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CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
Science. 2011 Mar 25; 331(6024):1612-6
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13 Apr 2011
Albert Deisseroth
F1000 Pharmacology & Drug Discovery
US Food and Drug Administration,
Silver Spring, MD, USA.
F1000 Pharmacology & Drug Discovery
US Food and Drug Administration,
Silver Spring, MD, USA.
Clinical Trial, Novel Drug Target
DOI: 10.3410/f.9582967.10243065
Systemic administration of antibodies that are agonistic to the CD40 receptor were shown to induce regression of pancreatic cancers in human and mouse test subjects that appeared to be dependent on the infiltration of macrophages (not T cells) into the stroma of pancreatic cancer. This was true in human...Continue reading
Systemic administration of antibodies that are agonistic to the CD40 receptor were shown to induce regression of pancreatic cancers in human and mouse test subjects that appeared to be dependent on the infiltration of macrophages (not T cells) into the stroma of pancreatic cancer. This was true in human subjects (receiving the CD40 agonistic antibody with gemsar) as well as in KPC mice, which is a transgenic mouse model in which spontaneous pancreatic cancer develops. These results show that the activation of macrophages at the time of tumor cell death (induced by chemotherapy) can induce an infiltration of pancreatic cancer tissue and induce tumor regression through a mechanism that appears not to involve the adaptive immune response but the innate immune response. Given the refractory nature of pancreatic cancer, this finding should open the door to novel approaches to the treatment of pancreatic cancers and perhaps other cancers.
The paper reports that the combination of gemsar chemotherapy and intravenous administration of antibodies agonistic for the CD40 receptor induces regression of tumors and infiltration of the tumor stroma with macrophages but not T cell lymphocytes. A total of 88% of the human subjects treated with gemsar and CD40 agonistic antibody showed evidence of a 'metabolic response' using fludeoxyglucose- positron emission tomography/computerised tomography (FDG-PET/CT). Response evaluation criteria in solid tumors (RECIST) showed that 4/21 patients developed partial responses by conventional criteria. The combination of gemsar and CD40 agonistic antibody induced regression in 30% of the KPC mice with detectable tumor nodules in the pancreas. The absence of both CD4 and CD8 T cell lymphocytes did not diminish the responses. Ten minutes after administration of the CD40 antibody, the macrophages disappeared from the peripheral blood and were found in the spleen and lymph nodes but not the tumor. At 18 hours, the macrophages bound to the anti-CD40 antibody were found in the tumor tissue, not the lymph nodes. Macrophages showed an increased expression of Class II major histocompatibility complex (MHC) molecules and CD86 at day 3, and cytokine surge in the blood (increased interleukin (IL)-12, TNG-alpha, and interferon-gamma but not IL-10). Depletion of macrophages from the KPC mice abrogated the ability of the CD40L agonistic antibody/gemsar treatment to induce tumor regression. These results suggest that in pancreatic cancer, a combination of chemotherapy-induced tumor cell death and infiltration of the tumor with activated macrophages can induce tumor regression.
The paper reports that the combination of gemsar chemotherapy and intravenous administration of antibodies agonistic for the CD40 receptor induces regression of tumors and infiltration of the tumor stroma with macrophages but not T cell lymphocytes. A total of 88% of the human subjects treated with gemsar and CD40 agonistic antibody showed evidence of a 'metabolic response' using fludeoxyglucose- positron emission tomography/computerised tomography (FDG-PET/CT). Response evaluation criteria in solid tumors (RECIST) showed that 4/21 patients developed partial responses by conventional criteria. The combination of gemsar and CD40 agonistic antibody induced regression in 30% of the KPC mice with detectable tumor nodules in the pancreas. The absence of both CD4 and CD8 T cell lymphocytes did not diminish the responses. Ten minutes after administration of the CD40 antibody, the macrophages disappeared from the peripheral blood and were found in the spleen and lymph nodes but not the tumor. At 18 hours, the macrophages bound to the anti-CD40 antibody were found in the tumor tissue, not the lymph nodes. Macrophages showed an increased expression of Class II major histocompatibility complex (MHC) molecules and CD86 at day 3, and cytokine surge in the blood (increased interleukin (IL)-12, TNG-alpha, and interferon-gamma but not IL-10). Depletion of macrophages from the KPC mice abrogated the ability of the CD40L agonistic antibody/gemsar treatment to induce tumor regression. These results suggest that in pancreatic cancer, a combination of chemotherapy-induced tumor cell death and infiltration of the tumor with activated macrophages can induce tumor regression.
