Highlights from Day 2
The Analysis of Tumor Microenvironments: gaining depth and granularity.
Dr. Wolf Fridman (Cordeliers Research Centre, Paris), abstract 1A10, presented tools for the analysis of cell populations in the TME of colorectal cancer (CRC) and clear cell renal cell cancers (RCC). The CRC analysis produced 4 distinct subtypes, with wildly variable cell types and pathogenic pathways supported by the dominant cell populations. The subtypes aligned with standard CRC immunohistochemcial analyses, with molecular classifications, and with prognoses. Several subtypes were readily apparent in RCC. The results provide a compelling framework for cancer classification across indications and may allow the more precise pairing of immuno- and other therapeutics in a wide variety of cancer indications.
Dr. Shimon Sakaguchi (Osaka University), abstract 1A12, elucidated distinct T regulatory subsets in tumors and applied a Treg classification scheme to CRC, an indication in which the role of Tregs has been controversial. By carefully delineating suppressive and (paradoxically) inflammatory Treg populations, diverse roles in different CRC subtypes were proposed. Notably, the inflammatory subset appeared in the context of tumor invasion by bacteria that can access the tumor interstitial space as the mucosa is breached. Importantly, anti-CCR4 mAb treatment could selectively deplete the suppressive Treg subset and restore anti-tumor immunity in their models.
Dr David Denardo (Wash U School of Medicine, St Louis), abstract 1A14, introduced the hyper-fibrotic TME that characterizes pancreatic ductal adenocarcinoma (PDAC). The TME is composed of a collagen-I rich desmoplastic stroma that houses large numbers of immunosuppressive cells, creating both physical and biological barriers to T cell entry into the tumor. Fibrosis is induced and sustained by the TGFbeta pathway, leading to hyper-activation of focal adhesion kinase (FAK). A FAK inhibitor had monotherapeutic activity in a PDAC mouse model, leading to collapse of the fibrotic architecture and loss of the immunosuppressive myeloid cell compartment. In combination, FAK inhibition was synergistic with anti-PD-1 and anti-CTLA4 in PDAC mouse model that does not respond to either therapeutic given as monotherapy.
In related TGFbeta therapeutic development, Dr Maureen O’Connor-McCourt (Formation Biologics, Montreal), abstract B058, hosted a poster on a new and novel TGFbeta TRAP protein that is selective for TGFbeta isoforms 1 and 3 (but not 2). Merck Germany has an anti-PD-L1/TGFbeta TRAP bispecific (presented a few weeks ago in Boston). This remains a very hot area.
Given the positive CAR T news from KITE yesterday, their poster on TCR technology is worth a quick mention. Lorenzo Fanchi, abstract B044, hung a poster detailing the derivation and subsequent creation of patient-specific TCRs targeting the antigens mel526, mel624, and mel888. The TCRs were challenged in vitro and in vivo (in mouse) with PDX-matched tumors and HLA-matched tumor cell lines (the HLA-typing was not disclosed). Although mouse, the TCR therapy (20 x 1oe6 cells) sustained long term survival in 2/6 animals, which was an encouraging result.