AACR 2024 Posters: Sneak Peek

AACR 2024 Sneak Peek | Your All-In-One Guide to WuXi Biology’s Latest Advances in Cancer Research

The American Association for Cancer Research (AACR) Annual Meeting 2024, one of the largest global cancer research conferences, will take place from April 5 to 10 at the San Diego Convention Center. This year, WuXi Biology has been selected to present eight posters detailing its latest scientific insights in cancer research.

Eager to stay ahead of the curve? This article gives you a one-stop sneak peek into the advances that WuXi Biology will be showcasing at AACR 2024.

01 Poster #542 Development of Novel Syngeneic Tumor Models with Intrinsic or Extrinsic Resistance Mechanisms to PD-1 Blockade

Highlights: PD-1/PD-L1 blockade has demonstrated remarkable clinical efficacy across various tumor types. However, due to primary and acquired resistance, a substantial proportion of patients remain unresponsive to these treatments. To better understand the underlying mechanisms of resistance to immunotherapy and evaluate novel strategies for overcoming this resistance, we developed two types of anti-PD-1 antibody-resistant models based on the intrinsically PD-1 sensitive MC38 tumor models. We investigated the alterations in immune cells and differentially expressed genes within the tumor microenvironment in these models. This study enhances understanding of the biological basis of anti-PD-1 resistance and supports the discovery of mechanistically designed combination therapies to overcome resistance to anti-PD-1 therapy.

Session Date and Time: April 7, 2024, 1:30 PM-5:00 PM

Location: Experimental and Molecular Therapeutics-Drug Resistance 1: Models, Poster Section 22

02 Poster #1946 Elucidating the Mechanisms of Acquired Resistance to AMG510 in Cancer Models Harboring KRAS G12C Mutations

Highlights: AMG510, as the first KRAS-targeted drug approved for medical use, represents a breakthrough in addressing a previously ‘undruggable’ cancer target. This marks a significant milestone in the advancement of anti-cancer therapeutics. Despite the significant therapeutic effects observed with this drug AMG510 monotherapy eventually leads to resistance. Therefore, exploring the underlying mechanism of this resistance could guide the development of new and novel therapies.

In this study, our team generated AMG510-resistant tumor models, designated AMG510-R-MIA PaCa-2 and AMG510-R CT26 KRAS G12C. Compared with the parent MIA PaCa-2 cells, the resistant MIA PaCa-2 cells exhibited an abnormal activation of the RAS pathway, evidenced by a marked increase in KRAS and pERK protein expression. In parallel, we observed a significant increase in the secretion of chemokines CXCL2/3/5 in resistant tumors. Furthermore, resistance altered the tumor’s immune microenvironment. The resistant MIA PaCa-2 and CT26 KRAS G12C tumors were highly enriched in immunosuppressive cells such as MDSC and M2 macrophages.

In summary, the exploration of the resistance mechanism in AMG510-induced resistant models provides insights into the development of therapeutic strategies to overcome drug resistance.

Session Date and Time: April 8, 2024, 9:00 AM-12:30 PM

Location: Experimental and Molecular Therapeutic—Drug Resistance 2: Ras GTPase, Poster Section 24

03 Poster #2833: Validating Cancer Biomarker Expression on Mouse Cell-Derived Xenograft Models of Human Cancer

Highlights: The level of target antigen expression is critical for the potency of immune therapies such as ADCs, mRNA-LNPs, and CAR-T cells. However, selecting an appropriate cancer model for pre-clinical drug testing remains a challenge. We provide more than 1000 cell lines and 150 CDX mouse models for human cancers. Furthermore, we have validated the expression of three therapeutic targets, Nectin-4, Trop2, and PD-L1, in various CDX tumor tissues. This poster will highlight some recently established models as well as the antigen validation results. Our study serves as a reference for model selection in efficacy studies targeting Nectin-4, Trop2, or PD-L1. In addition, we offer a platform to validate the expression of target antigens in CDX mouse models across numerous cancer types.

Session Date and Time: April 8, 2024, 1:30 PM-5:00 PM

Location: Tumor Biology—Modeling Cancer in Mice, Poster Section 10

04 Poster #3257 Unleashing Immune Power: How mRNA-Encoded Modulators Suppress Tumor Growth

Highlights: Subsequent to the emergence of the COVID-19 pandemic, an increased number of nucleic acid-based therapeutics have secured clinical endorsement. Unlike conventional protein-targeted therapies, nucleic acid therapeutics provide the potential for long-lasting effects and can be further categorized into oligonucleotides, single-guide RNA (sgRNA), and messenger RNA (mRNA). In this study, we conducted in vivo and in vitro biological activity assays on mRNA encoding bispecific antibodies and cytokines.

We first designed an mRNA-encoded CD3-EpCAM bispecific antibody (BsAb) and verified in vitro that mRNA-encoded IL-12 can promote the activation of human T cells in PBMCs and the killing of tumor cells highly expressing the EpCAM protein. Subsequently, we subcutaneously inoculated tumors into humanized mice with PBMCs. Both intratumoral and intravenous administration of mRNA-LNP into tumor-bearing mice significantly inhibited tumor growth, and no notable side effects were observed.

Additionally, we designed an mRNA-encoded IL-12 and used synthesized and encapsulated mRNA-LNP to verify in vitro that it can promote the activation of NK cells in PBMCs and the killing of tumor cells. Subsequently, we subcutaneously inoculated tumors into humanized HSC mice, and intratumoral administration of mRNA-LNP in tumor-bearing mice exhibited significant inhibitory effects on tumor growth in vivo while maintaining a favorable safety profile. Our findings provide compelling evidence that mRNA therapeutics hold significant research value and can exhibit promising potential for clinical applications.

