Microbial-Based Cancer Therapy

Microbial-Based Cancer Imaging and Therapy

Microbial-based therapy is one of the oldest cancer therapy modalities, dating from the bacterial therapies of the late 19th and early 20th centuries. However, the subject is not well studied and research has yielded few effective and safe cancer treatments.

Recent scientific advances in tumor biology, microbial pathogenesis, cancer immunity, as well as new molecular tools and current scientific technologies, make it possible to revisit the old concept from new perspectives.

The National Cancer Institute Inaugural Microbial-Based Cancer Therapy Conference was held in Bethesda, Maryland, on July 11–12, 2017. This interdisciplinary forum included industry leaders, academic investigators, and regulatory officers involved in the development of microbial-based therapies for the treatment of cancer. The aim of the meeting was to discuss the potential of virus- and bacteria-based therapies to halt tumorigenesis and induce immune responses in cancers where conventional therapy is inadequate. A meeting report was published after the conference.

Following a meeting hosted by the National Cancer Institute in the summer of 2017 (‘Microbial-Based Cancer Therapy’), a white paper discussing the current state of microbial cancer therapy was published. The white paper titled “White paper on antimicrobial cancer therapy and prevention” discussed the potential, status, opportunities for microbial therapy, as well as strategies attempted to date. The authors suggest that the main areas of greatest impact are immune stimulation, control of efficacy, control of delivery and safety.

National Cancer Institute Conference on Microbial-Based Cancer Theranostics, May 25, 2022

Purpose

Microbial-based cancer theranostics is a treatment strategy that combines cancer therapeutics with cancer imaging in one multifunctional microbial agent. The purpose of this one-day NCI conference was to discuss the various aspects of the field including the biology of microbial-tumor interaction, microbial-based therapy, microbial-based imaging and diagnosis, microbial-based cancer theranostics and the potential clinical utility of this strategy.

Background

There is a clinical need to develop new cancer treatments (including oral cancer treatment) that are more targeted and effective under conditions where conventional cancer therapies are inadequate. Examples include metastatic cancer, poorly vascularized hypoxic solid tumors, immunologically “cold” tumors (that do not trigger an immune response), dormant or slowly dividing cells, tumors resistant to treatment, or islands of microinvasive tumor cells buried within normal brain tissues. An attractive characteristic of anaerobic microbial agents used for anticancer therapies is their capacity for tumor-specific targeting, and their ability to colonize the tumor, deliver a therapeutic payload to the tumor, and activate anti-tumor immunity. Microbial cancer theranostics can be used to study microbial-tumor interactions during microbial cancer therapy. They can also be used to directly monitor the therapeutic effect when they are engineered for use in various types of imaging/diagnosis modalities such as, MRI, PET, and ultrasound. Theranostics may make it possible to perform real-time, in vivo imaging of the microbial therapeutic agent in the tumor. This potentially provides immediate information about the localization of the microbial treatment agent. It enables estimation of the magnitude of the microbial colonization, its duration, and its impact on the tumor. This information may be used to facilitate timely, interactive adjustment of treatment and to improve microbial based cancer therapy. Finally, the relative ease of microbial genetic manipulation to create microorganisms that have selective tumor cytotoxicity and selective anti-cancer activation of the immune system also offers the prospect of developing relatively simple, low-cost cancer immunotherapy for global health and low resource settings.

Keynote: Jeff Hasty, University of California San Diego. Engineered bacterial population dynamics in solid tumors

SESSION 1: MICROBIAL-TUMOR INTERACTIONS AND THERAPY Chair: Neil Forbes, University of Massachusetts. Engineered Salmonella for drug delivery to solid tumors
Dan Littman, New York University. Mechanisms of gut microbiota-directed T cell differentiation programs in homeostasis and inflammation
Claudia Gravekamp, Albert Einstein College of Medicine. Tumor-targeted delivery of childhood vaccine recall antigens by attenuated Listeria as a powerful alternative to neoantigen-mediated cancer immunotherapy
Cammie Lesser, Massachusetts General Hospital, Harvard Medical School. STAMPing out Cancer
Q&A Phil Daschner, NCI, moderator

