CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study

O’Hara, Mark H.; O'Reilly, Eileen Mary; Varadhachary, Gauri R.; Wolff, Robert A.; Wainberg, Zev A.; Ko, Andrew H.; Fisher, George A.; Rahma, Osama E.; Lyman, Jaclyn P.; Cabanski, Christopher R.; Mick, Rosemarie; Gherardini, Pier Federico; Kitch, Lacey J.; Xu, Jingying; Samuel, Theresa; Karakunnel, Joyson; Fairchild, Justin; Bucktrout, Samantha; LaVallee, Theresa; Selinsky, Cheryl; Till, Jacob E.; Carpenter, Erica L.; Alanio, Cécile; Byrne, Katelyn T.; Chen, Richard; Trifan, Ovidiu C.; Dugan, Ute; Horak, Christine E.; Hubbard-Lucey, Vanessa M.; Wherry, E. John; Ibrahim, Ramy; Vonderheide, Robert H.

doi:10.1016/s1470-2045(20)30532-5

Cited by 216 publications

(169 citation statements)

References 13 publications

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“…In the TME, tumors and tumor-associated macrophages (TAMs) secrete immunosuppressive factors, such as the checkpoint modulator PD-L1, which diminish the cytotoxic functions of tumor-specific CD8 + T cells [ 187 ]. A recent study showed that in metastatic ductal pancreatic adenocarcinoma (PDAC) patients, the concurrent treatment with agonistic CD40 antibodies and anti-PD-1 treatment, can trigger effective T cell immunity [ 188 ]. In addition, the presence of Toll-like Receptors (TLRs) expressed in macrophages and other cells in the TME can provide immunosuppressive tumor protection.…”

Section: Discussion—future Perspectivesmentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

242

106

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The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis.

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Section: Discussion—future Perspectivesmentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

242

106

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show abstract

“…Two phase 2 studies are evaluating APX005M in combination with chemotherapy in advanced soft tissue sarcoma (NCT03719430) and resectable esophageal and gastroesophageal carcinoma (NCT03165994). Manageable safety profiles and promising antitumor activity were reported for patients with metastatic pancreatic adenocarcinoma (PR 58%) evaluating APX005M in combination with chemotherapy [104]. A phase 2 study is investigating APX005M in combination with anti-PD-1, one in NSCLC and metastatic melanoma (NCT03123783), and a second trial is evaluating local injection of APX005M in combination with pembrolizumab in unresectable melanoma (NCT02706353).…”

Section: Apx005mmentioning

confidence: 99%

Agonistic CD40 Antibodies in Cancer Treatment

Djureinovic

Wang

Kluger

2021

Cancers

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CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

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“…Mitazalimab (also known as ADC-1013 or JNJ-64457107) demonstrated early signs of clinical activity in a phase 1 dose escalation study in solid tumors with one partial response [61]. APX005M and Chi Lob 7/4 reported stable disease as the best response in phase 1a studies [81][82][83]. In addition, a phase 1 study using recombinant human CD40L in cancer patients provided early signs of clinical activity [84].…”

Section: Assessment Of Clinical Efficacymentioning

confidence: 99%

“…Promising preliminary data was recently presented from a phase 1b clinical study with APX005M in patients with pancreatic cancer, in combination with gemcitabine and nab-paclitaxel, with or without the addition of nivolumab [82]. Further, mitazalimab will be evaluated in metastatic pancreatic cancer in combination with mFOLFIRINOX, supported by promising preclinical data [96].…”

Section: Combination Therapy the Current Focus Of Cd40 Agonists In Clinical Developmentmentioning

confidence: 99%

“…In contrast, mitazalimab will be active in areas with high levels of FcγRI and FcγRIII and thus have a lower activity in the blood, but potentially a higher activity in the TME. Although mitazalimab is tolerable at higher dose levels compared to APX005M, the pharmacodynamic biomarker response in patients is very similar [61,82]. In vitro studies performed by Filbert et al [88], show large differences in potency between APX005M and mitazalimab.…”

Section: Format Function and Affinity For Fcγr Of Cd40 Agonist Antibodies In Clinical Developmentmentioning

confidence: 99%

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Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Smith

Deronic

Hägerbrand

et al. 2021

Expert Opinion on Biological Therapy

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CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has the potential to increase the fraction of patients that respond to established immunotherapies. Areas covered:This article reviews current as well as emerging CD40 agonist therapies with a focus on antibody-based therapies, including next generation bispecific CD40 agonists. The scientific rationale for different design criteria, binding epitopes and formats are discussed.

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CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study

Cited by 216 publications

References 13 publications

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Agonistic CD40 Antibodies in Cancer Treatment

Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

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