# Targeting the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer with a Neoadjuvant Platform Clinical Trial

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $581,039

## Abstract

Pancreatic ductal adenocarcinomas (PDACs) are known to be immunogenically “cold” tumors. To convert
PDACs into immune checkpoint inhibitor (ICI) responsive tumors, effective immunotherapy strategies are
required at a minimum to: 1) increase antigenicity; 2) enhance effector T cell function, and 3) overcome
immunosuppressive signals in the tumor microenvironment(TME). Previously, we demonstrated that the
pancreatic cancer GVAX can inflame PDAC tumors with the formation of intratumoral tertiary lymphoid
aggregates. Immune checkpoint signals such as PD-L1/PD-1 were induced and potentially primed PDAC for ICI
treatments. The concept was subsequently tested in our neoadjuvant clinical trial study in resectable PDACs
and supported by the previous R01 award. The addition of anti-PD-1 antibody(aPD1) to GVAX counteracts a T
cell exhaustion phenotype, however, did not enhance the effector T cell (Teff) “quality” as indicated by lack of
enhanced Granzyme B+ CD8+ T cells. Nevertheless, we noticed that a subset of PDACs that have a higher level
of CD137 expression do have a higher density of granzyme B+ CD8+ T cells following treatment with GVAX and
aPD1. Second, IL8 expression in CD11b+ myeloid cells positively correlates with tumor-associated neutrophil
(TAN) and higher density of TANs is associated with shorter survival following the neoadjuvant therapy with
GVAX and aPD1. These results support testing the hypothesis that anti-CD137 agonist antibody(aCD137) and/or
anti-IL8 antibody(aIL8) enhances the Teff function and overcomes the immunosuppressive TME in PDACs.
Thus, this project will test the hypothesis that increased “quantity” and higher “quality” Teffs are induced, re-
invigorated, and activated in PDACs by the triple combination of vaccine, aPD1 antagonist, and aCD137 agonist.
To this end, a third arm with this triple combo has been added to the previous R01-funded neoadjuvant clinical
trial platform of resectable PDACs. Using a mouse model of PDAC, we will further test the hypothesis that
aCD137 agonist expands and enhances the function of neoepitope specific T cells. Next, this project will test
the hypothesis that inhibiting the trafficking of TANs will overcome the barriers to high “quantity” and high “quality”
Teffs trafficking and function in PDACs. To this end, two new arms will be added to the neoadjuvant platform
clinical trial to test the combination of aIL8 and nivolumab with and without GVAX, respectively. Specially, we
will test the hypothesis that significantly greater infiltration of CD137+PD-1+ T cells and enhanced expansion of
CD8+ T cell clones that express granzyme B are induced by the combination of nivolumab and aIL8. The findings
from this study will directly inform the rational design of an immunotherapy combination to be tested in a large
randomized clinical trial in locally advanced and metastatic PDAC patients.

## Key facts

- **NIH application ID:** 10236830
- **Project number:** 2R01CA197296-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ELIZABETH M. JAFFEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $581,039
- **Award type:** 2
- **Project period:** 2015-07-21 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236830

## Citation

> US National Institutes of Health, RePORTER application 10236830, Targeting the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer with a Neoadjuvant Platform Clinical Trial (2R01CA197296-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10236830. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*