TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal, Induces Objective Responses in Patients with Advanced, Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Background

CD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 to evade macrophage-mediated destruction. TTI-621 (SIRPαFc) is an immune checkpoint inhibitor consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1 designed to both: 1) block the CD47 "do not eat" signal, and 2) engage macrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.

Methods

A phase 1, open-label, multicenter study is ongoing to evaluate the activity of weekly IV infusions of TTI-621 in multiple cohorts of adult patients (pts) with relapsed or refractory malignancies. Eligible pts are those who have progressed on standard anticancer therapy (including rituximab for pts with B-cell lymphomas), or those for whom no other approved therapy exists (NCT02663518). This data disclosure comprises all consecutively enrolled pts with diffuse large B-cell lymphoma (DLBCL) who received, at a minimum, 0.2 mg/kg/week TTI-621 monotherapy or 0.1 mg/kg TTI-621 in combination with 375 mg/m²/week rituximab for 8 weeks, after which TTI-621 monotherapy was permitted.

Results

As of June 1, 2017, 14 evaluable pts with DLBCL (7M/7F, age 42-72 years) have been enrolled and treated: 6 pts received TTI-621 monotherapy and 8 pts received TTI-621 plus rituximab. The number of prior systemic therapies ranged from 2 to 13; 6 pts had received prior autograft. Weekly outpatient treatments have been well tolerated. Mild-to-moderate infusion-related reactions were experienced by 9 pts following the first dose of TTI-621. Transient, dose-dependent decreases in platelets and leukocytes were generally without clinical sequelae. Objective responses were observed for 5/14 pts (36%): 1/6 pts treated with TTI-621 monotherapy and 4/8 pts treated with TTI-621 plus rituximab. Two pts attained complete responses (CR). One CR occurred in a pt treated with TTI-621 monotherapy who remains in continued CR at 20+ weeks. The second CR was in a pt treated with TTI-621 plus rituximab who remains in continued CR at 12+ weeks.

Conclusions

Weekly IV dosing employing TTI-621 to block the CD47 "do not eat" signal as monotherapy or in combination with rituximab was well tolerated. Treatment was associated with preliminary and promising anti-tumor activity in pts with advanced DLBCL as evidenced by 2 CRs and 3 PRs among 14 pts.