- Combinatory Treatment Modalities Utilizing Radiation to Locally Activate or Release
Systemically Delivered Therapeutics
Fast-Track proposals will be accepted.
Number of Anticipated Awards: 2-4
Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
This solicitation calls for the development of combinatory treatment modalities utilizing external ionizing radiation to locally activate or release systemically or intratumorally delivered therapeutics. The goal is to leverage an existing radiation therapy infrastructure to provide this radiation.
Systemic administration of therapeutic agents (TA) for cancer treatment is a common practice. However, their presence in normal tissues leads to adverse toxicities limiting the administered dose and the resulting treatment efficacy. The undue toxicity might be avoided if the TA remained encapsulated or inactive until exposed to an extremal radiation within a well-defined volume. In addition, the time of release/activation could be adjusted, so that the concertation of the TA at the target volume reaches levels necessary for an effective treatment. The key criteria towards achieving an effective and safe treatment include safe doses of the external radiation and quantitative control of localized TA release or activation. Remote triggering mechanisms may include X-rays or particle, e.g. proton, beam currently used for radiation therapy (RT) of cancer.
Use of heat or ultrasound to activate or release therapeutic agents has been an active research front in many academic centers with fruitful results. Thermal release of drugs from liposomes has been in clinical practice for years. An example is ThermoDox (Cesion Corporation: http://celsion.com/thermodox/), which uses LTSL (lysolipid thermally sensitive liposome) technology to encapsulate doxorubicin, a proven and commonly used cancer drug. The heat-sensitive liposome rapidly changes structure when heated to 40ºC-45ºC, creating openings in the liposome that release doxorubicin directly into and around the targeted tumor.
This solicitation focuses on systems that might release drugs or induce a toxic effect in response to external ionizing radiation that is currently used for cancer treatment. Such approach promises unique clinical benefits over conventional systems that release their cargo passively or are activated internally. For instance, X-ray might be used to stimulate local release of drugs from nanoparticles, or combination of X-rays with nanoscintilators emitting light that activates photosensitizers in photodynamic therapy (PDT) would allow extension of PDT to deep seated tumors. This approach could be implemented as an addition to the current standard of care involving RT. It will allow to utilize already existing radiation infrastructure. Patients undergoing RT will be given an opportunity to combine it with novel TAs or potent tumoricidal agents that could not be delivered by conventional systemic administration methods. Well defined spatial and temporal control of the TA release or activation will limit the toxicity while maximizing the efficacy of the combinatory treatment leading to an improvement of the quality of life and overall survival of cancer patients. Therefore, there is a need to encourage the development of such technologies.
This contract solicitation seeks to stimulate research, development, and commercialization of innovative techniques that could synergistically improve the effectiveness of RT and TA and reduce toxicity to normal tissues. Proposals addressing the following technology areas are encouraged: new treatment strategies, design, synthesis, and evaluation of innovative TA and formulations.
The short-term goal of the project is to perform feasibility studies for development and use of the combinatory treatment modalities for the treatment of cancer. The long-term goal of the project is to enable a small business to bring a fully developed combinatory treatment modalities to the clinic and eventually to the market.
To apply for this topic, offerors should:
- Identify or develop an appropriate TA that could be activated by radiation or TA formulations that could be triggered to release the TA by radiation in vivo.
- Define the mechanisms of the proposed TA tumoricidal activity in vivo.
- Identify the set of patients that are likely to be impacted by this technology.
Approaches using systemic administration of agents that act as radiation sensitizers are not appropriate for this solicitation. This solicitation is not intended for the development of the instrumentation for triggering the release of the TA. While modification of the device for eventual use with the TA in the clinic is acceptable, it must not be the focus of the proposal.
Phase I Activities and Deliverables
- Demonstrate that the expected release/activation action with a proper amplitude can be induced in vitro and in vivo by safe doses of radiation.
- Demonstrate (if appropriate) tumor-specific targeting and localization of the TA and activation of the TA only after exposure to radiation.
- Carry out a pilot animal pharmacokinetic/pharmacodynamic studies utilizing an appropriate animal model.
- Significantly characterize the chemistry and purity of the TA and chemistry of the reaction.
Phase II Activities and Deliverables
- Demonstrate an improved therapeutic efficacy and improved therapeutic index, assessment of toxicity to normal tissues in vivo.
- Development of the manufacturing and scale-up scheme.
- IND-enabling studies carried out in a suitable pre-clinical environment for PK/PD, preclinical efficacy, and safety assessment.
- When appropriate, demonstration of similar or higher efficacy of the proposed strategy when compared to current therapies.