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NIH/NCI 468 - Synthetic Microbes (Excluding Oncolytic Viruses) for Immuno-Oncology Therapies

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 2-4

Budget (total costs, per award):

Phase I: up to $400,000 for up to 12 months

Phase II: up to $2,250,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

 

Summary

Current immuno-oncology (IO) therapies have provided valuable options for cancer treatment. However, many adult and pediatric patients, especially those with solid malignancies, do not initially respond to these therapies or later relapse after treatment. Barriers to existing IO therapies (e.g., immune checkpoint blockade and cellular immunotherapies) include poor tumor immunogenicity, antigen escape, limited tumor penetration, poor persistence of effector T-cells, hypoxic and
immunosuppressive tumor microenvironment (TME), off-tumor effects, and systemic toxicities. Thus, there is an urgent unmet clinical need for innovative IO therapies that have the potential to address these challenges.

The use of bacteria as a cancer treatment is not a new concept. Research has revealed that microbes possess inherent immunostimulatory properties and that some microbes have a natural ability to selectively colonize tumors due to the hypoxic and immunosuppressive conditions of the TME. However, the use of bacteria came with infectious complications and many patients died because of these side effects. For this reason, the idea of using bacteria against cancer waned with the
advance of chemotherapy, radiotherapy, and other approaches. Recently, leveraging advances in synthetic biology and deeper knowledge about both microbiology and oncology, several studies have demonstrated the feasibility of engineering microbes towards safer and more efficacious outcomes such as selective delivery/guidance of immune-modulating chemotherapies and IO products including chimeric antigen receptor (CAR) T-cells into tumors and enabling TME changes
to promote or enhance anti-tumor immunity. Therefore, synthetic microbes provide promising options for improving IO therapy outcomes by enhancing patients' response to treatment and by avoiding relapse.


Project Goals

The overall goal of this topic is the development of safe and effective synthetic microbial-based IO therapies for clinical use. The supported activities focus on the development of a tumor-targeting and immune-modulating synthetic microbe for clinical use as IO therapy. Offerors must already have a synthetic microbe in hand for further testing and optimization. This topic will support development of the synthetic microbe for use as single-agent IO therapy or for combination therapy as an adjuvant to existing IO treatments. For combined therapy, the engineered microbe can be used to deliver other immunotherapeutics as well as chemotherapeutics with immunogenic cell death activity. Funded projects could offer exciting opportunities for developing next-generation IO therapies that could improve survival and quality of life of cancer patients, especially those with immunologically cold and/or difficult-to-reach solid tumors, such as pancreatic cancer and
pediatric solid tumors.

Activities not responsive to this announcement:

Proof-of-concept gene circuit design and engineering of microorganisms (including primary screening to identify “hit” products); development of non-synthetic microbial-based cancer therapies exploiting the use of natural or attenuated-only microorganisms; development of microbial-based cancer therapies based on “free” microbial products, microbiota transplantation of natural non-engineered microbial communities, or oncolytic viruses; development of microbial-based cancer monotherapies exploiting the use of synthetic microorganisms as delivery platforms of payloads acting only on tumors without a direct or adjuvant effect on the immune system; development of synthetic microbial-based imaging agents or diagnostics with no IO therapeutic activity.

 

Phase I Activities and Deliverables:

Offerors must already have a synthetic microbe in hand that is adequately designed for the proposed use – as single-agent IO therapy or adjuvant for enhancing existing IO product(s). Phase I activities should deliver confirmatory results on tumor selectivity and controlled delivery of the payload by the engineered microbe, as well as anti-tumor efficacy in appropriate cancer models. Activities in this phase should also generate preliminary toxicity and immune-related adverse events (irAEs) data; provide knowledge of the immunomodulatory action of the proposed agent; and demonstrate advantages of the technology as compared with current IO therapies or other relevant existing treatments for the oncology indication (e.g. less toxic and/or more efficacious). Expected 

Phase I activities and deliverables include but are not limited by the following:

