The Immuno-Oncology Revolution

For decades, it has been known that certain immune cells called cytotoxic T lymphocytes (CTLs) can destroy cancer cells, yet they fail to play this key role in many patients suffering from cancer. Today, we know that tumors produce “immune checkpoint proteins” that suppress the activity of CTLs, effectively putting “the brakes” on the immune system’s ability to fight cancer. This discovery of immune checkpoints spurred the immuno-oncology revolution and led to the development of a new class of anti-cancer therapeutics, called “checkpoint inhibitors.”

Why Do So Few Patients Respond To Checkpoint Inhibitors?

Despite the promise of checkpoint inhibition, not all patients with cancer benefit from this type of treatment. Too often, checkpoint inhibitor therapy “releases the brakes” on the immune system, but fails to mount an effective attack against the tumor, which continues to grow. When this happens, treatment with a checkpoint inhibitor may have limited clinical benefit.

How Can We Improve Patient Response To Checkpoint Inhibitors?

It is believed that the activity of checkpoint inhibitors may be dramatically increased by combining these anti-cancer therapeutics with an immune activator to stimulate T cell activity. Many different immune activators have been investigated and the Toll-like receptor 9 (TLR9) agonist CpG oligonucleotide (ODN) has been found to be the strongest at stimulating anti-tumor effects. Checkmate Pharmaceuticals believes that this combination of two important cancer-fighting mechanisms: CpG-A ODN to stimulate a T cell response to attack the tumor, along with checkpoint inhibition to release the tumor’s suppression of the immune system, may result in increased clinical benefits for patients.

Delivering on the Promise of Immunotherapy Using CMP-001

Checkmate Pharmaceuticals is pioneering new therapies to allow more patients living with cancer to benefit from immunotherapy treatments. Our lead clinical candidate, CMP-001, is a differentiated and potent activator of Toll-like Receptor 9 (TLR9) found in tumor infiltrating plasmacytoid dendritic cells (pDC)—commonly known as “the bad actors” of the immune system.

Immature pDCs are recruited by tumor cells to maintain an immune suppressed tumor microenvironment. This weakens the body’s defenses against cancer by preventing the immune system from recognizing and attacking unhealthy tumor cells. Clinical studies across various solid tumors demonstrate the ability of CMP-001 to safely and selectively activate the innate immune system and manipulate the tumor microenvironment, ultimately unleashing the body’s natural defenses to fight cancer.

Manipulating the Tumor Microenvironment:
A closer look at CMP-001 and its role turning “cold” tumors “hot”

CMP-001 works by activating TLR9 (the receptor for CpG-A) in plasmacytoid dendritic cells (pDC). pDCs are the only immune cells that produce large quantities of type I interferons (IFNα and others). When activated, pDCs increase their expression of important co-stimulatory molecules and tumor antigen presentation to T cells, culminating in the generation of effective anti-tumor T cell responses.

A tumor is immunologically cold when immature pDCs are recruited by the tumor to maintain an immune-suppressed tumor microenvironment (TME). Immune-suppressing regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) are supported by immature tumor-infiltrating pDC which do not produce type I IFNα.

CMP-001 activates immature pDCs through TLR9, releasing high concentrations of type I IFNα, along with a complex mixture of Th1-promoting cytokines and chemokines. This release of immune agents into the tumor and draining lymph nodes “resets” the TME making the cancer “hot”. pDC activation suppresses Treg and MDSC, attracts and activates other DCs and anti-tumor T cells into the tumor, and results in local and systemic tumor regression.

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