Martin and Datta et al. show that the TGFβ1 isoform plays a prominent role in the tumor microenvironment and in resistance to PD-1/PD-L1 checkpoint blockade across many human cancers. They identified the SRK-181 antibody and used it to selectively inhibit the activation of TGFβ1. In several mouse tumor models, this was sufficient to alter the tumor immune contexture and overcome resistance to PD-1 checkpoint blockade. Importantly, selective targeting of TGFβ1 circumvented cardiotoxicities that have been observed in treatment strategies that non-selectively target the TGFβ pathway.
ABSTRACT: Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-beta (TGFbeta) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFbeta signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFbeta isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFBeta1 is the most prevalent TGFbeta isoform expressed in many types of human tumors, suggesting that TGFbeta1 may be a key contributor to primary CBT resistance. To test whether selective TGFbeta1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFbeta1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFbeta1 was also effective in tumors expressing more than one TGFbeta isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8(+) T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFbeta1 activation may avoid dose-limiting toxicities previously observed with pan-TGFbeta inhibitors. These results establish a rationale for exploring selective TGFbeta1 inhibition to overcome primary resistance to CBT.
Author Info: (1) Scholar Rock, Inc., Cambridge, MA 02139, USA. (2) Scholar Rock, Inc., Cambridge, MA 02139, USA. (3) Scholar Rock, Inc., Cambridge, MA 02139, USA. (4) Scholar Rock, Inc., Cambri
Author Info: (1) Scholar Rock, Inc., Cambridge, MA 02139, USA. (2) Scholar Rock, Inc., Cambridge, MA 02139, USA. (3) Scholar Rock, Inc., Cambridge, MA 02139, USA. (4) Scholar Rock, Inc., Cambridge, MA 02139, USA. (5) Scholar Rock, Inc., Cambridge, MA 02139, USA. (6) Scholar Rock, Inc., Cambridge, MA 02139, USA. (7) Scholar Rock, Inc., Cambridge, MA 02139, USA. (8) Scholar Rock, Inc., Cambridge, MA 02139, USA. (9) Scholar Rock, Inc., Cambridge, MA 02139, USA. (10) Scholar Rock, Inc., Cambridge, MA 02139, USA. (11) Scholar Rock, Inc., Cambridge, MA 02139, USA. (12) Scholar Rock, Inc., Cambridge, MA 02139, USA. (13) Scholar Rock, Inc., Cambridge, MA 02139, USA. (14) Scholar Rock, Inc., Cambridge, MA 02139, USA. (15) Scholar Rock, Inc., Cambridge, MA 02139, USA. (16) Scholar Rock, Inc., Cambridge, MA 02139, USA. (17) Scholar Rock, Inc., Cambridge, MA 02139, USA. (18) Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (19) Scholar Rock, Inc., Cambridge, MA 02139, USA. (20) Scholar Rock, Inc., Cambridge, MA 02139, USA. (21) Scholar Rock, Inc., Cambridge, MA 02139, USA. (22) Scholar Rock, Inc., Cambridge, MA 02139, USA. thomas@scholarrock.com.
