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| Status |
Public on Dec 13, 2025 |
| Title |
FOLFIRINOX Plus Nivolumab Promotes Irregular Intra-Tumoral Lymphoid Aggregates in Borderline Resectable Pancreatic Adenocarcinoma: A Phase 1 Trial |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Combination therapies of chemotherapy and immune checkpoint inhibitors (ICIs) have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare MSI-H cases, despite their success in other solid tumors. Most prior studies have been conducted in advanced disease. Here, we present clinical, pathologic, and translational results from a phase 1b/2 investigator-initiated study evaluating neoadjuvant modified FOLFIRINOX (mFOLFIRINOX, mFFX) plus nivolumab in patients with borderline-resectable (BR) PDAC. Among 28 patients enrolled, 22 (79%) proceeded to surgery. Treatment was well tolerated with no significant delays or surgical complications, meeting the primary endpoint. Among patients who underwent surgical resection, median disease-free survival was 19.7 months, median progression-free survival was 26 months (95% CI: 14.7-34.3) and median overall survival was 38 months (95% CI: 27.9-not reached). The regimen demonstrated an acceptable safety profile, with all Grade 3-4 treatment-related adverse events due to chemotherapy and no Grade 3 immune related adverse events observed. Treatment effects were assessed using paired pre- and post-treatment samples and by comparing post-treatment tumors from the nivolumab cohort to historical BR mFFX-only controls. In paired analyses, intra-tumoral CD8 T cells and plasma cells increased together; in between-group comparisons, plasma cells were significantly higher in the nivolumab cohort, with a modest CD8 T cell increase. Immunohistochemistry revealed that plasma cell abundance correlated with dense intra-tumoral lymphoid aggregates (LA) lacking germinal center-like morphology, a pattern consistent with extrafollicular B cell differentiation. Single-cell spatial transcriptomics identified irregular lymphoid aggregates with high plasma cell to B cell ratios (PBRs) that were enriched for terminally exhausted CD8 T cells and de-enriched for progenitor exhausted CD8 T cells and central memory CD4 T cells. Together, these findings implicate intra-tumoral LA disorganization and skewed T cell subsets as complementary features associated with limited efficacy of PD-1-based chemoimmunotherapy in PDAC. (Clinicaltrials.gov identifier: NCT03970252).
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| Overall design |
RNA-seq was performed on RNA extracted from 6 pre-treatment biopsies from patient primary pancreatic adenocarcinoma (PDAC) tumors, 21 post-treatment (FOLFIRINOX+nivolumab) primary PDAC tumors, and 9 post-treatment (FOLFIRINOX) primary PDAC tumors
*** Raw data missing for the following Samples --GSM9360958 GSM9360959 GSM9360960 GSM9360961 GSM9360962 GSM9360963 GSM9360964 GSM9360965 GSM9360966 GSM9360967 GSM9360968 GSM9360969 GSM9360970 GSM9360971 GSM9360972 GSM9360973 GSM9360974 GSM9360975 GSM9360976 GSM9360977 GSM9360990 ***
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| Contributor(s) |
Link JM, Wainberg Z, Donahue T |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Dec 09, 2025 |
| Last update date |
Jan 09, 2026 |
| Contact name |
Jason Michael Link |
| E-mail(s) |
jmlink@mednet.ucla.edu
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| Organization name |
University of California, Los Angeles
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| Department |
Surgery
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| Lab |
CHS AR-243
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| Street address |
650 Charles E Young Dr S
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (37)
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| GSM9360961 |
PostFFX, Pt_F4 |
| GSM9360962 |
PostFFX, Pt_F5 |
| GSM9360963 |
PostFFX, Pt_F9 |
| GSM9360964 |
PostFFX, Pt_F6 |
| GSM9360965 |
PostFFX+nivolumab, Pt_1 |
| GSM9360966 |
PostFFX+nivolumab, Pt_4 |
| GSM9360967 |
PostFFX+nivolumab, Pt_5 |
| GSM9360968 |
PostFFX+nivolumab, Pt_12 |
| GSM9360969 |
PostFFX+nivolumab, Pt_11 |
| GSM9360970 |
PostFFX+nivolumab, Pt_13 |
| GSM9360971 |
PostFFX+nivolumab, Pt_15 |
| GSM9360972 |
PostFFX, Pt_F1 |
| GSM9360973 |
PostFFX, Pt_F2 |
| GSM9360974 |
PostFFX, Pt_F3 |
| GSM9360975 |
PostFFX+nivolumab, Pt_3 |
| GSM9360976 |
PostFFX+nivolumab, Pt_6 |
| GSM9360977 |
PostFFX+nivolumab, Pt_9 |
| GSM9360978 |
PreFFX+nivolumab, Pt_21P |
| GSM9360979 |
PreFFX+nivolumab, Pt_6P |
| GSM9360980 |
PostFFX+nivolumab, Pt_19 |
| GSM9360981 |
PostFFX+nivolumab, Pt_14 |
| GSM9360982 |
PreFFX+nivolumab, Pt_19P |
| GSM9360983 |
PostFFX+nivolumab, Pt_10 |
| GSM9360984 |
PostFFX+nivolumab, Pt_21 |
| GSM9360985 |
PreFFX+nivolumab, Pt_12P |
| GSM9360986 |
PreFFX+nivolumab, Pt_18P |
| GSM9360987 |
PostFFX+nivolumab, Pt_16 |
| GSM9360988 |
PostFFX+nivolumab, Pt_20 |
| GSM9360989 |
PostFFX+nivolumab, Pt_27 |
| GSM9360990 |
PreFFX+nivolumab, Pt_2P |
| GSM9360991 |
PostFFX+nivolumab, Pt_24 |
| GSM9360992 |
PostFFX+nivolumab, Pt_26 |
| GSM9360993 |
PostFFX+nivolumab, Pt_22a |
| GSM9360994 |
PostFFX+nivolumab, Pt_25 |
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| Relations |
| BioProject |
PRJNA1378327 |
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