Abstract 868: Oral SHP-1 inhibitor TPI-1a4 increases TILs in melanoma tumors and interacts positively with CTLA4 antibody for melanoma cure in mice

Abstract

Abstract SHP-1 phosphatase is a promising target for developing inhibitors as novel cancer immune therapeutics given its key role in negative regulation of immune cells. TPI-1a4 is a small molecule SHP-1 inhibitor identified recently and demonstrated activity for melanoma and colon cancer tumors in mice as a tolerated single oral agent. TPI-1a4 has been further evaluated herein for mechanism of action and potential clinical translation. Oral TPI-1a4 increased (up to 8x) in TILs in K1735 melanoma tumors in syngeneic mice in a dose-dependent manner and in correlation with tumor growth inhibition. The growth of 4-day established K1735 tumors (s.c.) in syngeneic C3H/HeJ mice was inhibited 44% (p < 0.05) by TPI-1a4 at 0.4 mg/kg (5 d/wk, gavage) or 90% (p < 0.01) at 0.8 mg/kg (5 d/wk, gavage) during a treatment period of 4 wks. Evaluation of tumor histology (H.E.) revealed increases (2x and 4x for the two treatments) of tumor-infiltrating lymphocytes (TIL). Immunohistochemistry analyses of the tumor samples demonstrate increases (∼3 and 6x) of CD45+ cells (pan-leukocytes), CD3+ cells (T lineage), B220+ cells (B/NK lineages), and Mac3+ cells (myeloid lineages). Oral TPI-1a4 interacted positively with CTLA4 antibody for survival extension and cure in K1735 melanoma tumor mice. TPI-1a4 (1 mg/kg, 5d/wk, gavage) or CTLA4 antibody (9H10, 100 ug x3, ip) as individual agents delayed tumor growth for ∼1-4 wks in C3H/HeJ mice with 4-day established K1735 tumors (s.c.). Their combination delayed tumor growth for 4-14 wks (4/5 mice) or completely blocked tumor growth (1/5 mice) by 20th wk in association with resistance to re-challenging with the melanoma tumor (s.c.). The combination was more effective in C3H/HeJ mice with 1-day established K1735 tumors, blocked tumor growth in most mice (4/5) comparing to mostly delayed tumor growth for several wks by the individual agents. TPI-1a4 in drinking water ad lib with weekly renewal was effective against the melanoma tumors in mice, suggesting chemical stability. Indeed, mass spectrometry verified structural integrity of TPI-1a4 stored as solid compound or in solvent at room temperature for 2 months. These data provide further evidences designate TPI-1a4 as a novel anti-cancer immune agent and a promising candidate for clinical translation. Our studies demonstrate for the first time the potential of TPI-1a4 to improve the clinical efficacy of CTLA4 antibody and other related cancer therapeutics. Future studies of TPI-1a4 analogs and derivatives are warranted and may lead to more refined and effective SHP-1 inhibitors and immune cell activators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 868. doi:1538-7445.AM2012-868