Food-Grade Bacterium as a Vehicle for Targeted Delivery of Immunotherapeutic Molecules into Colorectal Cancer
Abstract
This proposal targets the Peer Reviewed Cancer Research Program Topic Area of colorectal cancer (CRC). Globally, CRC is the third most diagnosed cancer and the second most deadly. Options for cancer treatment are rapidly developing, particularly in the realm of immunotherapy. For example, there is currently much excitement about immune checkpoint inhibitors (ICIs), which stop cancer’s interference with the immune system by putting brakes on cancer cell activity. Patients with melanoma or lung cancer have responded remarkably well to ICI treatment. Unfortunately, ICI immunotherapy is much less effective for patients with CRC. Our objective is to develop a highly effective and less toxic immunotherapy for CRC, based on two major approaches: (1) A new combination of treatment molecules (IL-12 and 4-1BBL) that provides co-stimulation to enhance the anti-tumor immune response of a currently used ICI drug, anti-PD-1. (2) Use of a food-grade lactic acid bacteria called Lactococcus lactis (L. lactis) to deliver the co-stimulatory combination treatment while reducing therapy-associated toxicity. We will genetically engineer L. lactis to express IL-12 and co-stimulatory molecule 4-1BBL with anti-PD-1 delivery. There is major potential benefit from the addition of IL-12 and 4-1BBL, because these molecules stimulate key components of immune system against cancer. Using L. lactis to deliver IL-12 and 4-1BBL with an ICI (anti PD-1) will create a superior anti-tumor immune response that prevents CRC recurrence, lowers the effective ICI dose, and thus lowers therapy-induced toxicity. Our new approach could benefit patients with CRC who are resistant to established ICIs and could also help patients by eliminating toxicity and addressing the exceedingly high cost of ICIs. To make immunotherapy more successful for patients with CRC, we must improve tumor-targeting and tumor- specific uptake. With this in mind, we will target tumor hypoxia, a common characteristic of solid tumors. Hypoxia refers to low levels of oxygen at the tumor site, which causes resistance to chemo- and immunotherapy. Remarkably, L. lactis is part of a group of bacteria that target and reproduce in hypoxic sites. We will exploit this unique feature of L. lactis to improve CRC tumor-targeting. L. lactis also has many other features that make it a desirable delivery vehicle, including: (1) It can penetrate difficult-to-reach tissue regions because it is self-propelled. (2) It is relatively easy to genetically engineer. (3) It is a probiotic bacteria used in the dairy industry that is generally recognized as safe (GRAS). (4) It is already under research for delivery of therapy molecules for infectious or gastrointestinal diseases as well as allergies. Further, L. lactis has no risk of reverting to a dangerous pathogenic strain or causing harmful reactions in immunocompromised patients, unlike other bacteria that have been modified for cancer therapy. In fact, some L. lactis by-products prevent cancer cell growth. This project addresses the Overarching Challenge of transforming cancer treatment through the improvement of immunotherapy and elimination of the risks of therapy-associated toxicity. This strategy could advance cancer research by providing evidence to support use of food-grade bacteria to target other cancers with marked hypoxia, including breast cancer and melanoma. This study may also provide supporting rationale for continued exploration of combinatorial approaches, such as combining L. lactis with chemotherapy. Filling the gap in treatment for CRC is highly relevant to the Military Health Focus Areas of Environmental exposure risk factors associated with cancer and Mission Readiness. Active-duty Service Members are at greater risk of increased exposure to chemicals and environmental carcinogens. Environmental factors such as exposure to carcinogens during active duty, infectious agents, antibiotic administration, high-fat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210295
Entities
People
- Jorge G Gomez-Gutierrez
Organizations
- Curators of the University of Missouri
- United States Army