The following description was taken from the R01 version of this FOA.
The purpose of this funding opportunity announcement (FOA) is to encourage submissions of applications proposing studies of novel microbial-based cancer therapies as solutions to the problem where conventional cancer therapies are inadequate. Examples include, but are not limited to poorly vascularized, hypoxic, solid tumors, dormant or slowly dividing cells resistant to current interventions, and brain tumors. Solutions may utilize bacteria, archaebacteria, bacteriophages and other non-virus microorganisms (but not oncolytic viruses).
This initiative will support research projects on the underlying mechanisms of the complex interactions between microorganisms, tumor, and immune system, and their use as delivery vehicles for cancer treatment to complement or synergize with current therapies. This FOA will accept basic, mechanistic and/or preclinical studies in cell culture and animal models in accordance with the state of the science. Applicants applying to this FOA are encouraged to address both the microbial and the tumor aspects of microbial-based cancer therapy.
Applicants are encouraged to propose basic or applied, multidisciplinary research collaborations between investigators from areas relevant to microbial-based cancer therapy, such as microbiology, oncology, immunology, and cellular and molecular cancer biology. The proposed projects should be state of the art and aim to advance pre-clinical development of novel microbial-based anticancer therapeutic agents, or study the complex biology involved in the interplay of microbe-tumor-immune system. An application may propose design-directed, developmental, discovery-driven, or hypothesis-driven research, and should apply an integrative approach to increase our understanding of biological, or translational aspects of microbial-based anticancer therapeutic agents.
This FOA will utilize the NIH Research Project Grant (R01) mechanism and is suitable for projects where proof-of-principle of the proposed methodology has already been established and supportive preliminary data are available.
This FOA runs in parallel with an FOA of identical scientific scope, PAR-19-194, which uses the Exploratory/Developmental Grant (R21) mechanism.
Early clinical observations in the 1880s suggested that tumor regression coincided with natural bacterial infections, leading to the first use of microbes as antitumor agents. With the development of the more effective and better understood radiation therapy, and later, chemotherapy-based cancer therapies this approach was largely abandoned in the 1930s and microbial-based therapy has remained an elusive goal. However, standard cancer therapies have several major disadvantages including rarity of complete and sustained remissions of most solid tumors, development of resistance and relapse and the frequent failure to clear micrometastases.
There is a clinical need to develop new cancer therapies that will be effective under conditions where conventional cancer therapies are inadequate such as poorly vascularized, hypoxic, solid tumors; dormant or slowly dividing cells resistant to treatment; or islands of microinvasive tumor cells buried within normal tissues. Among the most attractive characteristics of microbial agents for anticancer therapies are their capacity for tumor-specific targeting as well as the ease of genetic manipulation which enables the regulation of selective cytotoxicity.
Recent research advancements in bacterial anti-cancer activities
A recently published white paper on Challenges and Opportunities of Microbial Anti-Cancer Therapy and Prevention summarizes the potential of microbial anti-cancer based therapy, current status, and research advances and approaches to understanding microbial pathogenesis, host-microbial interactions, immuno oncology, mechanisms of activation of immune systems, tumor destruction, and other future approaches.
These insights and recent advances in genetic engineering and gene editing make possible deployment of new concepts and strategies for developing new microbial therapies to mitigate or solve unmet clinical needs. Microbes may be employed to augment multiple antitumor mechanisms, including selective tumor cell infection, killing and induction of systemic antitumor immunity. Microorganisms potentially could stimulate long lasting anti-tumor immune responses and broaden tumor targeting. Most cancer therapeutics are costly, not widely available, nor accessible to most patients in low and middle-income countries (LMIC). The concept of a microbial-based therapy unique for self-regenerating cancer therapeutics, which may offer new therapeutic opportunities for cancer patients worldwide, including LMIC that account for most of the world population.
Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside anaerobic tumor tissues, kill tumor cells and activate anti-tumor immunity. Multiple studies have demonstrated that anaerobic microorganisms have the unique ability to grow selectively in hypoxic anaerobic areas of solid tumors that often are not accessible to drugs. While many anaerobic bacteria are facultative anaerobes (capable of infecting non-tumor tissue), molecular manipulation can create strictly anaerobic, attenuated Salmonella and Clostridium novyi which are able only to infect hypoxic tumor tissues, and non-viable outside the hypoxic tumor micro-environment.
- Clostridium novyi spores are being used in a Phase I clinical trial to treat patients with solid tumors.
- Salmonella has the potential to activate dormant cells normally resistant to treatment, enabling treatment of activated cells with conventional therapy.
- A “Trojan Horse” strategy that uses attenuated Salmonella expressing aquatic flagellin as a “foreign” antigen to activate the immune system against tumor cells harboring the Salmonella cells.
- Bifidobacterium and several other commensal bacteria have been shown to enhance the efficacy of checkpoint inhibitors both in mouse and in human.
- Listeria monocytogenes bacteria have been engineered to deliver recombinantly expressed tumor-specific antigens for activating tumor-specific cytolytic T lymphocyte (CTL), with the goal of inducing long-lasting tumor-specific cytolytic T lymphocyte (CTL) responses.
