A Phase 1b clinical trial of dual myeloid blockade in metastatic pancreatic adenocarcinoma (PDAC) is planned. Patients will be treated with standard chemotherapy (FOLFIRINOX) and 2 orally available, small molecule allosteric chemokine receptor inhibitors to CCR2 (CXC872) and CXCR1/2 (SX682). The primary endpoint of the trial is safety and tolerability, and the secondary endpoint is clinical effectiveness as measured by progression free survival at 24 weeks. Baseline and on treatment tumor biopsies will be subjected to genomic analysis as well as sophisticated immune monitoring using mass cytometry. Genetic and immunologic biomarkers of treatment resistance and response will be explored. Preclinical studies will also be performed throughout the study to inform and perfect subsequent clinical translation of the most effective ways to immunologically reprogram the immunosuppressive tumor microenvironment that is characteristic of PDAC.

Public Health Relevance

The TME in PDAC is immunologically ?cold? due to the high prevalence of immunosuppressive myeloid cells (both macrophages and neutrophils) that infiltrate tumors; in the parent R01 we have shown that these cells are actively recruited to the TME by known chemokine/receptor pathways that can be blocked with small molecule allosteric chemokine receptor inhibitors. We propose a clinical trial (based on promising results from our previous studies) of dual myeloid inhibition that blocks both TAM and TAN in combination with standard chemotherapy in PDAC. Correlative immune and genetic studies are planned on baseline and on-treatment biopsies that will help us elucidate mechanisms of treatment resistance and discover biomarkers that predict response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168863-08
Application #
10077544
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2013-07-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Rochester
Department
Surgery
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Nywening, Timothy M; Wang-Gillam, Andrea; Sanford, Dominic E et al. (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17:651-62
Connolly, Kelli A; Belt, Brian A; Figueroa, Nathania M et al. (2016) Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 7:86522-86535
Zhu, Yu; Knolhoff, Brett L; Meyer, Melissa A et al. (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057-69
Sanford, Dominic E; Belt, Brian A; Panni, Roheena Z et al. (2013) Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 19:3404-15
Panni, Roheena Z; Linehan, David C; DeNardo, David G (2013) Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy 5:1075-87
Capietto, Aude-Hélène; Kim, Seokho; Sanford, Dominic E et al. (2013) Down-regulation of PLC?2-?-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer. J Exp Med 210:2257-71
Sanford, Dominic E; Porembka, Matthew R; Panni, Roheena Z et al. (2013) A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma. J Cancer Ther 4:797-803