Session2-6 Transforming Cold Tumors Hot: A Novel Strategy to Fight Off Immune Checkpoint Inhibition-Resistant Tumors

Naozumi Harada  ~United Immunity Co. Ltd. ~


Thanks to the clinical success of immune checkpoint inhibitors, now we know the immune system, especially T cells within our body can detect and destroy cancer cells in a highly selective and efficient fashion. Some T-cell activating immune therapies have been emerging as a new effective modality for cancer treatment. However, many cases of human cancer are still resistant to these existing therapies. The resistant tumors are so called 'cold tumor', where cold means that these tumors are immunologically inactive as comparted to immunologically active 'hot tumors' with marked infiltration of T cells. Some recent studies reported that we can distinguish hot and cold human tumors by analyzing gene expression in the patients' tumor tissues, and that many human cancers are cold tumor across a variety of cancer types. Indeed, these cold tumors show poor prognosis after the treatment with immune checkpoint inhibitors. This is our shared, big problem among patients, doctors, and pharmaceutical companies.
To solve this, our company aims to understand how cold tumor is generated. In a collaboration with Kyoto University and Mie University, we compared some good animal models with cold or hot tumor in details in the terms of gene expressions and immune cell profile, and successfully identified macrophages, a sort of immune cells residing in tumor tissue are the key underlying mechanisms of cold tumor. Macrophages are well-known phagocytic immune cells and can efficiently present antigens to T cells. In cold tumor, macrophages specifically remain inactive, and more importantly, they do not play their critical role to present tumor antigens to T cells (it is the transduction of information on our enemy, tumor cells to T cell army). Inactive and silent macrophages thus likely make tumors highly cold and resistant to immunotherapy.
These results led us to an assumption that the manipulation of macrophage function may improve the sensitivity of cold tumor to immunotherapy by converting cold tumor to hot tumor. But how can we do so? We can do that if we use our 'T-ignite' technology. It means T-cell ignitor and was developed by the researchers of Kyoto University and Mie University. T-ignite includes two components: one is a long peptide antigen with optimized sequence for the robust stimulation of tumor-specific T cells. It is a kind of information on the enemy, cancer cells for T-cells. Another component is our unique delivery system nanogel, which can selectively deliver long peptide antigen to macrophages in the tumor tissue. When injected into cold tumor bearing mice, T-ignite goes into the tumor tissue immediately and selectively, where it is incorporated into macrophages. These cells then initiate antigen presentation to T cells using long peptide antigen contained in the T-ignite product. This reaction - antigen presentation - is known to induce the production of inflammatory cytokines and T cell- attracting chemokines in the tumor tissue, leading to the enhanced infiltration or proliferation of T cells in the tumor tissue. Thus a cycle of these processes triggered by T-ignite transforms cold tumor lacking T cells into T cell-rich hot tumor. Indeed, this treatment greatly sensitize cold tumor to other immunotherapy. For example, we treated our cold tumor models with a combination of T-ignite with immune checkpoint inhibitor or TCR gene-engineered T cells. In both cases, these combination immunotherapies bring great inhibitory effect on cold tumors. Of course, the tested cold tumors are totally resistant to monotherapy with immune checkpoint inhibitor or TCR gene-engineered T cells. These preclinical data strongly support that macrophages in the tumor tissue are the key for immune resistance.
Immunotherapy using our macrophage-targeting T-ignite could be also effective for the treatment of human cold tumors, so we are eager to move this technology to the clinical stage. We have two products for this, UI-1 and UI-2. UI-2 is more advanced one and is a combination of T-ignite with TCR-engineered T cell product for the treatment of soft tissue sarcomas, a well-known human cold tumor. It has been tested in a clinical trial supported by AMED. We already treated our first patient last year. It is now 10 months after the treatment. So far we have observed good safety profile of the treatment, and more importantly a good sign of efficacy. Motivated by this, we are trying to generate our next product, UI-1, a combination of T-ignite with immune checkpoint inhibitor. If we successfully develop these products in United States and Japan, we can expect 800 million dollars as an annual sale of these products, and it can be further increased by developing the products for other indications and other countries.
I like to emphasis that all of us is facing a new clinical problem, cold tumor, a new emerging class of hard-to-treat tumor protected by silent or hostile immune cells. Immunotherapies using T-ignite will be effective to treat this kind of difficult tumors.


harada.jpg 20+ years research experience in pharmaceutical companies and biotechs. In a recent decade, has studied cancer immunotherapy focusing on tumor immune resistance and exploiting nanotechnology to immunotherapy. Recently invented a technology to improve macrophage function using a Kyoto University-originated unique nanoparticle. To make it as a new weapon against cancer, launched United Immunity.