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J. Liu



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    SC14 - Immunotherapy of NSCLC (ID 338)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      SC14.04 - The CD47 Macrophage Checkpoint as a New Immunotherapy Target (ID 6656)

      11:55 - 12:10  |  Author(s): J. Liu

      • Abstract
      • Presentation
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      Abstract:
      Background: Hu5F9-G4 is a humanized monoclonal antibody that targets CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on human cancers and also on red blood cells (RBCs). In primate toxicology studies, Hu5F9-G4 caused a transient anemia that was improved with a single lower Priming Dose allowing higher Maintenance Doses. Materials and Methods: Relapsed/refractory solid tumors and lymphomas were included. This dose escalation study included: Part A, to determine the Priming Dose and Part B, to determine the Maintenance Dose. The maximum tolerated dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4 dosed weekly). The primary objective is to determine safety and secondary objectives are to determine PK and PD. Preliminary data reported from data cutoff of July 22, 2016.Results: 25 patients have enrolled. Part A included 0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100% RBC receptor occupancy at the Priming Dose. Treatment-related adverse event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3 G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea (3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing). There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose (ongoing). Most toxicities were was associated with the initial single Priming Dose and were completely reversible. TRAE in Part B at 3 mg/kg included: anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1). Two patients with adenoid cystic carcinoma in Part A had stable disease for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months (myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20 mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational Research Unit; California Institute for Regenerative Medicine; Forty Seven, Inc.Trial Registration: NCT02216409References: 1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. References 1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.Figure: CD47 is a myeloid-specific immune checkpoint. Figure 1Figure 2





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