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 abnormalities in the tumor microenvironment (TME). Specifically, many tumors, such as subsets of colorectal, breast, and pancreatic cancer, become stiff as they grow.

Effects of Tumor Stiffening

• Tumor stiffening causes compression of intratumor blood vessels.
• This compression impairs blood flow/perfusion and oxygen supply.
• Hypoperfusion reduces ICIs delivery to the tumor.
• Hypoxia induces immunosuppression, compromising immunotherapy.

Novel Therapeutic Strategy

To restore 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 repurposes 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, as 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 that offer unique advantages for delivering enzymes to normalize the TME.

Advantages of Engineered Live Biotherapeutics

• Even a small fraction of 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.

Commercialization Potential

This bacterial product has great potential for commercialization, and a plan is proposed.