Drugs or Devices to Exploit the Immune Response Generated by Radiation Therapy

391. Drugs or Devices 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

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

Summary

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.

• RT-induced cell death releases danger signals including heat-shock protein (Hsp), HMGB1, and calreticulin
  (eat-me signal for phagocytes).
• RT induces increased expression of tumor antigens and MHC class I molecules on tumor cells.
• RT-induced T cell activation increases expression of negative stimulatory molecules such as CTLA-4.
• Certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGFb.
• Activated APCs migrate to the draining lymph node, further mature upon encountering T helper cells, 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 systematically from the draining lymph node to infiltrate and lyse primary and distal tumors.

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.

Project Goals

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.

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 (mice or rat) studies demonstrating augmentation or inhibition of radiation-induced immune activation or suppression respectively with the combination of the agent or device.
  • Demonstrate augmentation of immune activation in irradiated environment with appropriate standard markers showing an increased influx of positive effector immune cells (such 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 (such neutrophil, T-reg and MDSCs) in the tumor micro environment.
• Proof of concept animal (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 could be syngeneic rodent models, humanized rodent models or canine models) and 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
  • Comparative (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 will support pilot human trials.