The American Association for Cancer Research (AACR) Annual Meeting is one of the largest and most prestigious cancer research conferences in the world. It’s an important forum for researchers, clinicians, industry partners and other experts in the field to share the latest advances in oncology. From population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy; the AACR Annual Meeting highlights the work of the best minds in cancer research from institutions all over the world.

Discovery Life Sciences is proud to have a strong scientific presence at AACR with expert attendees and posters that will highlight our latest research and contributions to the field. Additionally, two of Discovery’s industry partners will be presenting our collaborative projects focused on two promising biomarkers, CEACAM5 and SORT1.

As a lead-up to the conference, we are sharing our lineup of experts and scientific posters. We hope you will make time in your schedule to check them out in the poster areas and stop by our booth (#243) during AACR!

Discovery Life Sciences Posters

Single cell evaluation of intratumoral B cells across solid tumor indications

Presented by: Shawn Fahl, PhD

Date: April 16, 2023

Time: 1:30 PM – 5 PM EDT

Abstract Number: #602 – Sec 21 – Board 3

The immune system is a critical component of the tumor microenvironment (TME) capable of both tumor-promoting and tumor-eradicating functions depending on the specific immune cell subtype and their activation status. Numerous immunotherapies have been developed with T lymphocytes, the largest lymphocyte population within the TME, but recent studies have identified the critical role of intratumoral B cells in the production of tumor-reactive antibodies. To further investigate this immune cell subset, human dissociated tumor cells (DTCs) samples were used to profile intratumoral B cells frequency and subset breakdown across thirteen different solid tumor indications. Intratumoral B cells prevalence was found to be highest in cancers of the lung cancer and gastrointestinal tract (esophageal, gastric, and colorectal), and rarer in cancers of the female reproductive tract (endometrial and ovarian). Spatial transcriptomics was also used to understand the transcriptional profile and B cell repertoire of the intratumoral B cell subsets to provide a deeper understanding of their biology and to explore their spatiotemporal location within the TME. The data from these studies provides critical insight that will aid in the development of the next generation of cancer immunotherapies.

Multiplex immunofluorescence and image analysis to investigate the role of the immune contexture and fibroblast activation for tumor cell budding in colorectal cancer

Presented by: Dirk Zielinski, PhD

Date: April 16, 2023

Time: 1:30 PM – 5 PM EDT

Abstract Number: #1018 – Sec 41 – Board 28

The stratification of cancer patients has been significantly influenced in recent years by the emergence of immune oncology. Furthermore, immunophenotyping of immune cell types within the tumor microenvironment (TME) is increasingly being utilized to discover new predictive biomarkers for cancer immunotherapy as well as to identify prognostic markers that can provide mechanistic insight into invasion and epithelial-mesenchymal transition (EMT). Here, multiplexed immunofluorescence (mIF) assays using Akoya Bioscience’s Opal detection system and digital image analysis were used to study the role of the TME and fibroblast activation for tumor budding in colorectal cancer. The 6-plex mIF panel included CD4 (clone SP35), CD8 (clone C8/144B), CD68 (clone PG-M1), FoxP3 (clone SP97), PD-L1 (clone SP263) and pan-Cytokeratin (clones AE1/AE3) were used to analyze human normal tonsil control tissues and FFPE colorectal cancer specimens. FAP-alpha single-plex IHC was also used to assess the stroma reactivity surrounding the tumor cell buds. The tissue was segmented into regions of interest (with and without tumor cell budding and bud microenvironment) and additional parameters such as MSI (Microsatellite Instability) status and TNM classification were considered in the data analysis. A custom workflow developed with Visiopharm apps automated the image analysis and cellular phenotyping, which identified a broad spectrum of immune cell phenotypes, including rare double- or triple-positive subtypes, and their spatial relation to tumor cell buds within the activated stroma region. These results shed light on the complexity of the TME in colorectal cancer around tumor cell buds, and the role of the immune repertoire and stroma in tumor cell invasion into surrounding tissues.

