Paul’s introduction: Enumeral has been sending ’round some interesting updates to several of their programs and I asked for some more detail. Below is a quick primer sent along by Cokey Nguyen. More detail is available in Enumeral’s recent 8K filings, including one that dropped this morning. Also the company will present this and other work at the AACR Tumor Microenvironment Meeting in January (http://www.aacr.org/Meetings/
New data from Enumeral, by Cokey Nguyen
PD-1 biology in human lung cancer is an active area of research, as these cancers have shown PD-1 blockade responsiveness in clinical trials. Enumeral has a drug discovery effort aimed at generating novel anti-PD-1 antibodies to develop into potential therapeutic candidates. Using a proprietary antibody discovery platform, two classes of PD-1 antagonist antibodies were discovered: the canonical anti-PD-1 antibody which blocks PD-L1/PD-1 interactions and a second class of antibody which is non-competitive with PD-L1 binding to PD-1. These antibodies were validated first in a pre-clinical model of NSCLC using NSG mice with a humanized immune system and a patient derived NSCLC xenograft (huNSG/PDX) (Figure 1). Here either class of antibody demonstrated activity on par with pembrolizumab, confirming that PD-1 blockade can slow tumor growth.
In order to confirm these pre-clinical findings, Enumeral began proof of concept studies with NSCLC samples. The first question was if resident TILs, as found in tumors, could be reinvigorated (Paukken and Wherry, 2015) or if PD-1 blockade is mainly a phenomenon that affects lymph node-specific T cells that have yet to traffic to the tumor. In these studies, Enumeral found PD-1 blockade can, in fact, increase effector T cell function, as readout by IFNg, IL-12, TNFa and IL-6. In addition, in a NSCLC sample that showed PD-1hi/TIM-3lo expression, PD-1 blockade strongly upregulated TIM-3 expression (~5% to ~30%, see Figure 2).
In these NSCLC-based studies, it was also found that an anti-PD-1 antibody (C8) which does not bind to PD-1 in the same manner as nivolumab or pembrolizumab (PD-L1 binding site) displays differentiated biology: increased IFNg production and significantly higher levels of IL-12 in these bulk (dissociated) tumor cultures (Figure 3). As IL-12 is thought to be a myeloid derived cytokine, this mechanism of action is not yet well understood, but has been now observed in multiple NSCLC samples as well as in MLR assays.
In these NSCLC studies, while a subset of patient samples demonstrates PD-1 blockade responsiveness, the co-expression of TIM-3 on NSCLC TILs suggests this is a validated path forward to increase the response rate in lung cancer. As with the PD-1 program, armed with a substantial portfolio of diverse anti-TIM-3 binders, Enumeral is actively testing single and dual checkpoint blockade on primary human lung cancer samples.
Look for the companies 2 posters at AACR/TME in January