CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma(PDAC) is resistant to the PD-1/PD-L1 blockade therapy. Previously, the combination of PD-1 blockade and vaccine therapy was shown to have a modest antitumor activity in murine models of PDAC. We used a murine syngeneic model of metastatic PDAC to identify, among multiple T cell modulators tested, which therapeutic agents in combination with the GVAX cancer vaccine and an anti-PD-1 antagonist antibody(αPD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody(αCD137) most significantly improved survival in the mouse PDAC model. Moreover, αPD-1 and αCD137 together in combination with vaccine therapy more significantly increased the expression of costimulatory molecules CD137 and OX40 on CD4+PD-1+ and CD8+PD-1+ T cells comparing to αPD-1 or αCD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of αCD137 and αPD-1. On another hand, αCD137 treatment led to an increase in effector memory T cells independent of αPD-1. Although αCD137 does not increase the cytotoxic effector T cell function, the addition of αCD137 to GVAX+αPD-1 increased expression of IFNγ in EOMES + exhausted tumor-infiltrating T cells. Taken together, this preclinical study established the mechanism of targeting CD137 to enhance effector memory and activated T cells in PDAC. Immunohistochemistry analysis of resected human PDACs following the neo-adjuvant GVAX treatment showed increased levels of CD8+ T cells in those with high levels of CD137 expression, supporting an ongoing clinical trial of testing CD137 as a potential target in treating PDACs that are inflamed with T cells by vaccine therapy.

Muth ST ，Saung MT ，Blair AB ，Henderson MG ，Thomas DL 2nd ，Zheng L ... -  《-》

Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer.

Saung MT ，Muth S ，Ding D ，Thomas DL 2nd ，Blair AB ，Tsujikawa T ，Coussens L ，Jaffee EM ，Zheng L ... -  《Journal for ImmunoTherapy of Cancer》

Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies.

Kim VM ，Blair AB ，Lauer P ，Foley K ，Che X ，Soares K ，Xia T ，Muth ST ，Kleponis J ，Armstrong TD ，Wolfgang CL ，Jaffee EM ，Brockstedt D ，Zheng L ... -  《Journal for ImmunoTherapy of Cancer》

Combination of PD-1 Inhibitor and OX40 Agonist Induces Tumor Rejection and Immune Memory in Mouse Models of Pancreatic Cancer.

Advanced pancreatic ductal adenocarcinoma (PDAC) is resistant to therapy, including immune checkpoint inhibitors. We evaluated the effects of a neutralizing antibody against programmed cell death 1 (PD-1) and an agonist of OX40 (provides a survival signal to activated T cells) in mice with pancreatic tumors. We performed studies in C57BL/6 mice (controls), KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mice, and mice with orthotopic tumors grown from Panc02 cells, KrasG12D;P53flox/flox;PDX-1-Cre;Luciferase (KPC-Luc) cells, or mT4 cells. After tumors developed, mice were given injections of control antibody or anti-OX40 and/or anti-PD-1 antibody. Some mice were then given injections of antibodies against CD8, CD4, or NK1.1 to deplete immune cells, and IL4 or IL7RA to block cytokine signaling. Bioluminescence imaging was used to monitor tumor growth. Tumor tissues collected and single-cell suspensions were analyzed by time of flight mass spectrometry analysis. Mice that were tumor-free 100 days after implantation of orthotopic tumors were rechallenged with PDAC cells (KPC-Luc or mT4) and survival was measured. Median levels of PD-1 and OX40 mRNAs in PDACs were determined from The Cancer Genome Atlas and compared with patient survival times. In mice with orthotopic tumors, all those given control antibody or anti-PD-1 died within 50 days, whereas 43% of mice given anti-OX40 survived for 225 days; almost 100% of mice given the combination of anti-PD-1 and anti-OX40 survived for 225 days, and tumors were no longer detected. KPC mice given control antibody, anti-PD-1, or anti-OX40 had median survival times of 50 days or less, whereas mice given the combination of anti-PD-1 and anti-OX40 survived for a median 88 days. Mice with orthotopic tumors that were given the combination of anti-PD-1 and anti-OX40 and survived 100 days were rechallenged with a second tumor; those rechallenged with mT4 cells survived an additional median 70 days and those rechallenged with KPC-Luc cells survived long term, tumor free. The combination of anti-PD-1 and anti-OX40 did not slow tumor growth in mice with antibody-mediated depletion of CD4+ T cells. Mice with orthotopic tumors given the combination of anti-PD-1 and anti-OX40 that survived after complete tumor rejection were rechallenged with KPC-Luc cells; those with depletion of CD4+ T cells before the rechallenge had uncontrolled tumor growth. Furthermore, KPC orthotopic tumors from mice given the combination contained an increased number of CD4+ T cells that expressed CD127 compared with mice given control antibody. The combination of agents reduced the proportion of T-regulatory and exhausted T cells and decreased T-cell expression of GATA3; tumor size was negatively associated with numbers of infiltrating CD4+ T cells, CD4+CD127+ T cells, and CD8+CD127+ T cells, and positively associated with numbers of CD4+PD-1+ T cells, CD4+CD25+ T cells, and CD8+PD-1+ T cells. PDACs with high levels of OX40 and low levels of PD-1 were associated with longer survival times of patients. Pancreatic tumors appear to evade the immune response by inducing development of immune-suppressive T cells. In mice, the combination of anti-PD-1 inhibitory and anti-OX40 agonist antibodies reduces the proportion of T-regulatory and exhausted T cells in pancreatic tumors and increases numbers of memory CD4+ and CD8+ T cells, eradicating all detectable tumor. This information can be used in development of immune-based combination therapies for PDAC.

Ma Y ，Li J ，Wang H ，Chiu Y ，Kingsley CV ，Fry D ，Delaney SN ，Wei SC ，Zhang J ，Maitra A ，Yee C ... -  《-》

Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer.

Pan Y ，Lu F ，Fei Q ，Yu X ，Xiong P ，Yu X ，Dang Y ，Hou Z ，Lin W ，Lin X ，Zhang Z ，Pan M ，Huang H ... -  《Journal of Hematology & Oncology》