PF-04136309 / Pfizer - LARVOL DELTA

Targeting tumor-associated CCR2+ macrophages to inhibit pancreatic cancer recurrence following irreversible electroporation. (PubMed, Sci Adv) - "Consequently, we developed a macrophage-based proteolipid vesicle (mPLV) coencapsulating the CCR2 antagonist PF-4136309 (PF) and gemcitabine (GEM), named PF/GEM@mPLV. PF/GEM@mPLV markedly inhibits tumor recurrence following iIRE, diminishes hepatic metastases, and prolongs survival in preclinical PDAC models. These findings uncover the role of CCR2+ TAMs in iIRE-induced immunosuppression, offering a promising strategy to enhance the clinical potential of IRE in PDAC."

Journal • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCR2 • MPL

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes (AACR 2024) - P1 | "Analysis of a phase Ib trial FOLFIRINOX in combination with a CCR2 inhibitor (PF-04136309; NCT01413022) , we found that in patients with classical tumors, increasing permCAF probability was associated with response (r = -0.688, p<0.001)...DeCAF subtypes are associated with histological subtype in MESO (p = 0.021) and grade in KIRC (p = 0.056). Taken together, DeCAF subtypes explain the role of CAF subtypes in patients, provide a foundation for the translation of preclinical studies, and facilitate the design of future therapeutic approaches and clinical trials."

Clear Cell Renal Cell Carcinoma • Gastrointestinal Cancer • Mesothelioma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • CAFs • CCR2

Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier. (PubMed, Mater Today (Kidlington)) - "Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist PF-6309 (PF) into PGEM micellar system. Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment. In addition, this work paved a new way for bioinformatics and computer modeling-guided rational design of nanomedicine."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCL2 • CCR2 • STING

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis. (PubMed, Acta Pharmacol Sin) - "Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • CCL2

Phase Ib study of PF-04136309 (an oral CCR2 inhibitor) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic adenocarcinoma (ESMO 2017) - P1b/2; "Encouraging safety, favorable PK, clinical responses and POM with CCR2 inhibition plus nab-P+Gem in mPDAC pts."

Biomarker • Clinical • Combination therapy • P1 data • Pancreatic Cancer

Bioinformatics and computer modeling-guided polymeric formulation for overcoming pancreatic cancer immune resistance (ACS-Fall 2022) - "Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist PF-6309 (PF) into the polymeric carrier system...Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment. In addition, this work paved a new way for bioinformatics and computer modeling-guided rational design of nanomedicine."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCL2

HYPERGLYCEMIA SENSITIZES PANCREATIC CANCER TO MACROPHAGE-SPECIFIC IMMUNOTHERAPIES: AN UPDATE (APCM 2022) - "Hyperglycemic conditions promote M1 survival and function, while preventing a switch to an M2 phenotype in both in vitro and in vivo assays. Hyperglycemia appears to sensitize PC to an otherwise ineffective CSF1R inhibitor. We are currently testing the efficacy of D30 and pexidartinib in a model of hepatic metastases and studying effectiveness of D30 combined with PF-4136309, a CCR2 inhibitor."

IO biomarker • Diabetes • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • ARG1 • MRC1 • PTPRC

GOLM1 Drives Colorectal Cancer Metastasis by Regulating Myeloid-derived Suppressor Cells. (PubMed, J Cancer) - "PF-04136309, a small molecule and specific inhibitor of CCR2 can largely suppressed GOLM1-mediated CRC metastasis. These results suggest that GOLM1 can promote CRC metastasis and is a prognostic biomarker in human CRC."

Journal • Myeloid-derived suppressor cells • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Tumor-associated macrophages: A promising target for a cancer immunotherapeutic strategy. (PubMed, Pharmacol Res) - "To date, TAM-targeted therapeutic strategies have mainly been divided into two kinds: inhibiting pro-tumor TAMs and activating anti-tumor TAMs. We reviewed the heterogeneous and plastic characteristics of macrophages in the TME and the feasible strategies to target TAMs in cancer immunotherapy and summarized the complementary effect of TAM-targeted therapy with traditional treatments or other immunotherapies."

Journal • Review • Oncology

Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. (PubMed, Invest New Drugs) - P1b/2; "Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938."

Clinical • Combination therapy • Journal • P1 data

BIOGEL DELIVERY OF STING LIGANDS IS EFFECTIVE IN A MURINE MODEL OF LOCALLY ADVANCED PANCREATIC ADENOCARCINOMA, AND IS POTENTIATED BY LOCAL CCR2 INHIBITION (AHPBA 2019) - "...Combination with local CCR2 inhibition was evaluated in a subcutaneous flank model using a sub-therapeutic dose of S100 (10ug), combined with a titration of PF-4136309, a small molecule inhibitor of CCR2... STING ligands can be used in conjunction with thermogel delivery systems to produce durable tumor regression in both direct injection and margin accentuation applications. This effect is potentiated by CCR2 inhibition. These results suggest that STING activation is a flexible approach that can be potentiated through biomaterial delivery strategies, and CCR2 inhibition to achieve high response rates even with advanced tumors."

Preclinical