An in vitro assay to evaluate the roles of hepatic metabolism on anticancer drug safety andefficacy

Presented by: Albert Li, PhD

Date: April 18, 2023

Time: 1:30 PM – 5 PM EDT

Abstract Number: #5338 – Sec 30 – Board 20

It is well-established that hepatic drug metabolism can significantly impact the efficacy of anticancer drugs; therefore, it is a critical parameter to evaluate during drug development. A proof-of-concept study was executed using an in vitro metabolism-dependent cytotoxicity assay (MDCA) to evaluate the roles of specific pathways on the efficacy of anticancer drugs. In the study, the MDCA assay uses a novel exogenous hepatic metabolic activation system, the permeabilized cofactor-supplemented human hepatocytes (MetMax Human Hepatocytes, MMHH), to profile the cytotoxicity of cyclophosphamide—a drug used for the treatment of renal carcinoma—towards a renal cancer cell line, HEK293 cells. It was observed that NADPH enhanced the cellular cytotoxicity, consistent with the known metabolic activation of cyclophosphamide to 4-hydroxycloophosphamide, which forms cytotoxic metabolites phosphoramide mustard and acrolein, and are responsible for its anticancer properties. L-glutathione addition was also found to attenuate cyclophosphamide cytotoxicity towards the HEK293 cells, consistent with the known roles of this cellular detoxification pathway in tumor cell resistance to chemotherapeutic agents. Learn how the in vitro MDCA assay can be an effective tool to understand the influence of hepatic drug metabolism in efficacy and safety of candidate molecules during drug development.

Characterization of a novel immunohistochemistry (IHC) assay for CEACAM5 using a commercial antibody

Discovery Presenter: Ching Leng Cheng

Date: April 17, 2023

Time: 1:30 PM – 5 PM EDT

Abstract Number: #602 – Sec 17 – Board 3

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is expressed on the surface of some tumor epithelial cells and is a potential therapeutic target for antibody-drug conjugates (ADC) in development such as tusamitamab ravtansine. A validated IHC assay is critical to provide insight into the specificity and sensitivity of an ADC drug to its target antigen, which is essential for the selection of the appropriate drug candidate and dosage. For non-small cell lung cancer (NSCLC), a fit-for-purpose validated IHC assay has been developed, which uses a proprietary CEACAM5-specific murine antibody (Sanofi clone 769) on the Dako/Agilent Autostainer Link 48 platform. Here, five commercial antibody clones were tested using this validated IHC assay to compare CEACAM5 detection to the Sanofi clone 769 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissues from Discovery Life Sciences using the Leica BOND III platform. Differences in staining pattern, intensity, and cross reactivity were observed with the five antibodies tested, but overall, the commercial antibody CI-P83-1 showed comparable staining to 769 in the IHC assay to evaluate clinical samples for non-squamous NSCLC. Further testing and validation will be needed to define the finer differences between 769 and CI-P83 but these results are promising that CI-P83 is a suitable antibody for use in the IHC assay.

Differential expression of a novel transport receptor, SORT1 (sortilin), in cancer versus healthy tissues that can be utilized for targeted delivery of anti-cancerdrugs

Discovery Presenter: Jess Dhillon, PhD

Date: April 18, 2023

Time: 9:00 AM – 12:30 PM EDT

Abstract Number: #3942 – Sec 17 – Board 30

Sortilin (SORT1), or neurotensin receptor-3, is a scavenging receptor in the Vacuolar Protein Sorting 10 protein (Vps10p) family. SORT1 is a candidate for novel drug delivery because of its involvement in the internalization and trafficking of its ligands through an endocytic process and is associated with cancer cell survival and progression. To better understand SORT1 expression, tissues from different cancer types were screened using the same immunohistochemistry (IHC) method. Nineteen cancer tissue microarrays (TMAs) containing 1394 evaluable cancer cores were analyzed. SORT1 expression in each core was scored using an H-score range of 0-300, where 0 indicated no cell staining, and 300 indicated strong staining in all cells. Additionally, 234 healthy or normal adjacent tissue cores were examined, which exhibited weak or null SORT1 staining. Moderate staining was observed in specific cell types in kidney tubules and glomeruli, colonic mucosa, splenic sinusoidal spaces in red pulp, blood vessels in smooth muscle of spleen and colon, dendritic and axonal extensions of pyramidal-type neurons in brain, and testicular seminiferous tubules. SORT1 is currently being studied as a cancer target in a first-in-human (FIH) study of a peptide-drug conjugate ( NCT04706962). These results suggest that SORT1 is highly expressed in multiple tumors and is a promising target for the delivery and internalization of cancer therapeutic agents.

The Discovery team isexcited for AACR and ready to connect. Make sure you stop by the poster sessionsand ourbooth #243.We’dlove the opportunity todiscusshow our integrated products and services can accelerate your cancer research.

For more information on theAACRmeeting, please visit the AACR website.