While recent research demonstrates the potential of microbial-based cancer therapy, more research is needed to realize this potential and to bring novel microbial-based therapies to the clinic especially for conditions where conventional cancer therapies are inadequate
The complex nature of interactions between the microbe, tumor, and immune system requires multidisciplinary collaboration between microbiologists, cancer researchers and immunologists with the goal of developing innovative approaches to improve our understanding of this system and utilize it for cancer therapy. This initiative seeks to support studies of the various aspects of microbes-tumor interaction necessary to ultimately address the clinical need to develop new cancer therapies especially for conditions where conventional cancer therapies are inadequate.
Applicants responding to this FOA are encouraged to address both the microbial and the tumor aspects of microbial-based cancer therapy – research topics supported by this FOA may include, but are not limited to:
- Microbe-tumor interactions;
- Novel microbial species that might have therapeutic potential;
- Novel cancer targeting approaches;
- Approaches for treating poorly vascularized hypoxic solid tumors or islands of microinvasive tumor cells buried within normal tissue;
- Activation of anti-tumor immunity (including expressing foreign proteins on the surface of the tumor cell which induce a strong immune response, developing long lasting immunity, overcoming immune suppression etc.);
- Novel targeting approaches of poorly-vascularized, hypoxic, solid tumors or islands of microinvasive tumor cells buried within normal tissue;
- Tumor cell inactivation (including colonization, disrupting cell function, activation of cell death programs etc.);
- Activation of dormant tumor cells;
- Novel drug delivery approaches;
- Preclinical research on microbial based cancer therapies aimed to provide new cancer therapy options for cancers prevalent in LMIC which are compatible with available local medical/health infrastructure.
Multi-disciplinary research teams are expected to conduct cutting-edge research within the scope of the FOA (see above) aimed at advancing pre-clinical development of novel microbial-based anticancer therapeutic agents, or to study the complex biology involved in the interplay of microbe-tumor-immune system interactions. Applicants applying to this FOA are expected to address both the microbial and the tumor aspects of microbial cancer therapy, the goal is to conduct research that could have a major impact on cancer therapy and related research.
Potential areas of research may include, but are not limited to:
- Mechanisms of tumor-microbes-host interactions, such as tumor-specific targeting, microbial and tumor cell signaling, interaction with the immune system against tumors, microbial-specific tumor cell lysis and other basic aspects of microbial-based cancer therapy.
- Natural or engineered non-pathogenic microbes with therapeutic potential to selectively infect and treat cancers of various organs, solid tumors, metastasis, microinvasion, hypoxic or poorly vascularized tissues not accessible to chemical or monoclonal antibody drugs;
- Novel microbes, e.g., soil, aquatic and plants bacteria, archaebacteria, bacteriophages and other non-virus microorganisms as potential therapeutics to overcome the issues of microbial pathogenicity and clearance by the immune system;
- Targeting specificity for primary and metastatic tumors, hypoxic tissues, poorly vascularized tissues, neovascularization or slowly dividing/dormant cancer cells
- Microbial payload delivery of therapies, e.g., anti-cancer drugs, radiotherapy, other tumor relevant payloads.
- Microbial induction of specific antitumor immunity for primary and metastatic tumors including immune engagement, more robust tumor antigen presentation, immunostimulatory constructs such as “trojan horse” delivery of novel antigen expressions to overcome immune suppression.
- Tumor epitope spread to stimulate innate immune system response, e.g., pathogen associated molecular patterns (PAMPs).
- Long lasting approaches to anti-cancer immunity, such as surface expression of foreign proteins to induce a strong response or overcome immune suppression.
- Tumor cell inactivation, such as colonization, cell function disruption, programmed cell death activation;
- Approaches to balance among microbe-initiated immune stimulation, cancer neoantigen presentation, therapeutic microbes’ clearance, and microbial pathogenicity for more nearly optimal safety and efficacy of microbial-based anti-cancer agents;
- Strategies to prevent recurrence, such as prolonging microbial therapy efficacy with libraries of “foreign” antigens to restimulate the immune system after loss of initial antigen efficacy;
- Companion diagnostics to predict antitumor responses or improve microbial selections for patient treatment;
- Basic biology underlying microbe-tumor interactions such as invasion, lysis, antigen presentation, and other microbe-initiated tumor cell-death and immune responses;
- Preclinical research on new microbial based cancer therapies suitable for low resource settings, especially for cancers prevalent in LMIC and compatible with local medical/health infrastructure.
This FOA encourages formation of multidisciplinary teams with expertise in microbiology, immunology, and molecular/cellular cancer biology from diverse academic, clinical or industrial sources to ensure breadth sufficient to accomplish project goals. Each application should address how all project elements are represented, assignment of project modules, and performance targets for completion of all steps
Deadlines: standard dates apply (letters of intent due 30 days prior to deadline)
- R01 – https://grants.nih.gov/grants/guide/pa-files/PAR-19-193.html
- R21 – https://grants.nih.gov/grants/guide/pa-files/PAR-19-194.html
Filed Under: Funding Opportunities