CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8+ T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP+ stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP+ cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP+ CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and in flammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP+ CAF, may direct tumor immune evasion in a model of human PDA

Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial

Background: Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer. Patients and methods: Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m2 twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m2 with i.v. leucovorin 20 mg/m2 on days 1-5, repeated every 28 days (n = 974). Results: Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or ≥65 years old. Conclusions: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cance