Monthly Archives: September 2016

part 2: Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival

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.

Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival

A Few Day 1 Highlights

Ton Schumacher (Netherlands Cancer Institute), abstract IA04 ,has discovered a novel regulator of PDL1 expression called PD-L1M1. PD-L1M1 associates with PD-L1 and modulates the T cell inhibitory function of PD-L1. The protein is expressed ubiquitously, so unclear if this finding has therapeutic implication.

Michael Peled and Adam Mor (NYU School of Medicine), abstract A059, had a poster on molecules that interact with the cytoplasmic tail of PD-1 using high resolution Mass Spec. Two proteins were highlighted on their poster: EFHD2 and SH2D1A. EFHD2 co-localized with PD-1 and was essential for clustering and signal transduction (thus, ablation of EFHD2 blocks PD-1 mediated inhibitory activity). SH2D1A had the opposite function as evidenced by increased PD-1 inhibitory signaling when SH2D1A was knocked down and reduced PD-1 inhibitory signaling when overexpressed. SH2D1A physically competed with SHP2 for access to the PD-1 cytoplasmic tail.

Dario Vignali (U. Pitt School of Medicine), abstract IA05, focused on several emerging immune checkpoints. The first, IL-35, was investigated using anti-IL-35 antibody in various tumor models, with very nice results (similar to anti-PD-1). I liked the neuropilin story – this is a Sema4a binding protein and was offered up as a central control node for Treg activity. NRP1 controls Treg T cell expression of IFNgamma, acting in cis and in trans (so self-regulation and neighborhood regulation). Of interest he identified subsets of melanoma and H&N cancer patients having high levels of NRP1 in the TME, so this is perhaps an actionable finding.

Susan Kaech (Yale Univ Med School), abstract 1A07, presented data showing that the PEPCK overexpression ups the anti-tumor activity of T cells in the TME, thus showing that T cells – if given the tools – can co-opt the same metabolic pathways (lactate, fatty acids) used by tumor cells in the tumor microenvironment (TME). A consequence of this metabolic checkpoint is the upregulation of PD-1 via fatty acid signaling through the PPARs, delta I think. Of interest is that the metabolic switch is supported by gross upregulation of CD36, a fatty acid active transporter, on T cells in the TME.

Greg Delgoffe (U Pitt Cancer Inst), abstract IA08, picked up this general theme, demonstrating that T cells dividing in the TME rapidly lose mitochondrial (MT) mass, and therefore their ability to metabolize glucose ( a T cells preferred energy source). This is a failure of MT biogenesis, due to the downregulation of PGC1alpha, which is required for the process. In the TME, T cell PGC1alpha expression is regulated by AKT – robust AKT signaling leads to PGC1alpha downregulation. If note, PGC1alpha transgenic T cells retain high proliferative activity, do not lose MT, and are highly active Teffector cells.