A Single Direct Intratumoral Injection of TTI-621 (SIRPαFc) Induces Antitumor Activity in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Preliminary Findings Employing an Immune Checkpoint Inhibitor Blocking the CD47 "Do Not Eat" Signal

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. It is hypothesized that direct intratumoral injection of TTI-621 may enhance both local and systemic antitumor activity.

Methods

A Phase 1, multicenter, open-label study is ongoing to characterize the safety and tolerability of intratumoral injection of TTI-621 (NCT02890368). Eligible patients (pts) are adults with relapsed or refractory mycosis fungoides/Sézary syndrome or percutaneously-accessible solid tumors who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are enrolled in sequential cohorts to receive a single intratumoral injection of TTI-621 at increasing dose levels to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Repeat TTI-621 intratumoral dosing has recently been initiated. Serial, post-injection biopsies are collected to assess the temporal impact of TTI-621 on the tumor microenvironment.

Results

Nine pts (6 M/3F, age 57-85 years) have been enrolled as of July 2017. Diagnoses include mycosis fungoides/Sézary syndrome (N=6), melanoma (N=1), leiomyosarcoma (N=1), and squamous cell carcinoma (N=1). A single intratumoral injection of 1 mg, 3 mg, or 10 mg TTI-621 has been well tolerated by all enrolled pts. The most frequently reported adverse events were fatigue in 5 pts, chills in 4 pts, and decreased appetite in 3 pts. All treatment-related AEs were Grade 1 or 2 in severity. No dose limiting toxicity has been observed to date. All 6 pts with mycosis fungoides/Sézary syndrome experienced decreases in tumor size and/or decreased circulating Sézary cells (3 of 3 pts) as determined by a decrease in a peripheral clonal T-cell populationor CD4:CD8 ratio after a single intratumoral injection of TTI-621. Responses ranged from loco-regional to systemic effects. One pt with localized refractory mycosis fungoides on the dorsum of the foot obtained a complete response of the injected lesion that is ongoing after 17+ weeks of follow up. NanoString analysis of peripheral blood and tumor tissue pre- and post-intratumoral injection of TTI-621 indicated alterations in genes associated with activation of the innate immune system and upregulation of IFN-associated genes.

Conclusions

These preliminary Phase 1 data suggest that mycosis fungoides and its leukemic variant, Sézary syndrome, are highly responsive to a single dose of TTI-621 delivered by intratumoral injection. One pt achieved a complete response of the injected lesion and 5 additional pts experienced decreases in tumor size and/or decreased circulating Sézary cells. Intratumoral injections were well tolerated by all pts. Evidence of innate immune activation was documented, consistent with the proposed function of TTI-621 as an innate immune checkpoint inhibitor.