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Drugs to Exploit the Immune Response Generated by Radiation Therapy


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
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.

Project Goals
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 anti-tumor 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.
Phase I Activities and Deliverables
 Selection of cancer type(s), organ site(s), immune modulation agent(s), and radiation dose & fractions, with adequate justification.  Proof of concept animal (e.g., mice or rat) studies demonstrating augmentation or inhibition of radiation-induced immune activation or suppression respectively with the combination of radiation and the agent.
Demonstrate augmentation of immune activation in irradiated environment with appropriate standard markers showing an increased influx of positive effector immune cells (e.g., T-cells, macrophages, dendritic cells, etc.) in the tumor micro environment.
Demonstrate negation of immune suppression in irradiated environment with standard appropriate markers showing reduction in the influx of negative effector immune cells (e.g., neutrophil, T-reg, and MDSCs) in the tumor micro environment.
 Proof of concept animal (e.g., mice or rat) studies demonstrating tumor regression in a syngeneic contra-lateral tumor model whereby regression is observed in both the irradiated primary tumor as well as distal non-irradiated tumor when the agent is combined with radiation.
Phase II Activities and Deliverables
 Perform absorption, distribution, metabolism, and excretion (ADME) of agents with bioavailability and efficacy studies in appropriate animal models with adequate justification. The models chosen may be syngeneic rodent models, humanized rodent models, or canine models and should demonstrate:
Improved efficacy, both immune modulation and tumor regression, compared to radiation or agent alone.
Radiation sensitizing effects on tumors using standardized in vivo radiation regrowth delayed assays.
o Comparative (i.e., similar or lower) toxicity compared to the agent or radiation alone.
 Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.
 For offerors that have completed advanced pre-clinical work, NCI may support pilot human trials.

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