Therapy candidate INB03, meant to inactivate a kind immunosuppressive cell called myeloid-derived suppressor cells (MDSCs) while boosting anti-tumor immune cells, may help overcome resistance to immunotherapies, including immune checkpoint inhibitors, INmune Bio’s co-founder Raymond J. Tesi, MD, said at a conference.
Tesi, CEO of INmune Bio, presented the potentialities of the company’s new therapy at the Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology Summit Europe recently in London.
His presentation was titled “Targeting Myeloid-Derived Suppressor Cells to Overcome Resistance to Checkpoint Inhibitors.”
MDSCs appear in advanced forms of cancer and are at the heart of cancer resistance to the body’s immune system. MDSCs move to where tumors are and release cell signaling proteins called cytokines to form an immunosuppressive shield that protects tumors from immune system attacks.
The shield also neutralizes treatments that rely on anti-cancer immune responses, such as immunotherapy with checkpoint inhibitors. In fact, the higher the number of MDSCs in a patient’s blood, the more severe the cancer is predicted to be and the more likely it is to be resistant to immunotherapy.
“Experts agree that decreasing the number of MDSC may improve the response to immunotherapy such as checkpoint inhibitors and may improve the ability of the immune system to fight the cancer,” INmune Bio states on its website.
INB03 was designed to inactivate MDSCs and destroy the protective shield that prevents immune cells from coming in and fighting it. The treatment is expected to strengthen patients’ immunity to cancer and give immunotherapies a better chance at being effective.
Specifically, INB03 is a second-generation inhibitor of tumor necrosis factor (TNF). It targets only cell-free TNF without affecting other types of TNF that are attached to the membrane of cells.
Because of this selectivity, the therapy does not suppress the immune system, a known side effect of currently approved, first-generation TNF inhibitors, such as those used for autoimmune disorders including rheumatoid arthritis.
The new compound acts in three steps. First, it blocks the proliferation and function of MDSCs, breaking the protecting shield of immunosuppressive signals produced by those cells.
This promotes the infiltration of innate immune cells (part of the body’s first-line of defenae), specifically natural killer (NK) cells and dendritic cells, which recognize and attack the tumor and also cross-talk with other immune cell types to reinforce subsequent immune responses.
From this cross-talk, more cytokines are released that call in cytotoxic T-cells, immune cells able to directly attack and kill the tumor. In animal studies, treatment with INB03 resulted in smaller and fewer tumors, extending survival.
A video explaining INB03’s mode of action is available here.
The potential therapy is now being tested in patients with advanced, metastatic, solid tumors in a Phase 1 trial (ACTRN12618000675224). The study is intended to address if the treatment is safe and well-tolerated and collect initial data about its efficacy. Its target population are patients with increased biomarkers of inflammation and a high number of MDSCs in their blood.
Three different doses of the treatment will be tested, all given by under-the-skin (subcutaneous) injections once per week for nine months or until disease progression.
Primary outcome measures will be the occurrence of adverse events, the therapy’s pharmacokinetics (absorption, distribution, metabolism, and elimination) of single and multiple doses, and change in high sensitivity C-reactive protein serum levels, a biomarker of inflammation.
Participants may opt to continue on INB03 at any time if their doctor believes the therapy is beneficial in any way.
An interim analysis of the results will be conducted after three months of treatment, and an optimal dose for a subsequent Phase 2 trial will be determined.
“I am excited to have the opportunity to present and exchange ideas with some of the most influential members of the immuno-oncology community,” Tesi said in a press release. “We are committed to developing treatments that target the patient’s innate immune system and facilitating an understanding that chronic inflammation is a root cause and agitator of cancer and many other diseases. By exchanging ideas with top researchers, we can help further push developments that lead to effective patient responses at the bedside.”