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 NCI's Inaugural Microbial-Based Cancer Therapy Conference was held in Bethesda, MD, 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.
In addition, following the meeting, a white paper discussing the current state of microbial cancer therapy was published, which 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 and 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
Dr. Avraham Rasooly (rasoolya@mail.nih.gov)
NCI Fecal Microbiota Transplants and Defined-Microbial Consortia Cancer and Other Chronic Diseases Clinical Research and Working Group
Workshops
The microbiome is increasingly recognized as a key contributor to cancer therapeutic outcomes, particularly in patients receiving anti-PD-1 immunotherapy (Gopalakrishnan et al., Science, Matson et al., Science, Xi et al., J Natl Cancer Inst Monogr). Preliminary clinical trial reports in 2019 suggested that fecal microbiota transplantation (FMT)—an investigational agent under FDA oversight—may enhance immunotherapy response in some melanoma patients who initially did not respond to checkpoint inhibitors (NCT03341143, NCT03353402).
To investigate the potential role and mechanisms of FMT and pre/probiotics in cancer therapy, and to address challenges related to scientific rigor, reproducibility, standardization, regulatory oversight, knowledge gaps, and patient safety, NCI convened its first Strategic Workshop on Rigor and Reproducibility: Precision Fecal Microbiota Transplant and Microbiome Cancer Therapeutics on September 5, 2019. The meeting brought together leading scientists and FDA regulatory staff in areas including FMT, pre/probiotics, nutrition, the microbiome, synthetic biology, biomarkers, computational biology, immunology, gastroenterology, oncology, and infectious disease.
Key discussion highlights included:
- Preliminary human and mouse data indicated that FMT from anti-PD-1 responders may improve immunotherapy outcomes in some non-responders.
- In mouse models, fiber-rich diets enhanced anti-PD-1 immunotherapy efficacy. Similar associations were observed in humans, including improvements in gut microbiome diversity.
- A collaboration with the national FMT registry was recommended to include cancer patients for long-term safety and outcomes tracking.
- Coordinated, collaborative, multi-center FMT clinical trials in cancer therapy were strongly endorsed.
- A network to develop Human Cancer Immunotherapy Fecal Microbiome Atlas or Biobank was proposed to support future research.
NCI hosted its second NCI/NIH Microbiome-Targeted Intervention Clinical Research Workshop virtually on March 5–6, 2024. The event highlighted scientific advances in the field, including findings from the first-in-human pilot trial in 2021 that showed fecal microbiota transplantation (FMT) improved response to immune checkpoint inhibitors in melanoma patients. This study, funded by NCI in 2018 under grant 1R01CA222203-01A1 was published by Davar et al. in Science. FDA approved Rebyota, the first microbiota-based therapy for C. difficile infection in 2022 and a second orally administered product, Vowst, in 2023.
This 2024 workshop convened national and international experts—including scientists, physician-scientists, and FDA regulatory specialists—across a range of disciplines, such as FMT, pre/probiotics, nutrition, the microbiome, epidemiology, bioinformatics, cancer biology, immunology, neuroscience, bioengineering, gastroenterology, oncology, infectious diseases, neurology, mental health and behavioral science, and drug development.
Seminars and Presentations
Dr. Giorgio Trinchieri presented at the October 2022 Microbiome Targeted Intervention Clinical Research Seminar Series, and in November 2023, the Microbiome-Targeted Intervention Cancer Network presented to the NCI BSA Meeting.
Contact
Dr. Dan Xi (xida@mail.nih.gov)