Live biotherapeutics to potentiate cancer immunotherapy

Introduction

Immunotherapy, including immune checkpoint inhibitors (ICIs), has revolutionized the treatment of multiple cancers. Anti-tumor responses are often durable, but overall, only a subset of patients receiving ICIs has exhibited sustained tumor shrinkage. Conversely, a substantial fraction of patients receiving these therapies develops immune-related adverse events.

Challenges in Immunotherapy

The absence of dramatic responses is attributed to several factors, including:

1. Abnormalities in the tumor microenvironment (TME).
2. Tumor stiffening, which occurs in many tumors such as subsets of colorectal, breast, and pancreatic cancer.

Impact of Tumor Stiffening

Tumor stiffening causes compression of intratumor blood vessels, impairing blood flow/perfusion and oxygen supply. This hypoperfusion reduces ICIs delivery to the tumor, while hypoxia induces immunosuppression, compromising the effectiveness of immunotherapy.

Novel Therapeutic Strategy

To address these abnormalities, a novel therapeutic strategy to normalize tumor stiffness prior to ICIs has been tested in preclinical studies and in the clinic. This strategy involves repurposing clinically approved drugs to target the factors contributing to tumor stiffening, leading to a new class of therapeutics known as mechanotherapeutics.

Limitations of Drug Repurposing

However, drug repurposing poses certain limitations. Adding a new drug to the treatment regimen of patients with cancer is not feasible in many cases.

Proposed Alternative Approach

As an alternative to these approaches, we propose to test the ability of engineered live biotherapeutics in the form of programmable bacteria. These bacteria offer unique advantages for delivering enzymes to normalize the TME.

Advantages of Engineered Live Biotherapeutics

• Even a small fraction of the bacterial dose reaching the tumor is sufficient to colonize it.
• This allows therapeutic concentrations of tumor-remodeling enzymes to be maintained for a long period of time.

Evaluation Plan

We propose to evaluate the ability of a novel live biotherapeutic product to improve perfusion and potentiate ICIs in preclinical tumor models of colorectal and breast tumors. This bacterial product has great potential for commercialization, and a plan is proposed.