May 2014 Edition Vol.11, Issue 5

Can Innate Immune Cells Engage in Anti-Tumor Activity?

Can Innate Immune Cells Engage in Anti-Tumor Activity? (continued)

The Sleeping Giant of Cancer Immunotherapy

Despite tremendous promise, most cancer immunotherapies, including the new classes directly modulating T-cell receptors, focus on harnessing the function of cells of the adaptive immune system. Historically, the conventional wisdom of the medical community is that only the adaptive immune system can be used to target cancer. However, the cellular stars of adaptive immunity – cytotoxic T-cells, CD4 T-cells and natural killer cells – account for less than 30% of the entire immune cell population.

The tumor microenvironment from an immune perspective is complex, but the question of whether immunotherapy can win the cancer battle may come down to a simple issue: numbers. Even if new immunotherapies can activate T-cells to attack the tumor, are there enough T-cells to overcome those cells in the tumor microenvironment that are working to suppress the effect?

The innate immune system is perhaps the sleeping giant of cancer immunotherapy. This arm of the immune system is the body’s first line of defense against invading pathogens such as bacteria, viruses and fungi. Although highly effective at killing infectious organisms, the innate immune system’s inability to distinguish cancer cells from other “self” cells has convinced most researchers that it has no role in oncology treatments.

In contrast to the adaptive immune system, the innate immune system relies on an entirely different set of effector cells, neutrophils and monocytes, that comprise about 65% of the body’s immune cell population – a formidable army of approximately 17 trillion cells.

One of the most successful immunotherapies for solid cancer is in bladder cancer, where a patient is administered weekly intravesical instillation of Bacillus Calmette Guerin (BCG).7 The BCG induces a strong local immune response within the bladder characterized by massive secretion of cytokines as well as inflammatory cellular infiltration. Recent research has demonstrated that the immune cells that mediate the anti-tumor activity are neutrophils.8 Is it possible to engage and redirect this much larger population of innate immune cells against other cancers?

Minnesota-based Biothera’s investigative drug, Imprime PGG®, is a new immunotherapy that, like Yervoy and the PD-1 monocolonal antibodies, targets the patient’s immune system rather than the cancer cells. However, Imprime PGG mobilizes and directs the much larger population of innate immune cells to recognize and kill cancer cells.

Imprime PGG binds directly to specific receptors on neutrophils and monocytes and modulates their function to partially activate the cells. This effectively raises the readiness of these cells but another trigger is required before they will recognize and kill cancer cells – the cancer cells have to be targeted, or “flagged”, by a complement-activating antibody. 9, 10, 11

Researchers hypothesized that administering Imprime PGG to cancer patients receiving anti-cancer monoclonal antibodies would redirect their innate immune cells to kill cancer cells as if they were killing invading pathogens. In short, Imprime PGG would bring this large population of innate immune cells into the fight against cancer.

Imprime PGG has been evaluated in multiple Phase 1 and 2 clinical trials in colorectal cancer (CRC), non-small lung cancer (NSCLC) and chronic lymphocytic leukemnia (CLL) and is currently under investigation in a Phase 3 CRC trial. In completed trials, substantial improvements in response rates versus historical or randomized controls were observed.12-14

Recently, Biothera announced top-line results from its randomized controlled Phase 2b clinical trial in NSCLC that evaluated the combination of Imprime PGG, cetuximab [Erbitux®, Bristol Myers-Squibb], and carboplatin/ paclitaxel compared with the cetuximab and chemotherapies alone.15

The primary endpoint of this open-label, multicenter, randomized trial in 90 patients with untreated advanced NSCLC was objective response rate (ORR). The combination of Imprime PGG with cetuximab and carboplatin/paclitaxel showed substantial and statistically significant improvement in ORR compared to the control group. Imprime PGG was also well tolerated, with adverse events consistent with toxicities attributable to the cetuximab or chemotherapy drugs alone.

The study’s ORR was improved further in the subset of subjects who tested positive for a biomarker linked to the ability of their innate immune cells to bind and respond to Imprime PGG. More importantly, a secondary endpoint of overall survival showed substantial improvement among biomarker-positive subjects.

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