# RP-4: Immunologic Predictors of BCG Immunotherapy for Bladder Cancer

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $343,314

## Abstract

PROJECT SUMMARY/ABSTRACT
The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is cystoscopic
resection followed by intravesical therapy with bacillus Calmette-Guérin (BCG). Outcomes for patients treated
with BCG are comparable to those of patients treated with radical cystectomy, and are superior to intravesical
chemotherapy; however, there is still a substantial risk of recurrence of bladder cancer among BCG-treated
patients. Currently, there are no reliable methods to predict an individual patient's outcome. The mechanism of
action of BCG therapy for bladder cancer remains an area of active investigation. Using the MB49 orthotopic
mouse model of BCG therapy, we have compiled data demonstrating that BCG elicits an immune response to
tumor-specific antigens. Mice cured of MB49 bladder cancer by BCG therapy were specifically resistant to a
subsequent challenge with subcutaneous MB49 tumors. This resistance was not seen in mice that received
intravesical BCG therapy in the absence of a bladder tumor. Furthermore, adoptive transfer of T-cells from
mice surviving MB49 bladder cancer after BCG therapy conferred a survival advantage to naïve mice instilled
with intravesical MB49, but there was no advantage using T-cells from mice who received intravesical BCG
therapy in the absence of a bladder tumor. These results strongly suggest that an initial inflammatory reaction
invoked by BCG results in T-cell-dependent tumor immunity and put forward the possibility that interventions to
enhance tumor-specific immunity should enhance BCG efficacy. Based on these data, we propose a model of
BCG efficacy with the following components: A) The first phase of BCG therapy involves engulfment of BCG by
tumor cells, leading to local inflammation and immune-mediated tumor cell lysis. B) Tumor cell lysis in the
context of BCG-induced inflammation primes a T-cell-dependent, neoantigen-directed immune response that
results in elimination of tumor cells in the bladder and subsequent tumor immunity. We will test the hypotheses
generated by this model to identify strategies to enhance the efficacy of BCG therapy by: 1) testing BCG
strains with enhanced capacity to infect bladder tumor cells, enhanced or impaired survival within bladder
cancer cells, or enhanced ability to induce an inflammatory response in a mouse model of bladder cancer; 2)
determining the magnitude and diversity of the BCG-induced tumor neoepitope-specific T-cell response and
testing whether neoepitope vaccination can enhance BCG-induced tumor elimination in a mouse model of
bladder cancer. We will also attempt to develop a clinically useful tool to predict an individual patient's
likelihood of therapeutic response to BCG therapy by determining whether mutational or neoantigen load
predict the therapeutic efficacy of BCG in human patients with NMIBC.

## Key facts

- **NIH application ID:** 10453636
- **Project number:** 5P50CA221745-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Michael S Glickman
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $343,314
- **Award type:** 5
- **Project period:** 2018-08-24 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453636

## Citation

> US National Institutes of Health, RePORTER application 10453636, RP-4: Immunologic Predictors of BCG Immunotherapy for Bladder Cancer (5P50CA221745-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453636. Licensed CC0.

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