Fast-Track proposals will be accepted.
Number of Anticipated Awards: 2-3
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.
Tumor irradiation promotes recruitment of immune activating cells into the tumor microenvironment, including antigen presenting cells that activate cytotoxic T-cell function. However, tumor irradiation can also recruit immunosuppressive cells into the tumor microenvironment. Local irradiation can also impact tumor growth at a distance from the irradiated tumor site, known as the abscopal effect. This effect is potentially important for tumor control and is mediated through ceramide, cytokines, and the immune system.
Ionizing radiation can induce the following changes in the tumor micro-environment and such changes can be important targets to develop agents that can augment or negate radiation-induced immune activation or suppression respectively. Tumor-associated antigens (TAAs) are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation.
Several factors can influence the ability of radiation to enhance immunotherapy, including a) the dose of radiation (IR) per fraction and the number of fractions, b) the total dose of IR, and c) the volume of the irradiated tumor tissue. However, the impact of these variables is not well understood. Inducing anti-tumor cellular-mediated immune responses has been the subject of some pre-clinical tumor regression studies and is being applied in immune-modulatory clinical trials using antibodies against molecules that suppress immune responses such as PD1, PDL1 and CTLA4 or immune agonists such as OX40, CD27, GITR, 4-1BB, TNFR receptors, ICOS, and VISTA. Overall, discovery of checkpoint protein functional control of T-cells in tumor microenvironment led to the development of checkpoint blockade therapy and many checkpoint inhibitors including Nivolumab, Pembrolizumab, and Atezolizumab have been approved by the FDA for several indications. Several clinical trials testing combination of radiation with check point inhibitors are underway and have resulted in mixed results. Further, many of these combination trials lack robust pre-clinical scientific rationale raising queries if such checkpoint agents augment the immune modulating effects of radiation. Hence, more agents and/or devices that can augment immune activation or inhibit immune suppression induced by standard conventional 2 Gy fractions, (3-8 Gy) hypofractionation and high-dose hypofractionated (>10 Gy) radiotherapy are warranted.
Augmentation of radiation induced immune activation and/or inhibition of radiation induced immune suppression could enhance anti-tumor effects. The goal of this solicitation is to develop agents or devices (engineered cellular therapies, antibodies, small molecules, siRNA/CRISPR-CAS9 or in-vivo physical/chemical modulating instrumentation-based approaches) that can augment (immune stimulation) or negate (immune suppression) one or more of the immune modulation events induced by radiation therapy. Radiation therapy can include conventional clinically relevant radiation, hypofractionated radiation, and high-dose hypofractionated radiation.
It is critical that the proposed agent or device must specifically exploit the radiation induced immune response.
Projects That Will NOT Be Supported:
Immune modulating agents that are already being tested in combination with radiation in clinical trials will not be supported. Testing of immune modulating agents in the absence of radiation will not be supported.
Closing date: October 22, 2018, 5:00 PM Eastern Daylight Time
Apply for this topic on the Contract Proposal Submission (eCPS) website.
For full FY19 Contract Solicitation, CLICK HERE.