# Project 3

> **NIH NIH P50** · MAYO CLINIC ROCHESTER · 2024 · $441,978

## Abstract

PROJECT 3 - PROJECT SUMMARY
The combination of Immune Checkpoint Blockade (ICB) with the α-PD-L1 antibody atezolizumab, and the
vascular endothelial growth factor (VEGF)-targeting antibody bevacizumab, has become the new FDA
approved Standard of Care (SOC) for advanced Hepatocellular Carcinoma (HCC). However, the 3-year
survival for this SOC is still <30%, leaving a clear unmet need for novel therapies for advanced HCC patients
who have progressed on first-line ICB therapies. Whilst the immune suppressive liver/HCC tumor
microenvironment (TME) restricts the efficacy of anti-tumor T cell responses, the pro-inflammatory nature of
oncolytic virus (OV) infection/replication offers a complementary mechanism of action to ICB by promoting
immune infiltration (immunological heat) into poorly infiltrated (cold) HCC. Our group has conducted a Phase I
first-in-human study of Vesicular Stomatitis Virus (VSV) expressing human interferon beta (hIFN-β) in patients
with advanced sorafenib refractory/intolerant HCC. To investigate how OV could best synergize with ICB to
treat HCC, murine Sleeping Beauty (SB) models of HCC were established in which α-PD-L1 ICB induced 30-
50% long term cures through re-invigoration of specific α-tumor CD8+T populations. However, a combination
of α-PD-L1 ICB with VSV-IFNß to reverse immune suppression in the TME, led to the loss of the survival
benefit of α-PD-L1 alone, associated with replacement of a diverse profile of CD8+ T cell populations in α-PD-
L1-treated tumors with a dominant population of highly activated, α-viral effector CD8+T cells. However, by
expressing an HCC tumor associated antigen (HCCTAA) from VSV, the potent α-viral effector CD8+ T cell
response also became an α-tumor T cell response –with highly activated HCCTAA effector cells becoming
focused on the tumor. In parallel studies, we showed that a novel VSV platform in which the CSDE1 protein is
co-expressed within the virus induced significantly better therapy than the parental VSV-IFNß. Finally, to
enhance infiltration of immune-excluded (cold) HCC with effector α-tumor T cells, we developed novel
nanobody-based CAR T cells specific for the TAAHCC GPC3. In others studies, we have shown that CAR T
cells loaded with oncolytic VSV 1). mediate tumor-specific virus delivery and 2). are significantly more
therapeutically potent than conventional, non-loaded CAR T cells. Therefore, to test our overall hypothesis
that the highly immune suppressive HCC TME, which inhibits endogenous α-HCC T cell responses, can be
reversed in the setting of SOC therapies by administration of appropriately timed and optimally delivered
viro/cellular/immunotherapy, we have formulated 3 Specific Aims: 1: To test how appropriately timed VSV-
CSDE1-TAAHCC virotherapy can optimally enhance SOC immunotherapy in SB models of HCC; 2: To combine
CAR T cell/VSV virotherapy to enhance SOC immunotherapy in murine and human xenograft models of HCC;
and 3: To test the safety of adjuvant VSV-CSDE1-GPC...

## Key facts

- **NIH application ID:** 10935707
- **Project number:** 2P50CA210964-06A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Richard G. Vile
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,978
- **Award type:** 2
- **Project period:** 2018-09-10 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935707

## Citation

> US National Institutes of Health, RePORTER application 10935707, Project 3 (2P50CA210964-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10935707. Licensed CC0.

---

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