Fast-Track proposals will be accepted.
Number of anticipated awards: 2-3
Budget (total costs, per award):
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.
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 therapies and many checkpoint inhibitors including Nivolumab, Pembrolizumab, and Atezolizumab, which 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. Furthermore, 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 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.
The broad goal of this Topic is to develop agents (cellular therapies, antibodies, small molecules, or miRNA/siRNA/CRISPR-CAS9 based approaches) that can augment (immune stimulation) or negate (immune suppression) one or more of the immune modulation events induced by radiation discussed above. IR can include conventional clinically relevant radiation, hypofractionated radiation, and high-dose hypofractionated radiation. Ionizing radiation (RT) causes changes in the tumor microenvironment that can lead to intra-tumoral as well as distal immune modulation (i.e., so-called abscopal phenomenon). Tumor-associated antigens (TAAs) are released by irradiated dying cancer cells triggering danger signals such as heat-shock protein (Hsp), HMGB1, and calreticulin (i.e., “eat-me” signal for phagocytes). These TAAs and cell debris are eaten by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. At the same time, RT can induce increased expression of tumor antigens and MHC class I molecules on tumor cells. Consequently, activated antigen presenting cells (APCs) migrate to the draining lymph node, further mature upon encountering T helper cells, and release interferons (IFNs) and IL-12/18 to stimulate Th1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systemically from the draining lymph node to infiltrate and lyse in primary as well as distal tumors. Concomitantly, tumor irradiation can also recruit immunosuppressive cells into the tumor microenvironment. Further, expression of certain negative stimulatory molecules on T-cells and tumor cells (e.g., CTLA-4, PD-1, PDL1) are induced by RT and can curtail the activation of T-cells, leading to an immune suppressive environment. Other immune suppressive function of radiation can occur through induction IL-10 and TGF-β. Augmentation or inhibition of radiation induced immune activation and suppression could enhance antitumor effects.
Activities not supported by this topic:
Immune modulating agents that are already being tested in combination with radiation in clinical trials will not be supported. Immune modulating agents that augment or negate immune functions in the absence of radiation will not be supported.
Closing date: October 20, 2017, 5:00 PM Eastern Daylight Time
Apply for this topic on the Contract Proposal Submission (eCPS) website.
Full FY18 Contract Solicitation is available HERE.