The Checkpoint Inhibitor TTI-621 (SIRPaFc) Stimulates Innate and Adaptive ImmuneResponses in Patients with Hematologic and Solid Tumor Malignancies

Introduction:• CD47 is an immune checkpoint that binds to SIRPα and delivers

a “do not eat” signal to suppress macrophage phagocytosis• Tumor cells frequently overexpress CD47 and exploit this

pathway to evade macrophage mediated phagocytosis.• TTI-621 (SIRPαFc) is an immune checkpoint inhibitor that

promotes phagocytosis of tumor cells by blocking CD47 and engaging FcRs on macrophages.

• TTI-621 may stimulate T cell responses through enhanced antigen presentation and alteration of the tumor microenvironment.

• Two Phase 1 studies are underway evaluating the safety and tolerability of TTI-621 following intravenous delivery in subjects with hematologic malignancies and select solid tumors (Study TTI-621-01, NCT02663518) and intratumoral injection in subjects with solid tumors and mycosis fungoides (Study TTI-621-02, NCT02890368).

• Here we report preliminary and ongoing pharmacodynamics assessments from these trials.

Dose Intensification Results in Increased Exposure with Stable Platelet Levels

Figure 1. A representative plot of pre-infusion platelet levels andTTI-621 trough levels in a subject with CTCL and follicularlymphoma receiving Rituximab and TTI-621.

Conclusions:• Dose intensification achieved increased TTI-621 exposure that resulted in increased CD47 receptor occupancy while maintaining

clinically acceptable pre-dose platelet levels.

• TTI-621 injections and infusions resulted in cytokine signatures characteristic of an innate immune response.

• Achievement of a complete response in a subject with multiply relapsed, treatment-refractory DLBCL was associated with a significant increase in T-cell clonality.

Lisa DS Johnson1, Stephen M Ansell2, Robert Chen3, Ian Flinn4, Michael B Maris5, Owen A O’Connor6, Alexander M Lesokhin7, John Thompson8, Oleg Akilov 9, Christiane Querfeld10, Matthew H

Taylor11, Meghan Irwin1, Tina Catalano1, Penka S Petrova1, Eric L Sievers1, Robert A Uger1

1Trillium Therapeutics Inc. Mississauga, Ontario, Canada; 2Mayo Clinic, Rochester, Minnesota, USA; 3City of Hope, Duarte, CA, USA; 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 5Colorado Blood Cancer Institute, Denver, CO, USA; 6Columbia University Medical Center, New York Presbyterian Hospital, New York City, NY, USA; 7Memorial Sloan-Kettering Cancer Center, New York City, NY, USA 8University of Washington/SCCA, Seattle,

WA, USA; 9University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 10City of Hope, Duarte, CA, USA; 11Oregon Health and Science University, Portland, OR, USA

SITC 2017P42

Materials and Methods:• TTI-621-01: Subjects with relapsed/refractory hematologic

malignancies received weekly IV infusions of TTI-621 at 0.2mg/kg as monotherapy or 0.1 mg/kg in combination with Rituximab. At the investigators’ discretion, the protocol allows dose intensification in 0.1 mg/kg increments to a maximum of 0.5 mg/kg. Serial blood draws were taken to assess receptor occupancy, cytokine/chemokine levels, T cell repertoire, and immune phenotype.

• TTI-621-02: TTI-621 was administered intratumorally starting at 1 mg/injection up to a maximum of 10 mg/injection M/W/F for two weeks to subjects with percutaneously accessible solid tumors and mycosis fungoides. Blood draws and biopsies were collected to assess the impact of TTI-621 on the tumor microenvironment.

Peripheral Cytokines are Increased Following IV Infusion of TTI-621 at Week 1 and Week 6

Figure 4. Serum cytokine levels were serially evaluated at Week 1 and Week 6 of TTI-621 systemic therapy. Baseline (Wk1), pre-infusion (Wk6) and peak values at Weeks 1 and 6 (n=18) were assessed. Peak values at Week 6 are lower than at Week 1. Statistically significant differences are indicated (* p<0.05; ** p<0.01)

TTI-621 (SIRPaFc): A Novel CD47 Blocking

Agent to Promote Innate and Adaptive Anti-Tumor Immunity

TTI-

62

1 (

ng/

mL)

A

Increase in TCR Vβ Clonality Correlates with Clinical Response in a Subject Receiving TTI-621 and RituximabA Baseline Week 4 Week 8 Week 12 B

C

Figure 3. (A) PET scans of 61 year old male with DLBCL treated with TTI-621 and Rituximab. Pseudoprogression was observed at Week 4 and Week 8 response assessments. Acomplete metabolic response was identified at Week 12 (above) and confirmed at Week 20 (data not shown). (B) Clonality of TCR Vβ sequences in the peripheral blood of thissubject at baseline, Week 4, and Week 27. Response assessments are identified as arrows (red, pseudoprogression; blue, complete response). (C) Venn diagram indicating overlap ofproductive rearrangements at baseline (green), Week 4 (pink), and Week 27 (purple).

TTI-621 Peripheral CD47 Receptor Occupancy Increases with Dose Intensification

A B

Figure 2. End of infusion peripheral receptor occupancy was measured on CD3+ T cells at each dose intensification infusion of TTI-621. (A) A subject with aggressive B cell lymphoma received Rituximab and TTI-621 combination therapy (B) Subject with AML receiving TTI-621 monotherapy.

Increased NK and IFN Signature are Associated with TTI-621 Injection

Figure 5. Nanostring analysis of peripheral blood prior to, and one week following the end of treatment, in subjects (n=12) receiving intratumoral TTI-621 suggests increased circulating NK cells and an increase in an IFN signature. NK cell score: BCL2, FUT5, NCR1, ZNF205. IFN signature: IFNg, STAT1, CCR5, CXCL9, CXCL10, CXCL11, IDO1, PRF1, GZMA, HLA-DRA)

Week 4 Week 27

Baseline