Tumor Cells Recruit an Immunosuppressive “Cloak” that Hides them from the Adaptive Immune System and Initiates Metastasis
Tumors secrete chemo-attractive proteins, or chemokines, that bind to the chemokine receptors CXCR1 and CXCR2 on the surface of neutrophils and myeloid-derived-suppressor-cells (together “myeloid cells”). Chemokine-receptor binding recruits these myeloid cells to the tumor microenvironment, creating an immunosuppressive inflammatory “cloak” that hides the tumor from killing by T cells and natural killer cells (“effector cells”) of the adaptive immune system. Chemokine receptors CXCR1 and CXCR2 on MDSCs and tumor cells additionally drive tumor metastasis and resistance to chemotherapeutic and immunologic therapies through other mechanisms.
Best-In-Class Immuno-Oncology (I/O) Therapy for Abrogating the Tumor Immunosuppressive Microenvironment and Blocking Metastasis
SX-682 is a potent small-molecule dual-inhibitor of CXCR1 and CXCR2, the chemokine receptors pivotal to tumor metastasis, therapy-resistance, and myeloid cell suppression of cancer surveillance by the adaptive immune system. By blocking the CXCR1/2 pathway, SX-682 prevents tumor spread and depletes the tumor bed of immunosuppressive myeloid cells, thereby cutting off “at the source” dozens of downstream pro-tumor mechanisms mediated by these cells. The elimination of suppressive myeloid cells liberates effector cells to kill and eliminate cancer cells.
CXCR1/2 Control Two Major Arms of Pro-Tumor Microenvironment:
(1) Immunosuppressive Shield and (2) Metastasis/Resistance
CXCR1 and CXCR2 are validated immune-oncology targets with major pharmaceutical companies having oncology programs targeting parts of the CXCR1/2 signaling axis in the clinic. However, as a dual-inhibitor that blocks tumor signaling via both CXCR1 and CXCR2, SX-682 is the only therapeutic in development for oncology that blocks all parts of the CXCR1/2 signaling axis, and is thus best-in-class for oncology. SX-682 has nanomolar potency, satisfies Lipinski’s rules, and is highly selective for CXCR1/2 versus off-targets. SX-682 has completed GLP toxicology, and exhibits an exceedingly safe profile with no dose-limiting toxicities.
In collaborations with a host of top academic collaborators, SX-682 has been validated in numerous tumor models, where it exhibits single-agent activity, synergizes with checkpoint inhibitors and chemotherapy, and blocks metastasis. These models include melanoma, breast cancer and lung cancer.
A study published in Nature demonstrated that SX-682 potently blocked metastasis and activated checkpoint blockade by anti-PD-1 and anti-CTLA4 in a mouse model of castrate-resistant prostate cancer, a finding that has profound implications for the treatment of human prostate cancer which is unresponsive to either anti-PD-1 (nivolumab) or anti-CTLA4 (ipilimumab) therapy. (doi: 10.1038./nature21676)
SX-682 Clinical Program
SX-682 has an open IND with FDA for a Phase I/II trial in melanoma in combination with anti-PD-1 therapy at Massachusetts General Hospital (clinicaltrials.gov: NCT03161431) and NIH funding to conduct this trial.
A Cooperative Research and Development Agreement (CRADA) recently awarded by the NCI will fund up to two additional Phase I and two Phase II trials in solid tumors; under the CRADA, Syntrix will contribute SX-682 study drug and the NCI will be responsible for all other clinical trial expenses.
Beyond these NCI-funded trials, Syntrix is planning additional Phase I/II trials in myelodysplastic syndrome and solid tumor of the prostate, lung and breast.
Chemokine-Recruited Myeloid Cells, Including Neutrophils, are Key Players Forming the Immunosuppressive Tumor Microenvironment.
It has recently become clear that the presence of myeloid cells in tumors, including neutrophils and myeloid-derived suppressor cells (MDSCs), have the most adverse prognostic significance of any infiltrating immune cell type. This video shows how these cells reach their destination in a tumor through a process of chemokine-driven recruitment involving rolling, chemokine activation, adhesion and translocation (or, together: extravasation). SX-682 blocks this process.