Abstract 2646: Intratumoral delivery of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, inhibits tumor growth and prolongs animal survival in a subcutaneous B cell lymphoma model
Authors: Lin Gloria H. , Charbonneau Marilyse , Chai Vien , O'Connor Alison M. , Bossen Bolette , Chen Hui , Wong Mark , Viller Natasja N. , Linderoth Emma , Johnson Lisa D. , Pang Xinli , Winston Jeffery , Petrova Penka S. , Uger Robert A. 
Published: July 2017

Abstract
Tumor cells often evade macrophage-mediated destruction by increasing cell surface expression of CD47, which delivers an anti-phagocytic (“do-not-eat”) signal by binding the inhibitory signal-regulatory protein α (SIRPα) receptor on macrophages. We have previously shown that blockade of the CD47-SIRPα pathway using TTI-621, a soluble SIRPα-IgG1 Fc fusion protein, triggers macrophage phagocytosis of tumor cells in vitro as well as inhibits tumor growth in vivo when delivered systemically. In the current study, the efficacy of intratumoral delivery of TTI-621 was evaluated in a subcutaneous diffuse large B-cell lymphoma (Toledo) xenograft model.
Tumor bearing mice were randomized into treatment groups when tumor volumes reached approximately 120 mm3. Weekly intratumoral administration of TTI-621 at 10, 1 and 0.1 mg/kg dose levels resulted in statistically significant decreases in tumor growth and improved survival relative to vehicle control treatment. Notably, at day 50 post-tumor implantation 100% survival was achieved at the highest dose level (vs. 0% survival with vehicle control treatment). Moreover, weekly intratumoral administration of TTI-621 was efficacious even at a high tumor load setting in which the pre-dose volumes were approximately 300 mm3. Flow cytometry analysis of the dissociated tumor samples demonstrated no significant change in the numbers of M1 and M2 tumor-associated macrophages (TAMs) following intratumoral administration of TTI-621. Nevertheless, TTI-621 dramatically increased the phagocytosis of Toledo cells by both M1 and M2 TAMs to a similar extent ex vivo, suggesting that TTI-621 is efficacious in increasing the phagocytosis of tumor cells by a heterogeneous population of TAMs.
Collectively, these results demonstrate that TTI-621 is efficacious when delivered intratumorally and can increase the phagocytosis of tumor cells by both M1 and M2 TAM populations. These data support the evaluation of intratumoral administration of TTI-621 in cancer patients, and a Phase I study of intratumorally delivered TTI-621 in patients with percutaneously accessible solid tumors and mycosis fungoides is ongoing (NCT02890368).
Citation Format: Gloria H. Lin, Marilyse Charbonneau, Vien Chai, Alison M. O'Connor, Bolette Bossen, Hui Chen, Mark Wong, Natasja N. Viller, Emma Linderoth, Lisa D. Johnson, Xinli Pang, Jeffery Winston, Penka S. Petrova, Robert A. Uger. Intratumoral delivery of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, inhibits tumor growth and prolongs animal survival in a subcutaneous B cell lymphoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2646. doi:10.1158/1538-7445.AM2017-2646