Date: 2017-01-20
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the Keystone Symposia Conference , "PI3K Pathways in Immunology, Growth Disorders and Cancer,"
Company: Infinity Pharmaceuticals (USA - MA)
Product: IPI-549
Action
mechanism: phosphoinositide 3-kinase (PI3K) inhibitor. IPI-549 selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. IPI-549 inhibits immune suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.
Disease:
Therapeutic area: Cancer - Oncology
Country:
Trial
details:
Latest
news: * On January 20, 2017, during a plenary session at the Keystone Symposia Conference , "PI3K Pathways in Immunology, Growth Disorders and Cancer," Infinity Pharmaceuticals presented preclinical data for IPI-549. * On September 18, 2015, Infinity Pharmaceuticals announced the expansion of its pipeline with the addition of IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. Preclinical data demonstrating the potential of IPI-549 to disrupt the immune-suppressive tumor microenvironment and enable a heightened anti-tumor immune response have been being presented at CRI-CIMT-EATI-AACR - The Inaugural International Cancer Immunotherapy Conference : Translating Science into Survival Meeting in New York City . IPI-549 was discovered at Infinity and is expected to enter Phase 1 clinical development in early 2016. These data have been presented in a poster entitled, "The potent and selective phosphoinositide-3-kinase-gamma inhibitor, IPI-549, inhibits tumor growth in murine syngeneic solid tumor models through alterations in the immune suppressive microenvironment." In vitro data showed that IPI-549 blocks both the migration of murine myeloid cells and the differentiation of myeloid cells to the M2 phenotype, which is a type of myeloid cell known to promote cancer growth and suppress anti-tumor immune responses. In vivo data in murine solid tumor models demonstrated that IPI-549 treatment also decreased tumor-associated myeloid cells found in the immune suppressive microenvironment. Additionally, IPI-549 treatment increased the number of intratumoral CD8+ T-cells, which are known to play a role in inhibiting tumor growth.
Preclinical data showed that macrophage PI3K-gamma signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3K-gamma activated the immune response and significantly suppressed growth of tumors in preclinical models. These data demonstrate that PI3K-gamma plays a key role in cancer growth and also help to further elucidate the mechanism of action for IPI-549.
Preclinical data also demonstrated that resistance to immune checkpoint blockade is directly mediated by the suppressive activity of tumor-infiltrating myeloid cells in a number of preclinical tumor models and confirmed that immune-suppressive myeloid cells play a critical role in resistance to checkpoint inhibitors. Furthermore, the data showed that inhibition of PI3K-gamma by IPI-549 switched the activation of myeloid cells from an immune-suppressive state to a pro-inflammatory state, leading to enhanced anti-tumor cytotoxic T cell activity, particularly when combined with checkpoint inhibitors. Thus, in preclinical models, IPI-549 treatment is able to overcome resistance to checkpoint inhibition. These findings provide further rationale for the ongoing Phase 1 study of IPI-549 in combination with checkpoint inhibitors.
IPI-549 has demonstrated dose-dependent, single-agent, anti-tumor activity in multiple solid tumor models, including murine models of lung, colon and breast cancer. Additionally, mice treated with IPI-549 in combination with checkpoint inhibitors showed greater tumor growth inhibition than either treatment as a monotherapy. Preclinical in vivo data also demonstrated that T-cells are required for the anti-tumor activity of IPI-549, which is a hallmark of immunotherapy.