Disclosures
None declared
Add Comment
Deisseroth A: F1000Prime Recommendation of [Beatty GL et al., Science 2011, 331(6024):1612-6]. In F1000Prime, 13 Apr 2011; DOI: 10.3410/f.9582967.10243065. F1000Prime.com/9582967#eval10243065
02 Jun 2011
Clinical Trial
DOI: 10.3410/f.9582967.11861055
Combinations of chemotherapy with immunostimulatory agonist antibodies (Abs) were previously shown to have synergistic anti-tumor impact in multiple mouse models. This is the first study in which such a combination, gemcitabine and agonist anti-CD40 Abs, has been evaluated in the clinic. Furthermore accompanying...Continue reading
Combinations of chemotherapy with immunostimulatory agonist antibodies (Abs) were previously shown to have synergistic anti-tumor impact in multiple mouse models. This is the first study in which such a combination, gemcitabine and agonist anti-CD40 Abs, has been evaluated in the clinic. Furthermore, accompanying mouse studies indicate that the anti-tumor effect of the anti-CD40 Abs relies on the mobilization of macrophages, instead of dendritic cell (DC)-activated T cells as postulated in many prior studies {1-4}.
The combination of gemcitabine and agonist anti-CD40 Abs was tested for efficacy in patients with non-resectable pancreatic ductal adenocarcinoma (PDAC), as well as in a genetically engineered mouse model of PDAC. Although the clinical efficacy was modest, the studies indicated that the combination of drugs in this particular regimen was well tolerated. This opens the way for further clinical studies towards more potent dosing schedules. The same drug combination was evaluated in a genetically engineered mouse model of PDAC.
Interestingly, these experiments revealed that the anti-tumor effect of anti-CD40 Abs was primarily mediated by activated macrophages, not by T cells as shown in prior studies. A possible explanation for this difference with prior studies may be the use of an autochthonous tumor model, instead of the transplantable models used in prior studies. An attractive aspect of the involvement of macrophages in the therapeutic mechanism of anti-CD40 Abs may be that their mobilization by agonist Abs is much faster than the activation of T cells by, for instance, anti-CTLA-4 Abs (ipilimumab) or cancer vaccines. Time is precious, in particular in the case of non-resectable PDAC, where median survival time is less than 6 months. NB -- I am an author on ref {2}.
The combination of gemcitabine and agonist anti-CD40 Abs was tested for efficacy in patients with non-resectable pancreatic ductal adenocarcinoma (PDAC), as well as in a genetically engineered mouse model of PDAC. Although the clinical efficacy was modest, the studies indicated that the combination of drugs in this particular regimen was well tolerated. This opens the way for further clinical studies towards more potent dosing schedules. The same drug combination was evaluated in a genetically engineered mouse model of PDAC.
Interestingly, these experiments revealed that the anti-tumor effect of anti-CD40 Abs was primarily mediated by activated macrophages, not by T cells as shown in prior studies. A possible explanation for this difference with prior studies may be the use of an autochthonous tumor model, instead of the transplantable models used in prior studies. An attractive aspect of the involvement of macrophages in the therapeutic mechanism of anti-CD40 Abs may be that their mobilization by agonist Abs is much faster than the activation of T cells by, for instance, anti-CTLA-4 Abs (ipilimumab) or cancer vaccines. Time is precious, in particular in the case of non-resectable PDAC, where median survival time is less than 6 months. NB -- I am an author on ref {2}.
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Disclosures
None declared
Offringa R: F1000Prime Recommendation of [Beatty GL et al., Science 2011, 331(6024):1612-6]. In F1000Prime, 02 Jun 2011; DOI: 10.3410/f.9582967.11861055. F1000Prime.com/9582967#eval11861055
F1000Prime Recommendations, Dissents and Comments for [Beatty GL et al., Science 2011, 331(6024):1612-6]. In F1000Prime, 22 May 2013; F1000Prime.com/9582967
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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.
PMID: 21436454
