-antigen-presenting cells. In addition to signals that stimulate T cells to proliferate, differentiate, and produce effector-cytokine-secrete, a variety of other signals, that serve to inhibit T cell function, are presented. These signals can act to down-modulate T cells in a number of ways, including decreased proliferation, and decreased production of effector cytokines, and as a consequence, are able to drive T cells down a path of less effective killing of tumor cells.
How Does a PD-1 Inhibitor Work?
PD-1 inhibitors, given as monoclonal antibodies, bind to the PD-1 receptor on T cells (and also to dendritic cells) to block its interaction with PD-L1 or PD-L2 expressed on tumor cells and other cells in the tumor microenvironment.
By blocking the interaction of PD-1 with PD-L1 and PD-L2, PD-1 inhibitors block PD-1 pathway signalling and may help restore T-cell activity in certain clinical settings. These PD-1 inhibitors do not directly kill cancer cells but instead enable existing anti-tumor T cells to continue to recognize and attack cancer cells.
Note that although a PD-1 inhibitor prevents cancer cells from using the PD-L1/PD-1 interaction to suppress T cell function, it is not a direct antitumor agent. It does not, for example, stop the DNA replication of cancer cells. Therefore, a PD-1 inhibitor is an immunotherapy.
These drugs, approved by the FDA as a cancer treatment to prevent cancer from using the PD-L1/PD-1 interaction to suppress T cells function, in some cases, may be used in combination with other anti-cancer drugs.
PD-1 Versus PD-L1 Inhibition
Importantly, although both types of treatments target the same immune checkpoint pathway, PD-1 inhibitors and PD-L1 inhibitors are not identical and act at different points.
These types of cancer therapies do not directly kill cancer cells but instead remove a check point on T cells that cancer uses to keep the T cells from attacking the tumor cells. PD-1/PD-L1 blockade, therefore, can prevent cancer from using the PD-L1/PD-1 interaction to suppress T-cell function.
Both approaches reduce inhibitory signals on tumor reactive T cells. However, different PD-1/PD-L1 inhibitors have different pharmacologies, approved indications, clinical experience, and toxicity profiles, and should not be used interchangeably.
Why Do Some Tumors Respond Better Than Others?
Effects of PD-1 blockade can vary between tumors. There are several factors that could affect the effects of PD-1 blockade, including tumor biology, levels of immune cells within the tumor, ways in which tumors display antigens to T cells, genetic changes that occur in cancer cells as well as in immune cells, and the tumor microenvironment.
In certain cases of cancer, testing for PD-L1 expression is indicated. Immunohistochemistry (IHC) testing can detect the expression of PD-L1 on the tumor cells and/or the immune cells within the tumor of a patient. The clinical use of PD-L1 testing and the cut-off for positive results for PD-L1 expression varies by cancer type, treatment, and indication.
The presence of PD-L1 in a tumor does not necessarily mean that a patient will benefit from treatment with a PD-1 inhibitor. Conversely, the absence of detectable PD-L1 in a tumor does not necessarily mean that a patient will not benefit from such treatment. Thus, testing for PD-L1 is considered for selected cancer types and indicated for use as part of a treatment strategy for individual patients in certain treatment settings, as determined by the relevant regulatory approval and as indicated in the product label. Such testing is required as part of companion diagnostics.
The Role of PD-1 Inhibitors in Modern Immuno-Oncology
Certain PD-1 inhibitors have FDA-approved indications in multiple cancer types, subject to product-specific labelling and treatment settings. In terms of use as single agents or in combination with other anti-cancer therapies, including anti-tumor targeted therapies, anti-cancer therapies using radiation, and other immunotherapies, there are many different scientific rationales for the use of combinations of different anti-cancer therapies. For example, each different therapy can act on several different aspects of the tumor and/or on several different types of immune cells.
Of Note: FDA Identified Area of Interest for Future Immuno-Oncology Product Development – Combination of PD-1/PD-L1 pathway blockade with other immune checkpoint pathways.
Understanding Immune-Related Adverse Events
The effects of releasing an immune checkpoint such as a PD-1 inhibitor are not confined to the tumor. Increased immune activity results in inflammation in normal tissues which can in some cases even result in autoimmune-like damage.
The side effects of PD-1 inhibitors can affect almost any organ, single organ of the body and can range from mild to severe and even life threatening. The side effects are called immune-related adverse events (irAEs) and can affect organs such as the skin, GI tract, liver, lungs, endocrine organs, kidneys, heart and even the nervous system.
These can affect any organ including skin, GI tract, liver, lungs, endocrine organs, kidneys, heart and CNS. The clinical response to these adverse events can be along a spectrum of withholding PD-1 inhibitor for a few days or weeks to the use of corticosteroids and other immunosuppressive therapy as needed for more severe or life threatening adverse events.
Why Resistance Remains a Challenge
While clinical trials have reported durable responses in some patient populations with PD-1 blockade, resistance to these treatments remains a major issue in cancer therapy.
However, most tumors are insensitive to treatment with PD-1/PD-L1 blockade, because they lack tumor infiltrating immune cells (TICs), or are protected by alternative immune suppressive mechanisms, such as IDO1 or TGF-β, do not present tumor specific antigens, or have a non-functioning tumor mutational burden (TMB). Such tumors may initially respond to treatment but eventually relapse due to re-emergence of resistant clones.
As PD-1/PD-L1 inhibition cancer therapy continues to evolve, not only to explore different cancer applications, but also to investigate novel treatment combinations to address issues of cancer therapy resistance and improve cancer patient outcomes and define future directions for this promising form of immuno-oncology.
The Future of PD-1 Research
In ongoing scientific research to improve the use of PD-1 inhibitors to treat cancer, new features of tumors and of individual patients’ cancers are being identified that determine their sensitivity to PD-1 inhibitors and that are the basis of resistance to these compounds. New compounds are being investigated for use in combination with PD-1 inhibitors. The aim of ongoing research is to further evaluate treatment effectiveness, safety, biomarker selection, and resistance mechanisms.
Advances are being made in cancer biomarker testing, cancer tumor profiling, and the tumor’s immune microenvironment. This growing information on the effects of using single agents, such as PD-1 inhibitors, as well as in combination with conventional anti-cancer therapies, will allow for better selection of specific anti-cancer treatments for individual patients with specific types of cancer.
Cancer has developed to make use of the natural immune regulatory mechanisms in order to ensure its own survival. Immuno-oncology therapeutics are designed to modify these immune regulatory mechanisms in order to restore the immune system’s ability to recognize tumors.
PD-1 inhibitors represent an important area of study in immuno-oncology for Cancer Research, whether you are a Clinician, Researcher or Patient. How the Cancer behaves when treated with a PD-1 inhibitor is important to understand for each type of Cancer, to may contribute to treatment-selection decisions for that specific type of Cancer. With the ever-increasing field of immuno-oncology, continued research into these immuno-oncology therapies will be necessary to find the best use for them.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment. Consult Healthcare professionals for full prescribing information, peer-reviewed literature, and current national and international clinical guidelines before making treatment decisions. Patients should seek advice from their hematologist, oncologist, or other qualified healthcare professionals regarding diagnosis and treatment options.
