Preclinical Candidates for Immuno-Oncology

One of the most exciting advances in oncology in decades is the recent observation that modifiers of the activity of the patient’s own immune system can profoundly enhance their response to chemotherapy.

A critical cellular component of this response are the myeloid-derived suppressor cells (MDSCs), which inhibit the activity of the effector T cells, and thus dampen the immune response of the body to the tumor. These MDSCs express chemokine and chemoattractant receptors that they use to migrate to the tumor microenvironment. We believe that such immunotherapeutic agents could be effective as stand-alone therapies for certain cancers or result in synergistic effect when given in combination with traditional chemotherapies or other immunotherapies.

We have discovered small molecule inhibitors that target these chemokine and chemoattractant receptors, which may be developed in certain oncology indications targeting both solid and liquid tumors.

In our preclinical research, we are conducting studies with various chemokine receptor inhibitors in combination with check point inhibitors, such as those inhibiting the PD-L1 pathway, that we believe may result in a greater anti-tumor effect, than with check point inhibition alone.
A growing body of data suggest that a number of chemokine receptors, including, but not limited to, CCR1, CCR2, CCR5, and CXCR2, may play diverse roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the tumor microenvironment. Given the potential role of chemokine receptors in cancer cell survival, the combination of chemokine receptor antagonists with traditional chemotherapeutic agents or with immunotherapy, such as PD-1 or PD-L1 inhibitors is an attractive strategy because it may result in greater efficacy and/or allow dose reductions of the chemotherapeutic drugs and therefore limit systemic side effects.
Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates anti-tumor effects in a murine model of breast cancer. Heiyoun Jung, Ashley Bischof, Karen Ebsworth, Linda Ertl, Thomas Schall, and Israel Charo. Presented at the American Association for Cancer Research (AACR) Annual Meeting, April 2016.

Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates anti-tumor effects in a murine model of breast cancer, Heiyoun Jung, Ashley Bischof, Karen Ebsworth, Linda Ertl, Thomas Schall, Israel Charo. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2015.

Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates anti-tumor effects in a murine model of breast cancer, Heiyoun Jung, Ashley Bischof, Karen Ebsworth, Linda Ertl, Thomas Schall, Israel Charo. Presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting, 2015.

Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy. Steven L. Highfill, Yongzhi Cui, Amber J. Giles, Jillian P. Smith, Hua Zhang, Elizabeth Morse, Rosandra N. Kaplan and Crystal L. Mackall. Science Translational Medicine 21 May 2014, pp237.

CCR1 Blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease. Dairaghi DJ, Oyajobi B, Gupta A, et al. Blood 2012; 120:1449-1457.