  • Evaluate potential cross-reactivity of the therapeutic delivered by the engineered microbe between human and mouse (as appropriate).
  • Confirm tumor specificity and biocontainment of the selected synthetic microbe, as well as stable and controlled
  • expression of the therapeutic cargo or adjuvant activity.
    • Quantify the biodistribution within tumor tissue and healthy tissues, as well as shedding.
    • Confirm the absence of survival outside the host, in a natural environment.
    • Confirm spatial, temporal, and dose-controlled delivery of the therapeutic payload or adjuvant activity, as well as stability of therapeutic expression systems.
  • Confirm in vivo anti-tumor efficacy using appropriate cancer models and controls.
    • Measure tumor growth, quantify metastases, and monitor survival of tumor-bearing animals. Evaluate abscopal effect and protection from tumor rechallenge (as appropriate).
  • Assess toxicity, and irAEs in small in vivo studies with appropriate cancer model(s).
    • Assess toxicity and irAEs (including potential long-term exposure adverse effects) by body and organ weight measurements, screening for alterations in liver and other organs functions, and systemic inflammation (e.g., cytokine storm).
  • Evaluate systemic and intratumoral immune responses stimulated by the technology, administered as single-agent or combination therapy (as appropriate), in small in vivo studies using suitable tumor model(s).
    • Determine enrichment and activation of circulating and tumor-infiltrating immune cells by flow cytometry analysis, immunohistochemistry, confocal microscopy, and/or gene expression analysis techniques (e.g., singlecell RNA sequencing analysis).
  • Demonstrate advantageous benefits (e.g., better efficacy, improved safety, simpler/better route of administration) compared to relevant existing therapies for the oncology indication using the results from the efficacy and toxicity studies.
  • Present Phase I data and future steps of the development plan to NCI program staff.

 

Phase II Activities and Deliverables:

Depending on the product development stage, Phase II activities could include further optimization and large-scale in vivo efficacy and safety studies in appropriate cancer models (required), and/or IND-enabling studies (optional). Phase II studies should generate data demonstrating advancement of the technology towards commercialization. Expected activities and deliverables include but are not limited by the following:

Required

  • Optimize dose, frequency, and route of administration for use as single-agent or in combination with existing IO product(s) (as appropriate).
  • Optimize genetic modifications to ensure optimal attenuation, tumor tropism, as well as adequate and controlled delivery of the therapeutic payload or immunomodulatory activity (as appropriate).
  • Optimize genetic circuits for cargo secretion, vector lysis, expression of IO agent(s), expression of enzyme(s) enabling metabolic change(s) to boost anti-tumor immunity, as well as chemotherapy delivery system(s) (as appropriate).
  • Perform well-powered, large-scale in vivo efficacy and toxicity studies to statistically demonstrate advantageous benefits (e.g., clinical feasibility, superior efficacy and/or safety) as compared with current IO treatments or other relevant existing therapies for the oncology indication. Advantageous benefits may also include a simpler/better route of administration and affordability (more cost-effective).
  • Perform well-powered, large-scale in vivo studies in appropriate cancer model(s) and with proper controls to validate systemic and intratumoral immunomodulatory effects of the proposed product administered as single-agent or as combination therapy (as appropriate).
    • Include assessment of possible unwanted immune responses against the engineered vector that may impact efficacy and safety.
  • Engage in an INTERACT meeting with the FDA to obtain preliminary informal feedback on CMC, non-clinical, and clinical issues earlier in development than the pre-IND stage (as appropriate).
  • Provide a commercialization plan (e.g., partnership(s)/alliance(s) with strategic business partner(s) to secure funding for subsequent phases and cancer sites/clinicians to have access to cancer patients for clinical trials).
  • Communicate Phase II results to NCI program staff.

Optional

  • Engage in a pre-IND meeting with the FDA and discuss an appropriate IND plan before IND filing.
  • Show capabilities of scale-up and manufacturing of clinical-grade material for a clinical study.
  • Assess product purity, sterility, identity, viability, stability, antibiotic sensitivity (as appropriate), and potency.
  • Perform GLP pharmacology and toxicology studies.
  • Determine starting dose, dose-escalation, and dosing schedule for an early phase study in human cancer patients.
  • Select the patient population for a clinical trial.

 

Receipt date: Friday, October 18, 2024, 5:00 p.m. ET

Apply for this topic on the Contract Proposal Submission (eCPS) website.

View the full PHS2025-1 Contract Solicitation.

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