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A phase I study of an agonist anti-CD27 human antibody (CDX-1127) in patients with advanced hematologic malignancies or solid tumors
© Ansell et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
CD27, a member of the tumor necrosis factor receptor superfamily, is constitutively expressed on the majority of mature T cells, memory B cells, and a subset of NK cells. We previously demonstrated anti-tumor and immunological properties of the fully human anti-CD27 mAb 1F5 (CDX-1127) in murine tumor models of hematologic and solid tumors. A Phase I dose escalation study of CDX-1127 in patients (pts) with recurrent or treatment-refractory B-cell malignancies and select solid tumors is ongoing. CDX-1127 (0.1 to 10 mg/kg IV) is administered as a single-dose with 28-day observation, followed by 4 weekly doses before restaging at Day 85. Up to 4 additional re-treatment cycles (consisting of 4 weekly doses) are permitted in pts with stable disease or tumor response. Dose-escalation in pts with solid tumors has been completed with preliminary results presented in a separate abstract. Flow cytometry and functional immune analysis of peripheral blood lymphocytes from these solid tumor pts showed an increase in expression of activation markers on T cells (HLA-DR), increases in NK cells, decrease in Tregs, and enhanced T cell response to various stimuli in in vitro assays. Tumor shrinkage was also seen. Dose-escalation in pts with hematologic malignancies is ongoing. To date, 13 B-cell lymphoma pts (3 Hodgkin, 3 follicular, 3 marginal zone, 4 diffuse large B-cell) have received 0.1, 0.3, or 1 mg/kg CDX-1127, with no DLT. Treatment-related toxicity, generally Grade 1-2, included fatigue, nausea, decreased appetite and anemia. One pt with Hodgkin lymphoma who had previously progressed following treatment with chemotherapy, autologous stem cell transplant, and brentuximab vedotin had a partial response (PR) with 77% shrinkage in measurable disease; treatment is ongoing. Three additional pts had stable disease (range: 4.5 to 11+ months), including a pt with follicular lymphoma who has completed 3 cycles of therapy and a pt with marginal zone lymphoma with -36% shrinkage in measurable disease. Flow cytometry and functional immune analysis of peripheral blood lymphocytes are being performed to assess the immunomodulatory activity of CDX-1127 in patients with hematological malignancies. Emerging results suggest that weekly dosing of CDX-1127 is well tolerated with promising biological and early clinical activity. In addition, these data position CDX-1127 well for combination therapy with conventional and immunotherapy approaches as demonstrated in preclinical models.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.