# Generation of tumor specific immunity in canine osteosarcoma through dendritic cell hyperactivation

> **NIH NIH U01** · TUFTS UNIVERSITY BOSTON · 2024 · $683,986

## Abstract

PROJECT SUMMARY
Despite substantial improvements in therapeutic strategies, generating robust anti-tumor immune responses in
human cancers with a lower somatic mutation burden remains a substantial challenge. Recent data indicate that
a critical player in this process, dendritic cells (DCs), fail to effectively elicit efficient and durable T cell responses
unless they have entered a unique state of hyperactivation. In this setting, DCs exhibit enhanced migration to
local lymph nodes (LNs) and sustained secretion of IL-1β, a cytokine critical for memory T cell formation. In
mouse tumor models, vaccination with whole tumor lysate plus an adjuvant consisting of the TLR 7/8 agonist
R848 (resiquimod) in combination with a unique isolated lysophosphatidylcholine (22:0 Lyso PC) promotes DC
hyperactivation, expansion of antigen specific CD8+ T cells, and robust rejection of tumors. While these findings
are encouraging and suggest that identification of specific neoantigens is not necessary to prime and expand a
pool of cytotoxic T cells (CTLs), validation and optimization of this approach necessitates the use of a model
system that more closely recapitulates human cancers with respect to immune landscape. As such, the purpose
of this proposal is to use spontaneous canine cancer, specifically osteosarcoma (OS), as a bridging
animal model to validate the utility of DC hyperactivation as a foundational element for generation of
robust anti-tumor immunity. The central hypothesis to be tested in this application is that combining
hyperactivation of DCs with WTL derived neoantigen will expand a diverse and tumor-specific population of CTLs
capable of eliminating residual microscopic metastatic OS tumor cells in dogs following primary tumor removal
(amputation). We further predict, that combining DC hyperactivation/WTL with a novel tumor microenvironment
(TME) conditioning regimen consisting of toceranib/losartan/ladarixin will enhance the objective response rate
in dogs that develop macroscopic lung metastasis. To accomplish this, we will conduct a prospective randomized
clinical trial in dogs with OS combining amputation and standard of care carboplatin chemotherapy with adjuvant
alone or adjuvant+WTL. Dogs that develop lung metastasis will then be treated with the TME conditioning
regimen in combination with adjuvant+WTL. A biobank of tissue samples and blood will be collected from dogs
enrolled in these trials including matched primary/metastatic tumors and associated LNs, whole blood, plasma,
PBMCs, cell-free DNA, and samples from the vaccine draining LNs. These will be used to perform a set of
complementary assays designed to characterize the immune microenvironment and tumor genome over the
course of relapse/resistance, credential a novel neoantigen prediction pipeline, and evaluate antigen specific T
cell responses. An outstanding team with complementary sets of expertise across clinical trials, translational
oncology, comparative genomics, and immuno-o...

## Key facts

- **NIH application ID:** 10898910
- **Project number:** 5U01CA272268-03
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Cheryl A London
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,986
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898910

## Citation

> US National Institutes of Health, RePORTER application 10898910, Generation of tumor specific immunity in canine osteosarcoma through dendritic cell hyperactivation (5U01CA272268-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10898910. Licensed CC0.

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