Journal ArticleDOI
Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer
Kenneth J. Pienta,Jean-Pascal Machiels,D. Schrijvers,Boris Alekseev,Mikhail Shkolnik,Simon J. Crabb,Susan Li,Shobha Seetharam,Thomas A. Puchalski,C. H. Takimoto,Yusri Elsayed,Fitzroy Dawkins,Johann S. de Bono +12 more
TLDR
Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.Abstract:
Background CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. Methods In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. Results Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥3 AEs. Common grade ≥3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-μg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. Conclusion Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.read more
Citations
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Tumour-associated macrophages as treatment targets in oncology
Alberto Mantovani,Federica Marchesi,Federica Marchesi,Alberto Malesci,Alberto Malesci,Luigi Laghi,Paola Allavena +6 more
TL;DR: It is surmised that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapies.
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Targeting macrophages: therapeutic approaches in cancer.
TL;DR: The state of the art of TAM-targeting strategies is evaluated, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms.
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Tumor microenvironment and therapeutic response
TL;DR: The development of rational drug combinations that can simultaneously target tumor cells and the microenvironment may represent a solution to overcome therapeutic resistance.
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Immune cell promotion of metastasis
TL;DR: How tumour-infiltrating immune cells contribute to the metastatic cascade is described and potential therapeutic strategies to target these cells are discussed.
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Inflammation and cancer: advances and new agents
TL;DR: It is asserted that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data and potential for novel cancer prevention and treatment strategies.
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