SESSION 2: MICROBIAL-BASED IMAGING AND DIAGNOSIS Chair: Guanshu Liu, Johns Hopkins School of Medicine. Molecular imaging of bacteria by their inherent CEST MRI signal
Tal Danino, Columbia University. Engineering probiotics for colorectal cancer screening and prevention
David Wilson, University of California, San Francisco. Targeting bacteria-specific metabolic pathways for infection imaging
Lacey McNally, University of Oklahoma. Bacterial-based contrast agents for monitoring disease Q&A Charles Lin, NCI, moderator

SESSION 3: MICROBIAL-BASED CANCER THERANOSTICS Chair: Robert Hoffman, AntiCancer and University of California, San Diego. Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment
Dong-Hyun Kim, Northwestern University Catheter directed local delivery of nano-functionalized C. novyi NT bacteriolytic cancer therapy
Avinoam Bar-Zion, California Institute of Technology. Acoustically triggered mechanotherapy using genetically encoded gas vesicles
Assaf A. Gilad, Michigan State University. A Remote magnetic activation of theragnostic genes for cancer therapy
Q&A Miguel Ossandon, NCI, moderator

PANEL DISCUSSION: CHALLENGES AND OPPORTUNITIES FOR MICROBIAL- BASED CANCER THERANOSTICS
Jeff Hasty, University of California San Diego
Partha Basu, WHO, International Agency for Research on Cancer
Alejandro Salicrup, NCI, Center of Global Health,
Miguel Ossandon, NCI

Contact

Avraham Rasooly
Email: rasoolya@mail.nih.gov

NCI Fecal Microbiota Transplants and Defined-microbiota Consortia Cancer Therapeutics

Background

The gut microbiota is a complex ecosystem of microorganisms located in the human gastrointestinal tract. This microbial community is made up of mostly bacteria, but also viruses, fungi, and archaea. These microorganisms impact host physiology, metabolism, and vulnerable function. [1] They play a vital part in maintaining gut barrier integrity and regulating vulnerable responses. They have an impact on immune system development and function. [2] Dysbiosis, an imbalance in this microbial community, is linked to conditions such as metabolic disorders, autoimmune diseases, and cancers. Key genera, including Enterococcus, Ruminococcus, and Bacteroides, are essential for immune regulation and metabolic health. Microbiota-based therapies, including probiotics and fecal microbiota transplantation, offer the potential to restore balance and improve health outcomes. [3]

Cancer initiation and progression have been linked with specific microbial taxa and their metabolites. For example, in colorectal cancer, mechanisms involving inflammation, genotoxicity, and modulation of tumor microenvironment have been identified. [4] Certain bacterial species have been found to promote colorectal cancer by producing toxins that damage DNA or by inducing chronic inflammation. [5] Other microbes may have protective effects that enhance immune surveillance and inhibit tumor growth. The efficacy and toxicity of cancer treatments can be affected by Gut microbiota. [6] Personalized modulation of the gut microbiome could be a strategy for improving cancer treatment outcomes and reducing side effects. [7]

A 2016 NCI workshop titled "State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research" and the recent upsurge in the field of gut microbiota research suggest that the microbiome plays a role in cancer therapeutic outcomes. These therapeutics include anti-PD-1 immunotherapy. NCI convened a "Strategic Workshop on Rigor and Reproducibility: Precision Fecal Microbiota Transplant and Microbiome Cancer Therapeutics" on September 5, 2019. The following are the highlights and future research opportunities:

Human and mouse preliminary data demonstrated possible immunotherapy benefits from Fecal Microbiota Transplant (FMT) from anti-PD1 responders to some non-responders.
In mice, a fiber-rich diet improved anti-PD-1 immunotherapy, and an association was observed in humans along with improvement in gut microbiome diversity.
A collaboration with the FMT national registry was suggested to include cancer patients for long-term safety and outcome follow up.
Coordinated, collaborative, multi-center cancer therapeutic FMT clinical trials were endorsed.
A network to develop a Human Cancer Immunotherapy Fecal Microbiome Atlas or Biobank was proposed.

NIH funded research titled “Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients” was published in 2021 (Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients - PMC).

In October 2022, Dr. Giorgio Trinchieri, NCI, presented at the Microbiome Targeted Clinical Research Seminar Series.

Contact

Dan Xi
Email: xida@mail.nih.gov