Immune Regulatory Responses... The simple answer for those trying to understand the reason for adding a CSF-1Ri, which can be artificially manufactured by Daiichi-Sankyo as PLX3397, is that it addresses one of the multiple layers of the IMMUNE REGULATORY RESPONSE... Immune Regulatory Responses are pathways by which the immune system is triggered to stop the immune system from engaging in what the body thinks might be an autoimmune response. Arthritis, diabetes MS, and Lupus are autoimmune diseases. When the body overreacts, it can do itself harm.
DCVax-L sparks a response to the cancer. But cancer is adept at HIDING ITSELF from the immune system and it uses various methods related to the body's defenses against autoimmune responses. The cancer effectively tells the body to stop attacking it because it is SELF. Hence we have checkpoint inhibitor drugs like Keytruda, that turn off one layer of that "Self" identification mechanism that deactivates the body's defense mechanisms. But you add the checkpoint inhibitor, and as Dr. Liau has pointed out in numerous presentations, you find that there is a massive inflow of Tumor-Infiltrating Myeloid Cells (TIMs). These TIMs are a second line of autoimmune defense and they help to deactivate the immune response, which is not what we want when we are fighting cancer.
CSF-1R Inhibition (CSF-1Ri): CSF-1R is a receptor on myeloid cells. By inhibiting this receptor with drugs like PLX3397, you can reduce the number and/or function of immunosuppressive myeloid cells, including TIMs. In the context of GBM, CSF-1Ri aims to reprogram or inhibit these immunosuppressive cells, thereby improving the efficacy of other immunotherapies, and in our case, specifically to improve the efficacy of DCVax-L.
Some background:
CSF-1Ri stands for "Colony Stimulating Factor-1 Receptor inhibitor."
Colony Stimulating Factor-1 (CSF-1): It is a cytokine that plays a central role in the survival, proliferation, and differentiation of mononuclear phagocytes, such as macrophages and monocytes.
Receptor (CSF-1R): The receptor for CSF-1 is known as CSF-1R (or sometimes c-Fms). When CSF-1 binds to its receptor CSF-1R, it triggers a series of cellular responses, including the activation and survival of certain types of immune cells, particularly macrophages.
Inhibitor (CSF-1Ri): Compounds that block or inhibit the activity of the CSF-1R are termed CSF-1R inhibitors. By inhibiting this receptor, these drugs can modulate the behavior and prevalence of cells like macrophages in the tumor microenvironment, which can be therapeutically beneficial in certain cancer contexts. PLX3397 is such a compound.
Further, in the article waiting to be printed in Nature, the researchers appeared to discover other immune regulatory responses using poly-iclc, a TLR Agonist, as a stimulant.
TLR agonist treatment promotes the expression of IFNa/ß and IFNg-induced genes on the peripheral lymphoid and myeloid cells. Among the TLR agonists, we know that poly-ICLC appeared to be particularly effective. Patients treated with ATL-DC and TLR agonists, particularly Poly-ICLC showed extended overall time to tumor progression and slower rates of tumor growth.
IFNa/ß (Interferon alpha/beta) and IFN(G) (Interferon gamma): Interferons (IFNs) are a group of signaling proteins made and released by host cells in response to the presence of pathogens, such as viruses, bacteria, parasites, and tumor cells. They play a crucial role in the innate immune system to inhibit viral replication within host cells, activate immune cells, and increase host defenses.
IFNa/ß (Interferon alpha/beta) - Type I Interferons: These are produced in response to viral infections and have antiviral activities. They bind to a specific cell surface receptor, leading to the activation of the a certain signaling pathway. This signaling prompts the cell to express certain genes that help the cell resist viral infection. Various cells can produce type I interferons, but plasmacytoid dendritic cells are the primary producers of IFNa in the blood after a viral infection.
IFN(G) (Interferon gamma) - Type II Interferon: Unlike type I interferons that are mainly involved in antiviral responses, IFN(G) deals primarily with immune regulation. It activates macrophages, enhances the expression of class I and class II major histocompatibility complex (MHC) molecules, and promotes the differentiation of T helper cells into Th1 cells. This is mainly produced by natural killer (NK) cells and T cells.
The immune system consists of a wide variety of cells, each with a particular function. Broadly, these cells can be categorized into lymphoid and myeloid lineages.
Peripheral Lymphoid and Myeloid Cells:
Lymphoid Cells: These cells are primarily involved in the adaptive immune response and include T cells (which can be CD4+ helper T cells or CD8+ cytotoxic T cells), B cells (which produce antibodies), and NK cells (which can kill virus-infected cells and tumor cells).
Myeloid Cells: These cells are typically involved in the innate immune response and include monocytes (which can differentiate into macrophages or dendritic cells), granulocytes (like neutrophils, eosinophils, and basophils), and cells involved in clotting like platelets and erythrocytes.
How it all works together:
When a pathogen, like a virus, infects the body, the infected cells produce interferons (like IFNa/ß). These interferons act in an autocrine (acting on the same cell that produces it) and paracrine (acting on nearby cells) manner to induce a state of resistance to viral replication in all cells, alerting them to the presence of a virus in the body. They also activate immune cells, such as NK cells, which can kill virus-infected cells.
At the same time, dendritic cells, which are a type of myeloid cell, can take up viral particles, process them, and present them on their surface. These dendritic cells then migrate to lymph nodes where they activate T cells (a type of lymphoid cell), leading to a more specific, adaptive immune response against the virus. If these T cells become activated and differentiate into Th1 cells, they can produce IFN(G), further enhancing the immune response.
In essence, the production of interferons and the activation of both lymphoid and myeloid cells work in tandem to create a multi-pronged, effective immune response against pathogens.
There are also a whole variety of myeloid cells that suppress immune responses. As mentioned above, CSF-1Ri is intended to address what has been come to be known as the Tumor-Associated Immune Cells (TIMs).
We have Tumor-Associated Macrophages (TAMs): These are a major subset of the myeloid cells present in the tumor microenvironment and play a key role in promoting tumor growth and suppressing anti-tumor immune responses.
And we have Myeloid-Derived Suppressor Cells (MDSCs): These cells are also often found in the tumor microenvironment and have a potent immunosuppressive function.
Inhibition by CSF-1Ri:
CSF-1R (Colony Stimulating Factor-1 Receptor) is a receptor that binds to CSF-1 (Colony Stimulating Factor-1) and IL-34. Activation of CSF-1R plays a crucial role in the differentiation, survival, and function of monocytes and macrophages.
CSF-1R inhibitors (CSF-1Ri) are designed to block the signaling through this receptor.
By inhibiting CSF-1R, these drugs can reduce the number and function of TAMs in the tumor microenvironment. This is because CSF-1R signaling is essential for the differentiation and survival of TAMs. By targeting TAMs, CSF-1Ri can alleviate some of the immunosuppression in the tumor microenvironment, potentially making tumors more susceptible to other forms of treatment, such as immunotherapy.
MDSCs might also be affected by CSF-1Ri, but the primary target is generally the TAMs.
From a variety of sources, from my ongoing DD. I am not a doctor, so please be sure to do your own DD. Note the IFN(G) is for Interferon Gama but the "Gama" symbol is not working on the web, so it sometimes comes out as a "?". I've endeavored to change it to IFN(G). But that is not the technical symbol for the abbreviation.
