Background & Aims Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. Methods KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. Results Gemcitabine in combination with a CD40 agonist induced T cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4+ and CD8+ T cells infiltrated subcutaneous tumors, but only CD4+ T cells infiltrated spontaneous pancreatic tumors (not CD8+ T cells). In mice depleted of Ly6Clow F4/80+ extra-tumor macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8+ T cells and induced tumor regression, mediated by CD8+ T cells. Conclusions Ly6Clow F4/80+ macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extra-tumor macrophages, might increase the efficacy of T cell immunotherapy for patients with PDAC.

Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this anti-fibrotic activity, though, remain unclear. Here, we report that IFN-γ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFN-γ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMPs) in tumors leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes leading to enhanced chemotherapy efficacy.

This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.

INTRODUCTION CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. AREAS COVERED We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. EXPERT COMMENTARY There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance.

Inflammation mediated by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL-6 receptor (IL6R) as a strategy to inhibit IL-6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild-type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by immunohistochemistry to detect changes in STAT activation, tumor viability and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions and improved overall survival. Overall, we show that IL-6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL-6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC.

Macrophages constitute a dominant fraction of the population of immune cells that infiltrate developing tumors. Recruited by tumor-derived signals, tumor-infiltrating macrophages are key orchestrators of a microenvironment that supports tumor progression. However, the phenotype of macrophages is pliable and, if instructed properly, macrophages can mediate robust antitumor functions through their ability to eliminate malignant cells, inhibit angiogenesis, and deplete fibrosis. While much effort has focused on strategies to block the tumor-supporting activity of macrophages, emerging approaches designed to instruct macrophages with antitumor properties are demonstrating promise and may offer a novel strategy for cancer immunotherapy.

Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of the clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer.

Objective Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets. Methods Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (sclGVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. TGFβ activation was assessed using a responsive signature in mouse and Tnfrsf12a expression measured in SSc and mouse skin. Results Gene expression in skin from mice with sclGVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Bleomycin and Tsk2/+ mice showed enrichment of a TGFβ-responsive signature. Expression of Tnfrsf12a (the Tweak-Receptor / Fn14) is elevated in skin from fibroproliferative SSc patients and skin of Tsk2/+ mice. Conclusion This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGF-β, IL13 and IL4. We identify a novel target, Tnfrsf12a that is elevated in skin from fibroproliferative patients and Tsk2/+ mice. The information will serve to inform mechanistic and translational pre-clinical studies in SSc.