# Engineering immunotherapeutic probiotics to mitigate irAE

> **NIH NIH U01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2020 · $586,329

## Abstract

PROJECT SUMMARY/ABSTRACT
In recent years, the field of cancer immunotherapy has seen a renaissance – with the use of monoclonal
antibodies that target immune checkpoints to activate anticancer immune responses demonstrating unparalleled
clinical success. Several of these therapies have now gained FDA approval and are part of routine treatment
regimens for several malignancies. Despite the overall success of immunotherapeutic regimens, existing
modalities present complications that current research efforts seek to overcome: (1) systemic delivery of
checkpoint blockade monoclonal antibodies lead to diverse and unpredictable immune-related adverse events
(irAE), (2) boosting responses from the endogenous antitumor repertoire often relies on the existence of pre-
primed antitumor T cells, which in the case of highly immunosuppressive tumors or those with low mutational
burden may be extremely rare, and (3) attempts to combine immunotherapies to additively boost T cell responses
demonstrate increased on-target, off-tumor toxicity. Thus, to circumvent toxicity and immunosuppression,
contemporary strategies focus on developing methods to deliver potent immunostimulants directly into a tumor,
locally priming antitumor T cells to attack disseminated metastases exhibiting a similar antigenic profile. Bridging
these observations, the goals of this proposal are to engineer probiotic strains of bacteria that selectively colonize
colorectal cancer (CRC) and locally release immune checkpoint blockade. We hypothesize that this approach
will result in more robust and diversified antitumor T cell immunity and promote the clearance of colonized
primary and metastatic colorectal cancer lesions and systemically growing CRC-derived foci. The primary
innovations of this proposal are in engineering probiotics as an immunotherapeutic delivery vector to locally
release high-dose immune checkpoint blockade. Specifically, the proposed system has several advantages over
current therapeutic strategies, including: (1) tumor-specific production of immunotherapies and LPS adjuvant,
(2) bacteria lysis, leading to effective release of novel immunotherapeutics and LPS, (3) local delivery of novel
immunotherapeutics that are toxic to deliver systemically, and (4) oral delivery of probiotics that selectively
colonize CRC metastases. This work seeks to shift current research and clinical practice paradigms to overcome
current limitations of immunotherapies, by providing a unique vehicle to locally deliver immunotherapies that
stimulate antitumor immunity while preventing systemic toxicity and mitigating irAE.

## Key facts

- **NIH application ID:** 9921971
- **Project number:** 1U01CA247573-01
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Nicholas Arpaia
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,329
- **Award type:** 1
- **Project period:** 2020-01-21 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921971

## Citation

> US National Institutes of Health, RePORTER application 9921971, Engineering immunotherapeutic probiotics to mitigate irAE (1U01CA247573-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9921971. Licensed CC0.

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