Session Date and Time: April 8, 2024, 1:30 PM-5:00 PM

Location: Experimental and Molecular Therapeutics—Immune Modulators and Antisense Molecules, Poster Section 25 

05 Poster# 4138: Evaluation of Breast Triple-Negative 4T1-Derived Tumor Metastatic Development in Gender-Different Mouse

Highlights: Breast cancer in men is rare and less studied, with therapeutic strategies largely based on clinical treatment protocols for women. To support these strategies, researchers at Dr. Martin-Martinez’s lab found no differences in the timing of orthotopic mammary fat pad tumor development, necrosis, or tumor tissue color change between male and female mice. However, clinical treatment outcomes, especially regarding tumor metastasis, differ between men and women, and current breast cancer models are inadequate due to the lack of metastases. Despite similar primary breast tumor development in both genders, mouse sex influenced the timing of tumor metastasis when tumor cells were introduced via the caudal artery. Male mice demonstrated earlier femoral head metastasis and less lung metastasis than female mice. Sex hormones may influence not only hormone-related tumor metastasis but also non-hormone-related tumor metastasis. To investigate whether this phenomenon is due to estrogen or androgen influences, and to test potential therapeutic benefits, we provide established tumor metastasis models and over 1000 cancer cell lines for target validation and drug efficacy studies.

Session Date and Time: Apr 9, 2024, 9:00 AM-12:30 PM

Location: Tumor Biology-Detection, Treatment, and Prevention of Metastasis, Poster Section 7

06 Poster# 5871 Unveiling Mechanisms of CDK4/6 Inhibitor Resistance in ER+ Breast Cancer Models with Acquired Resistance

Highlights: This study aims to reveal the mechanisms of resistance to cell cycle-dependent kinase 4 and 6 (CDK4/6) inhibitors in estrogen receptor-positive (ER+) breast cancer. In developing resistance models for palbociclib, ribociclib, and abemaciclib, it was observed that the genes FAT1, CCNE1, and AR are highly expressed in all the models. The results suggest that the upregulation of these genes may be key factors mediating resistance to CDK4/6 inhibitors. The findings of this study not only elucidate the shared mechanisms of resistance to CDK4/6 inhibitors but also provide potential therapeutic targets for overcoming resistance, offering a new direction for breast cancer treatment.

Session Date and Time: April 9, 2024, 1:30 PM-5:00 PM

Location: Experimental and Molecular Therapeutics, Mechanisms of Drug Resistance 3, Poster Section 24

07 Poster #6335 Armoring CAR-T Therapy with PD-1 Blockade: A Powerful Strategy for Enhancing Anti-Tumor Effects in Pancreatic Cancer

Highlights: Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated significant therapeutic efficacy in the treatment of hematological malignancies. However, the effectiveness of CAR-T in treating solid tumors remains unsatisfactory. A well-studied mechanism is the regulation of T cells into an immunosuppressive state by tumors through the PD-L1/PD-1 immune checkpoint. In this study, our team designed a membrane-bound PD-1 blocking protein (aMSLN-28BBZ-mPD-1 CAR) for mesothelin-targeting CAR-T cells. This protein, which can anchor to the cell membrane and specifically bind to PD-1, acts as a blockade for T cell PD-1 by blocking the interaction between PD-L1 and PD-1. Compared to the conventional aMSLN-28BBZ CAR-T, the aMSLN-28BBZ-mPD-1 CAR-T exhibited prolonged cytotoxic activity in vitro. In in vivo experiments, immunofluorescence assays of tumor tissues showed an upregulation of PD-L1 expression and enhanced CAR-T cell infiltration in the aMSLN-28BBZ-mPD-1 CAR-T treatment group, demonstrating enhanced anti-tumor activity. In vitro and in vivo experimental data suggest that the membrane-bound PD-1 blocking protein designed in this study mitigates PD-L1 mediated immunosuppression of CAR-T cells. This innovative strategy underscores the therapeutic potential and value of this approach in treating solid tumors.

Session Date and Time: April 9, 2024, 1:30 PM-5:00 PM

Location: Clinical Research, Adoptive Cellular Therapy 2, Poster Section 40

08 Poster #6662: Modified Oncolytic Viruses with Immunomodulatory Genes Enhance Anti-Tumor Efficacy

Highlights: Although chemotherapy and radiotherapy are first-line treatments for most cancers, they often have significant side effects including toxicity and poor targeting. Oncolytic viruses (OVs), which selectively target and kill tumor cells, replicate specifically and induce anti-cancer immunity. In this study, we evaluated the anti-tumor pharmacodynamics of an oncolytic virus carrying several immunomodulatory factors both in vitro and in vivo. In vitro studies showed that this oncolytic virus could promote the activation of T cells, NK cells, and MoDCs, and increase the secretion of IFN-γ and IL-2 cytokines. Bio-distribution assay showed that 24 hours after administration, the virus was highly expressed in tumors, muscles, lymph nodes, colon, bladder, brain, and lungs, and gradually decreased over time. In vivo pharmacodynamic studies demonstrated that the oncolytic virus could activate CD3+, CD4+, and CD8+ T cells in mice, resulting in tumor growth inhibition.

Session Date and Time: April 10, 2024, 9:00 AM-12:30 PM

Location: Immunology, Immune Modulation by Viruses, Bacteria, Radiation, and Other Modalities, Poster Section 1