— Inhibition of PI3K-Gamma by IPI-549 Can Reverse Tumor Resistance to Checkpoint Inhibitors in Preclinical Models —
CAMBRIDGE, Mass., Nov. 9, 2016 /PRNewswire/ — Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) today announced the publication of new findings by research collaborators at Memorial Sloan Kettering Cancer Center (MSK) and Infinity scientists in the November 9 online issue of Nature. The paper, entitled “Overcoming resistance to checkpoint blockade by targeting PI3K-gamma in tumor-infiltrating myeloid cells,” describes research showing that the presence of suppressive myeloid cells play a critical role in tumor resistance to checkpoint inhibitors. IPI-549, an oral immuno-oncology development candidate that selectively inhibits PI3K-gamma, is able to help recover sensitivity to checkpoint inhibition in this setting by remodeling the immune-suppressive tumor microenvironment primarily through its effects on myeloid cells. Infinity is conducting a Phase 1 clinical study of IPI-549, which is the only PI3K-gamma inhibitor in clinical development.
The tumor microenvironment, or TME, refers to the non-cancerous cells present in the tumor. Cells within the TME, including immune-suppressive myeloid cells, can provide growth signals to tumor cells, as well as signals that inhibit an anti-tumor immune response. The presence of the supportive TME is thought to be one reason why some cancer therapies do not provide durable or effective results. Targeting the immune-suppressive myeloid cells represents an emerging approach within the field of cancer immunotherapy. Inhibition of PI3K-gamma represents a novel approach to targeting the immune-suppressive microenvironment.
“While new immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in the treatment of various cancers, multiple mechanisms of immune resistance exist in tumors and additional treatments are needed that can further improve outcomes for patients,” stated Jedd Wolchok, M.D., Ph.D., Chief of the Melanoma and Immunotherapeutics Service at MSK, as well as Associate Director of the Ludwig Center for Cancer Immunotherapy and Director of the Parker Institute for Cancer Immunotherapy, both at MSK. Dr. Wolchok is also a co-senior author on the Nature publication and lead investigator for the Phase 1 clinical study. “Our research suggests that targeting PI3K-gamma by IPI-549 within the immune-suppressive myeloid cells could offer a unique way to both enhance the activity of checkpoint inhibition in sensitive tumors, as well as to overcome tumor resistance to checkpoint inhibition.”
“The preclinical findings published today further reinforce the therapeutic potential of IPI-549 to alter the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition. These data, coupled with other data published earlier this year on the role of PI3K-gamma in tumor-associated myeloid cells, provide a strong rationale for the ongoing Phase 1 study,” stated Jeffery Kutok, M.D., Ph.D., vice president of biology and translational science at Infinity Pharmaceuticals and a co-author of the paper. “Infinity is excited to be developing a potentially first-in-class therapy that could offer a new and possibly complementary approach to existing immunotherapies, including checkpoint inhibitors.”
Details of Today’s Nature Publication
In the Nature paper, researchers demonstrate 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 confirm that immune-suppressive myeloid cells play a critical role in resistance to checkpoint inhibitors. Furthermore, they also 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 reverse the lack of response in tumor models that are resistant to checkpoint inhibitors. These findings provide further rationale for studying IPI-549 in combination with checkpoint inhibitors in the clinic.
PI3K-Gamma Research Also Published in September 19 Online Edition ofNature
In September, Infinity announced the first Nature publication on PI3K-gamma by research collaborators at University of California San Diego School of Medicine and Moores Cancer Center and Infinity scientists in the September 19 online issue of Nature. The paper, entitled “PI3K-gamma is a molecular switch that controls immune suppression,” described preclinical data which showed that macrophage PI3K-gamma signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Additionally, blocking PI3K-gamma activated the immune response and significantly suppressed growth of implanted tumors in animal models. Inhibiting PI3K-gamma also boosted sensitivity of some tumors to existing anti-cancer drugs and showed synergy with existing immunotherapies.
The September publication, along with today’s publication, will appear back-to-back in the November 17, 2016, issue of Nature.
Phase 1 Study of IPI-549 Ongoing
Earlier this year, Infinity initiated its first clinical study of IPI-549 designed to explore safety, tolerability, pharmacokinetics and pharmacodynamics of IPI-549 both as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in approximately 175 patients with advanced solid tumors, including non-small cell lung cancer, melanoma and squamous cell carcinoma of the head and neck. In September, initial clinical data were reported from nine patients who received monotherapy treatment with IPI-549. The data reported showed that the safety, pharmacokinetics and pharmacodynamics of IPI-549 monotherapy treatment appeared favorable. These data were presented in a poster session at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival.
IPI-549 is an orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, 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.
IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.
Infinity is an innovative biopharmaceutical company dedicated to advancing novel medicines for people with cancer. Infinity is advancing IPI-549, an oral immuno-oncology development candidate that selectively inhibits PI3K-gamma. A Phase 1 study in patients with advanced solid tumors is ongoing.