Background: Immune checkpoint blockade (ICB) has therapeutic benefit in several human cancers, but in many patients, ICB - induced T cells do not infiltrate tumors, preventing clinical benefit. Intratumoral T cell accumulation requires firm adhesion mediated by the integrins very late antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1) on activated T cells. The integrin class of cell adhesion receptors also play critical roles in multiple phases of tumor immune responses. Blocking the LFA-1 interaction with its ligand Intercellular adhesion molecule 1 (ICAM-1) abrogates CD8+ tumor infiltration after anti-CTLA4 therapy. Here, we evaluated the effect of an integrin activator, 7HP349, on promoting intratumoral T cell accumulation to potentiate CTLA-4 and PD-L1 checkpoint blockade anti-tumor activity.
Experimental Procedure: To evaluate the effect of 7HP349 in promoting ICB therapeutic activity, we combined 7HP349 with anti-CTLA-4 or anti-PD-L1 antibodies in preclinical murine models for melanoma and colon carcinoma.
Results: In cell adhesion assays, 7HP349 increased by >100-fold the number of VLA-4 or LFA-1 expressing T cells that bind to vascular cell adhesion molecule 1 (VCAM-1) and ICAM-1, respectively. 7HP349 facilitated chemo-attraction of T cells across matrices of VCAM-1 or ICAM-1, induced by the chemokine SDF-1α. In a PDL-1 negative B16/BL6 melanoma model, 7HP349 was dosed twice weekly at 1 mg/Kg intratumorally either alone as a single agent compared to vehicle control (13% vs 0%, p<0.01) or in combination with anti-CTLA-4 (44% vs 21%, p<0.01). After intraperitoneal administration, 7HP349 increased the complete response in combinations with anti-CTLA-4 (77% vs 27%, p<0.01). In addition, 7HP349 increased median survival in mice with CT-26 colon cancer when dosed either as a single agent versus control (21 vs 15 days, P<0.0012) or in combination with anti-PD-L1 (24 vs 21 days, P<0.02). 7HP349 may also increase the effectiveness of anti-CD137 without increasing liver toxicity. Levels of CD8 effector T cells (Teff) detected in tumor were significantly higher in mice treated with anti-CTLA-4 and 7HP349 than anti-CTLA-4 and vehicle. Some of these Teff showed specificity to p15E, an endogenous retroviral epitope expressed on B16. Mice treated with anti-CTLA-4 and 7HP349 showed increased depigmentation (vitiligo) suggesting immunity to melanocyte differentiation antigens.
Conclusion: 7HP349 described here represents a first-in-concept agent that positively regulate VLA-4 and LFA-1 function. Activation of integrin cell adhesion molecules with 7HP349 is a promising approach to enhance the anti-cancer activity of checkpoint blockade therapy with antibodies against CTLA-4 and PD-(L)1.
Citation Format: Yared Hailemichael, Peter Vanderslice, Robert V. Market, Ronald J. Biediger, Darren G. Woodside, Upendra K. Marathi, Willem W. Overwijk. Potentiating immune checkpoint blockade therapeutic efficacy using a small molecule activator of integrin cell adhesion receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5010.