Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies

Abstract

CD27, a costimulatory molecule on T cells, induces intracellular signals mediating cellular activation, proliferation, effector function, and cell survival on binding to its ligand, CD70. Varlilumab, a novel, first-in-class, agonist immunoglobulin G1 anti-CD27 antibody, mediates antitumor immunity and direct killing of CD27+ tumor cells in animal models. This first-in-human, dose-escalation, and expansion study evaluated varlilumab in patients with hematologic malignancies. Primary objectives were to assess safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. In a 3 + 3 dose-escalation design, 30 patients with B-cell (n = 25) or T-cell (n = 5) malignancies received varlilumab (0.1, 0.3, 1, 3, or 10 mg/kg IV) as a single dose with a 28-day observation period, followed by weekly dosing (4 doses per cycle, up to 5 cycles, depending on tumor response). In an expansion cohort, 4 additional patients with Hodgkin lymphoma received varlilumab at 0.3 mg/kg every 3 weeks (4 doses per cycle, up to 5 cycles). No dose-limiting toxicities were observed. Treatment-related adverse events, generally grade 1 to 2, included fatigue, decreased appetite, anemia, diarrhea, and headache. Exposure was linear and dose-proportional across dose groups and resulted in increases in proinflammatory cytokines and soluble CD27. One patient with stage IV Hodgkin lymphoma experienced a complete response and remained in remission at >33 months with no further anticancer therapy. These data support further investigation of varlilumab for hematologic malignancies, particularly in combination approaches targeting nonredundant immune regulating pathways. This trial was registered at www.clinicaltrials.gov as #NCT01460134.

Conflict of interest statement

Conflict-of-interest disclosure: S.M.A. reports research funding (to his institution) from Celldex, BMS, Merck, Pfizer, Seattle Genetics, Takeda, AI Therapeutics, Regeneron, and Affimed. I.F. reports research funding and consultancy from AbbVie, Seattle Genetics, and Verastem; research funding from Acerta, Agios, ArQule, BeiGene, Calithera, Celgene, Constellation, Curis, Forma, Forty-Seven, Genentech, Gilead, Incyte, Infinity, Janssen, Karyopharm, KITE, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Roche, Takeda, Teva, TG Therapeutics, and Trillium; and consultancy for TG Therapeutics. M.H.T. reports honoraria and being an advisory board member and speaker (unbranded/nonpromotional talks) for BMS and Eisai Inc; and reports honoraria and being an advisory board member for Array Biopharma, Blueprint Medicines, LOXO Oncology, Arqule, Bayer, and Novartis. B.I.S. is a member of Data Monitoring Committees for Pfizer and Immune Design, Inc. J.B. has received research funding from Merck, BMS, Celldex, Acerta, Celgene, Seattle Genetics, and Pharmacyclics. T.R.H., T.R., T.K., and M.J.Y. are employed by and have ownership interest (including stock options, but excluding direct investments through mutual funds and the like) in Celldex Therapeutics, Inc. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Mechanism of varlilumab antitumor activity. Interaction of CD27 and CD70 (A) and varlilumab and the Ag-specific TCR (B) in the immune activation of effector T cells. (C) Interaction of CD27-expressing tumor cells with varlilumab on natural killer (NK) cells for a cytolytic response. APC, antigen-presenting cell; MHC, major histocompatibility complex.

Figure 2.

Study design/treatment schema. (A) Using a standard 3 + 3 design, the B-cell malignancy and T-cell malignancy dose escalations proceeded separately. Patients who did not complete the multidose phase for reasons other than DLT were replaced as necessary. The B-cell malignancy dose escalation completed through the maximum planned dose level (10 mg/kg). After the B-cell malignancy dose escalation component of the study, an expansion cohort was enrolled to further explore the clinical and biological activity of varlilumab (at 0.3 mg/kg every 3 weeks) in patients with Hodgkin lymphoma. The study was closed after treatment of 4 patients in the Hodgkin lymphoma expansion cohort and 5 patients at the 3 mg/kg dose level in the T-cell malignancy dose-escalation phase. (B) During the dose-escalation phase, varlilumab (represented by red circles) was initially administered as a single dose with 28-day observation. Additional multidose treatment (4 weekly doses with a 4-week observation) and retreatment (up to 4 additional cycles, each consisting of 4 weekly doses with an 8-week observation) were allowed for patients who had not experienced progressive disease or DLT. Patients in the Hodgkin lymphoma expansion cohort received varlilumab at 0.3 mg/kg, every 3 weeks (up to 5 cycles, each consisting of 4 doses). Diagnostic imaging and restaging were repeated every 12 weeks (as indicated by asterisks).

Figure 3.

Patients with stage IV Hodgkin lymphoma with complete response (CR) to varlilumab. PR, partial response; SD, stable disease.

Figure 4.

Immunohistochemistry of a pretreatment lymph node biopsy sample from a patient with complete response to varlilumab. (A) Hematoxylin and eosin stain (magnification ×20) from a patient with classical Hodgkin lymphoma. (B) Atypical lymphohistiocytic infiltrate within a background of normal reactive cells (magnification ×100). (C) CD27 expression on malignant cells, intratumoral lymphocytes, and histiocytes. Malignant cells and intratumoral T cells were positive for CD27 expression (magnification ×100). (D) CD70 staining was negative on both malignant cells and the intratumoral immune infiltrate (magnification ×100).

Figure 5.

Varlilumab serum levels in patients with hematologic malignancies. Mean concentration–time curves for varlilumab for the dose-escalation cohorts. Black triangles represent varlilumab dosing. LLOQ, lower limit of quantification.

Figure 6.

Changes in serum levels of soluble factors after varlilumab administration. MIP-1β (A), monocyte chemoattractant protein-1 (MCP-1) (B), monokine induced by gamma interferon (MIG) (C), and IL-12 (D). Serum cytokines were measured by using the Luminex 200 System at the indicated times. Data represent the mean and standard error of patients across different dose levels (n = 9 to 11). Black triangles represent varlilumab dosing. Statistics are shown for paired Student t test vs baseline samples. *P < .05; ***P < .001.