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NIH grant 1R43CA310345-01: Novel macrophage repolarization therapy for colorectal cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: JAMES W LARRICK. Award: $387240.
Start: 2026-09-25T00:00:00.
Colorectal cancer ranks third in cancer deaths among men and fourth among women in the US. While immunotherapy response rates in CRC are 30-70% for patients with microsatellite instability, this group makes up only 15% of CRC patients, and only 3-6% of advanced CRC. Response rates remain low for the majority of the remaining patients, and durable responses remain elusive, even with combination therapies.
The reason for the overall failure of immune checkpoint inhibitors (ICI’s) to achieve higher response rates is generally ascribed to factors in the tumor microenvironment (TME) that culminate in immune evasion by tumor cells. The presence of immunosuppressive immune cells, including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSCs), in the TME is one mechanism by which tumor cells evade the immune system. Myeloid cells play a key role in suppression of anti-tumor T cell responses. The myeloid cell fraction in the TME is significant and most likely includes both immunostimulatory and immunosuppressive subtypes. Within the immunostimulatory subset are type 1 dendritic cells (DC1s) and M1-like IFN-g-induced macrophages. The immunosuppressive myeloid subset includes M2-like macrophages (TAMs) and MDSCs. Depletion, inactivation, or repolarization of TAMs and MDSCs comprises an important approach to improve immunotherapy responses that is differentiated from immune checkpoint blockade and is potentially synergistic with current immune checkpoint therapies. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed at high levels in multiple solid tumor types and is associated with poor outcomes in a variety of cancer types, including CRC. Moreover, TREM2 is a key regulator for expansion of MDSCs. In humans and murine models, TREM2 expression levels inversely correlate with survival. Knock-out mice lacking TREM2 exhibit attenuation of tumor growth and longer survival. Similar anti-tumor activity is seen with knockdown by antisense oligonucleotides or inhibition with anti-TREM2 antibodies. Reduction in TREM2 function is accompanied by immune activation and interferon-gamma production. Inhibiting TREM2 significantly enhanced anti-PD-1 immunotherapy in models of CRC. We are developing an anti-TREM2 blocking antibody that transforms the TME into an immunostimulatory environment by repolarizing TAMs. Importantly, this approach, unlike TREM2 depleting antibodies, should durably re-shape the TME. In this Phase 1 project, we will evaluate the efficacy of our anti-TREM2 human monoclonal antibody, both as monotherapy and in combination with anti-PD-1, in a murine model expressing human TREM2. Evaluation in an intact animal is required due to the interplay of digestive and immune systems involved in tumor growth and the immune response to the proposed antibody therapy.document fetched 2026-10-04 02:43