A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

Nowak, Anna K.; Cook, Alistair; McDonnell, Alison M.; Millward, Michael; Creaney, Jenette; Francis, Roslyn J.; Hasani, Arman; Segal, Amanda; Musk, Arthur W.; Turlach, Berwin A.; McCoy, Melanie J.; Robinson, Bruce; Lake, Richard

doi:10.1093/annonc/mdv387

Cited by 84 publications

(54 citation statements)

References 15 publications

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“…As in previous studies of CP-870,893 – either alone or in combination with chemotherapy 7,11–15 – mild to modest and transient CRS was the most common adverse event. Published concerns of clinical unsuitability or lethal hepatotoxicity from intravenous agonistic CD40 mAb based on murine studies 25,26 were once again not realized in this clinical trial.…”

Section: Discussionsupporting

confidence: 71%

“…Prior clinical trials of single-agent agonistic CD40 mAb, or CD40 mAb in combination with chemotherapy, have demonstrated clinical activity. 7,11–13,15,21 In a previous trial, 4 patients among 15 with advanced melanoma had a PR to a single dose of the CD40 mAb CP-870,893. 7 Potential synergy of CD40 activation and CTLA-4 blockade has been established in mouse tumor models, 6 but this study is the first to test this hypothesis in patients.…”

Section: Discussionmentioning

confidence: 99%

“…8 CP-870,893 is a fully human IgG2 agonist mAb evaluated in a single-dose study, a weekly infusion study, and studies combining CP-870,893 with chemotherapy. 7,11–15 The most common side effect with CP-870,893 is transient, grade 1–2 cytokine release syndrome. We and others have shown that CP-870,893 activates human B cells and dendritic cells in vitro which in turn can induce T cell proliferation and cytokine production.…”

Section: Introductionmentioning

confidence: 99%

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Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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“…This finding, though, is very similar to the best overall response reported for CP-870,893 alone in patients with metastatic melanoma where 27% (4 of 15) of patients achieved a PR [23]. In the second study, CP-870,893 was combined with cisplatin and pemetrexed in patients with malignant pleural mesothelioma [46]. Here, CP-870,893 was administered 7 days after chemotherapy.…”

Section: Clinical Application Of Cd40 Agonists To Cancer Therapysupporting

confidence: 63%

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

Beatty

Long

2016

Expert Review of Anticancer Therapy

111

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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.

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“…Immune modulators, such as CP-870,893 (an anti-human CD40 mAb), recently been shown to be useful in treating a broad range of cancers and function as a strong adjuvant component [49, 50]. Patients who have received agonistic anti-CD40 have shown an increase in memory CD8 + CTLs, CD27 + memory B-cells, and CD27 + /CD86 + memory Bcells [51, 52]. An adjuvant that increases memory B-cells and CD8 memory T-cells would potentiate vaccines to confer better immune protection against broad range of diseases.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a Broadly Reactive Anti-CD40 Agonistic Monoclonal Antibody for Potential Use as an Adjuvant

et al. 2017

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Lack of safe and effective adjuvants is a major hindrance to the development of efficacious vaccines. Signaling via CD40 pathway leads to enhanced antigen processing and presentation, nitric oxide expression, pro-inflammatory cytokine expression by antigen presenting cells, and stimulation of B-cells to undergo somatic hypermutation, immunoglobulin class switching, and proliferation. Agonistic anti-CD40 antibodies have shown promising adjuvant qualities in human and mouse vaccine studies. An anti-CD40 monoclonal antibody (mAb), designated 2E4E4, was identified and shown to have strong agonistic effects on primary cells from multiple livestock species. The mAb recognize swine, bovine, caprine, and ovine CD40, and evoked 25-fold or greater proliferation of peripheral blood mononuclear cells (PBMCs) from these species relative to cells incubated with an isotype control (p<0.001). In addition, the mAb induced significant nitric oxide (p<0.0001) release by bovine macrophages. Furthermore, the mAb upregulated the expression of MHC-II by PBMCs, and stimulated significant (p<0.0001) IL-1α, IL6, IL-8, and TNF-α expression by PBMCs. These results suggest that the mAb 2E4E4 can target and stimulate cells from multiple livestock species and thus, it is a potential candidate for adjuvant development. This is the first study to report an anti-swine CD40 agonistic mAb that is also broadly reactive against multiple species.

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A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

Cited by 84 publications

References 15 publications

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

Characterization of a Broadly Reactive Anti-CD40 Agonistic Monoclonal Antibody for Potential Use as an Adjuvant

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