P302 - Combination Chemotherapy And Immune Checkpoint Blocker Treatment Response In MSS/MSI Colorectal Cancer Using A Humanized Murine Model

Monday, May 12, 2025

4:01 PM – 4:09 PM PT

Location: San Diego Convention Center, Ballroom 6B, Upper Level

Abstract Podium Presenter(s)

Koby Herman, MD

Research Fellow
Ochsner Medical Center
New Orleans, LA, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no financial relationships with ineligible companies.

Author(s)

XZ

Xin Zhang, MD, PhD

Staff Scientist
Ochsner Medical Center
Metairie, Louisiana, United States

Disclosure information not submitted.
GM

Grace A. Maresh, PhD

Research Manager
Ochsner Health
New Orleans, Louisiana, United States

Disclosure information not submitted.
Cyrena Lam, MD (she/her/hers)

Surgeon
Ochsner Medical Center
New York City, New York, United States

Disclosure information not submitted.
CB

Chad Becnel, MD

General Surgery Resident
Ochsner Medical Center
New Orleans, Louisiana, United States

Disclosure information not submitted.
CZ

Chase Zibilich, BS

Sr. Clinical Research Coordinator
Ochsner Medical Center
Metairie, Louisiana, United States

Disclosure information not submitted.
HG

Heather Green, MS

Research Coordinator
Ochsner Medical Center
New Orleans, Louisiana, United States

Disclosure information not submitted.
LL

Li Li, MD, PhD

Principal Investigator
Ochsner Medical Center
New Orleans, Louisiana, United States

Disclosure information not submitted.

Senior Author(s)

Jennifer L. Paruch, MD (she/her/hers)

Surgeon, Principal Investigator
Ochsner Medical Center
Ochsner Medical Center
New Orleans, Louisiana, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no relevant relationships with ineligible companies.

All of the relevant financial relationships listed below have been mitigated.

Koby Herman, MD: This individual has no financial relationships with ineligible companies.

Jennifer L. Paruch, MD: This individual has no relevant relationships with ineligible companies.

Image or Table (Do Not add text here):

Purpose/Background: Most colorectal cancer (CRC) is microsatellite stable (MSS), however microsatellite unstable (MSI) CRC is a subset with important clinical and pathologic characteristics that impacts treatment options. MSI-CRC responds well to immune checkpoint inhibitors (ICB), particularly to anti-PD1/PDL1 treatment. We hypothesized that chemotherapy may sensitize MSS CRC to ICB treatment and potentiates ICB response for MSI CRC. We tested 5FU + ICB combination therapy in MSI-CRC and MSS-CRC patient tumors using our established humanized patient-derived orthotopic xenograft (PDOX) mouse model.

Methods/Interventions: MSI or MSS-CRC tumor cells were injected intrarectally into immunodeficient Rag2 mice. After tumor formation, mice received intraperitoneal infusion of healthy donor peripheral blood mononuclear cells (PBMCs) to establish the humanized immune system. Mice then received either no treatment (control), ICB, 5FU, or combination therapy weekly for 3-4 weeks. After sacrifice, tumor weight was recorded and blood was collected to confirm humanization and evaluate T-cell profile by fluorescence-activated cell sorting (FACS) analysis. OPAL Multiplex staining of human EpCAM, cytokeratin, Ki67 and CD8 was performed on tumor sections to assess tumor and tumor-infiltrating T-cells. Statistical analysis between groups was performed by unpaired T-tests. A p-value of < 0.05 was considered to be significant.

Results/Outcomes: 5FU inhibited tumor growth in both MSS(p=0.08) and MSI (p=0.03) tumors as compared to the control group. ICB alone inhibited MSI tumor growth (p= < 0.0001), but not in MSS tumors (p=0.806). Combination therapy significantly inhibited tumor growth in both MSS (p=0.003) and MSI (p= < 0.0001) tumors . All mice included in the study achieved humanization as confirmed by percentage of human CD45+ cells in murine blood by FACS. Circulating CD8+ T cells were significantly reduced by 5FU in MSI tumors (p=0.003). The ICB in the combination group rescued the circulating CD8+ T cells reduced by 5FU (p=0.01). In addition, significantly less Ki67+ proliferating cells were found in the ICB (p=0.006) and combination (p=0.006) groups as compared to the control in MSI tumors.

Conclusion/Discussion: MSS and MSI tumors have distinct responses to 5FU-based chemotherapy and ICB treatment in our humanized PDOX mouse model. ICB alone inhibited tumor growth in MSI but not MSS CRC tumor. ICB may also sensitize 5FU-based chemotherapy in both MSI and MSS-CRC. Ongoing studies utilizing our humanized mouse model are needed to further characterize the response of MSS- or MSI-CRC to anti-PD1/PDL1 therapy and other ICB treatments in combination with chemotherapies.