CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Science (Impact Factor: 33.61). 03/2011; 331(6024):1612-6. DOI: 10.1126/science.1198443
Source: PubMed


Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

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    • "mice), with tumor regression being observed in 30% of mice. Interestingly, the activity of FGK45 in KPC mice did not appear to be dependent on the presence of T-cells or gemcitabine but did require macrophages, with CD40-activated macrophages being shown to rapidly infiltrate tumors where they transformed into tumoricidal cells, facilitating depletion of the tumor stroma [29]. "
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    ABSTRACT: Ever since a pivotal study in 1997 demonstrated superiority of gemcitabine over 5-FU, gemcitabine monotherapy has, until recently, comprised the standard of care in patients with advanced pancreatic cancer. However, the emerging recognition of the pancreatic cancer microenvironment, including the particularly abundant stroma, as playing a key role in disease progression and resistance to chemotherapy has marked somewhat of a paradigm shift in the way treatment of advanced pancreatic cancer is viewed, with these very same biological defenses conversely offering an Achilles heel with which to combat this aggressive disease. Recently, this approach was validated for the first time in a pivotal phase III trial in which patients received nab-paclitaxel, a stroma-targeted drug, with gemcitabine. Overall survival was significantly (p<0.001) prolonged in the combination arm, compared with gemcitabine alone, and thus these convincing results pave the way forward for future treatment regimens that employ a multipronged approach, targeting not only the primary tumor but the surrounding microenvironment as well.
    Cancer Treatment Reviews 10/2014; 40(9). DOI:10.1016/j.ctrv.2014.07.003 · 7.59 Impact Factor
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    • "Recently, it has become clear that there is probably not one single compound that can achieve this goal [22]. A proposed strategy therefore is a combination of infusion of antibodies against CD40 in order to stimulate the secondary lymph node resident macrophages to migrate into the tumor tissue with IFN-γ to effectively reprogram tumor-induced M2-like macrophages into activated IL-12 producing M1 cells [41]. In addition, targeting the nuclear factor κB (NF-κB) signaling pathway, a crucial pathway in the activation of M2 TAMs, was shown to switch M2 TAMs to a M1 phenotype [42]. "
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    ABSTRACT: Hypothesis The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells. Methods 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment. Results The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r −0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found. Conclusions The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.
    PLoS ONE 09/2014; 9(9):e106742. DOI:10.1371/journal.pone.0106742 · 3.23 Impact Factor
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    • "Based on promising results in recent pilot clinical trials for cancer there has been a renewed interest in IL-2 based immunotherapy [7] as well as in agonistic CD40 antibodies [8]. We previously described that a combination immunotherapy consisting of agonist CD40 antibody and high dose systemic IL-2 (IT) resulted in synergistic antitumor effects which were CD8+ T-cell dependent [9]. "
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    ABSTRACT: We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated" (CD8+CD44high) T cells displaying a CD25-NKG2D+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.
    PLoS ONE 08/2014; 9(8):e102709. DOI:10.1371/journal.pone.0102709 · 3.23 Impact Factor
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