# Chemotherapy and the Bladder Cancer Immune Microenvironment

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $82,863

## Abstract

In the United States urothelial carcinoma (UC) of the bladder is the 4th most frequent malignancy in men,
with around 80,500 new cases and 17,500 deaths in 2019. Despite being the most costly cancer to treat over a
patient's lifetime, bladder cancer remains underfunded. High-grade (HG), muscle invasive bladder tumors
account for the majority of these deaths as patients with metastatic disease have a 5-year survival rate of only
15%. The current standard first line therapy for metastatic disease is cisplatin-based combination chemotherapy
or immune checkpoint inhibition in patients who are platinum ineligible. Novel immune checkpoint (IC) inhibitors,
including anti-PD1 and anti-PD-L1, represent a paradigm shift in cancer therapy in patients with advanced UC
however, only 15-25% of patients treated in published trials had objective responses to single agent IC inhibition.
 In patients with clinically localized, muscle-invasive bladder cancer (MIBC), there is a high level of
evidence to support the use of cisplatin-based neoadjuvant chemotherapy. Two widely accepted regimens with
therapeutic equipoise are MVAC (methotrexate, vincristine, adriamycin, and cisplatin) and GC
(gemcitabine/cisplatin). While trials in advanced bladder cancer therapy are evaluating the combination of
chemo and immunotherapy, to rationally combine these two therapeutic modalities it is imperative to precisely
understand how MVAC and GC impact the immune microenvironment and how to best sequence chemo and
immunotherapy.
Preliminary studies from the Kim and Vincent laboratories show that MVAC and GC have differing effects
on the immune microenvironment in bladder cancers of the luminal molecular subtype. Tumors of the luminal
subtype, which have low baseline immune infiltration have a significant increase in immune gene signature
expression and restriction of tumor-specific T cell receptor (TCR) clonotypes in the peripheral blood after MVAC
but not GC treatment. In contrast, GC significantly increases gene signatures known to promote resistance to
IC therapy in bladder cancer (Fibroblast TGFB Response Signature [FTBRS] and EMT_Stroma). These results
in aggregate suggest that in luminal bladder cancers, MVAC promotes an inflamed tumor immune
microenvironment permissive to IC inhibition, while GC increases stromal expansion, known to correlate with
immunotherapy resistance. In aggregate our preliminary data suggest that MVAC should combine better with
IC therapy than GC. Successful completion of this proposal will validate these findings in a prospective cohort
of paired pre and post MVAC or GC samples collected in the context of a randomized clinical trial (SWOG1314),
determine which specific anti-neoplastic agents alter the immune microenvironment and promote sensitivity to
immunotherapy, as well as outline how to best sequence anti-neoplastic agents and immune checkpoint
blockade in urothelial bladder cancer.

## Key facts

- **NIH application ID:** 10977321
- **Project number:** 3R01CA241810-05S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** WILLIAM Y. KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,863
- **Award type:** 3
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977321

## Citation

> US National Institutes of Health, RePORTER application 10977321, Chemotherapy and the Bladder Cancer Immune Microenvironment (3R01CA241810-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10977321. Licensed CC0.

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