The Wisconsin Immunomodulatory Targeted Radionuclide Therapy (ITRT) Program Project Grant is soliciting applications for Pilot Awards each spring:
Submit Letter of Intent
Apply
Targeted radionuclide therapies (TRT) are a type of cancer treatment that preferentially accumulate in tumors and selectively deliver radiation to these locations. Radiation can damage tumors in a way that makes them more susceptible to being killed by a patient’s own immune cells. The objective of the Wisconsin Immunomodulatory Targeted Radionuclide Therapy (ITRT) Program Grant (MPI: Jamey Weichert, PhD and Zachary Morris, MD, PhD) is to evaluate what effects targeted radionuclide therapies have on immune recognition of tumor cells and test whether these agents may enhance response to diverse forms of cancer immunotherapy. The ultimate goal of the Wisconsin ITRT program is to develop non-toxic, curative treatment approaches for patients with metastatic cancers of any type.
The ITRT Pilot Grant Program seeks to fund pilot project applications that will:
- Attract new investigators to the field of ITRT. Areas of potential interest include but are not limited to:
- Development and testing of novel TRT agents
- Testing TRT agents in combinations with innovative immunotherapies
- Evaluation of ITRT approaches in unique model systems
- Image-based dosimetry
- Development of advanced methodologies for determining the effects of TRT on immune cells, tumor cells, and/or the tumor microenvironment
- Translational research that may expedite or improve the methodologies for clinical testing and evaluation of ITRT in cancer patients
- Result in preliminary data to support successful competitive national grants
- Have potential to develop into a full ITRT P01 project in renewal application
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PROJECT PERIOD
July 1 – June 30, annually (with potential for competitive renewal)
DEADLINES
LOI: Feb 15
Application: Mar 11
FUNDING LEVEL
Up to $50,000 per year (2nd year dependent on competitive renewal)
ELIGIBILITY
Funds from this program will support applicants with a UW faculty appointment (including Assistant, Associate and full Professor series). Senior Scientists or similar may serve as PI if a faculty co-investigator is also included. Collaborations with outside investigators are encouraged.
The University of Wisconsin is an equal opportunity/affirmative action employer. The ITRT P01 program places special emphasis on recruiting qualified women and minorities.
Final recommendations for funding will be made by the P01 executive committee.
LETTER OF INTENT
LOI Recommended
Please submit online by Feb 15: https://trt.humonc.wisc.edu/submit-loi/.
We request a 1-2 sentence description of your proposal theme to help the P01 group identify reviewers with relevant expertise.
Your LOI title and list of collaborators can be changed for final application.
APPLICATION FORMAT
Scientific Abstract
- Lay Abstract
- NIH Biosketch for PI(s) and key personnel
- Protocol Assurances (Biosafety, Vertebrate Animals, & Human Subjects):
- Indicate associated protocols for vertebrate animals, human subjects and research involving recombinant DNA technologies.
- Protocols do not need to be approved at time of submission but must be approved before funds can be released.
- If human subjects research is involved, contact Shari Piaskowski during application process to discuss additional requirements and timelines.
- Budget
- Budget Justification
- Specific description of how the $50,000 award will be used.
- If full project costs exceed $50,000, please indicate how you will cover remaining costs (matching funds or otherwise).
- Research Strategy (limit 4 pages)
- Specific aims
- Background and significance
- Innovation and approach
- P01 Biostats Core is available for biostatistical support
- Anticipated results and implications
- Bibliography
- Description of Project Structure–How it will the project fulfill the ITRT P01 mission* and incorporate with current projects and cores? Include a timeline for completing the aims within project period.
- Resources and Environment (limit 1 page)
- Verification of Department Support
- Simple verification on web application, noting your home department is aware of and supports your application with the appropriate resources and protected time to fulfill the aims of the project.
- Letter(s) of Support (optional)
*The objective of the Wisconsin ITRT Program is to evaluate what effects targeted radionuclide therapies have on immune recognition of tumor cells and test whether these agents may enhance response to diverse forms of cancer immunotherapy, with the ultimate goal to develop non-toxic, curative treatment approaches for patients with metastatic cancers of any type.
EVALUATION CRITERIA
The Wisconsin ITRT P01 Pilot Program targets applications that:
- Attract innovative investigators to the field of immunomodulated targeted radionuclide therapy
- Promote high impact ITRT research
- Utilize current institutional and P01 shared resources
- Result in preliminary data to support successful competitive national grants
- Have potential to develop into a full ITRT P01 project in renewal application
Proposals must be focused on ITRT to be eligible for funding support. Proposals will be scored based on the following criteria:
- Significance
- Innovation
- Approach
- Environment
- Investigator(s)
- Potential to develop into or contribute to a new ITRT P01 Research Project
AWARD TERMS AND CONDITIONS
Upon receipt of an award, awardees will receive an overview of program obligations and agree to the terms of the program. Specifically, applicants will be required to:
- Attend relevant ITRT meetings, such as
- monthly ITRT research meeting (4th Tuesday of each month, 10:30am-noon (WebEx)
- ITRT annual retreat
- Submit an interim (Jan 15) and annual (July 15) progress report.
- Present a research project update at an ITRT meeting.
Contact
Please direct inquiries to:
Shari Piaskowski
ITRT P01 Administrative Manager
Department of Human Oncology
(608) 263-6686
smpiasko@wisc.edu
2022 awards
Huy Dinh, PhD
Assistant Professor
Department of Oncology
Neutrophil heterogeneity and modulation in Immunomodulatory Targeted Radionuclide Therapy
Abstract
Neutrophils can be either protumoral (N1) or antitumoral (N2) in their functions. Despite recent developments in defining the diverse roles of neutrophils in the tumor microenvironment (TME) , their phenotypes and functions in both targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) therapy remain largely unknown. Recent work showed that depleting neutrophils overcame tumor resistance to radiation therapy (RT) in a mouse model of soft tissue sarcoma. In addition, a study published last year showed that tumor-associated neutrophils (TANs) promote RT resistance in bladder cancer by forming neutrophil extracellular traps (NETs). However, TANs are considered a homogenous subset. We and others used single-cell technologies to define neutrophil progenitors and heterogeneity in the bone marrow and their functions when they egress to tumors. In the immunologically cold MOC2 mouse model for head and neck squamous cell carcinoma (HNSCC), the same model used by UW ITRT P01 projects, we found TANs to be a predominant component of the TME based on single-cell transcriptome (scRNA-Seq) analysis. Furthermore, their abundance was greatly reduced when we converted MOC2 tumors to an immunologically hot, ICB-responsive state by knocking out the immunosuppressive gene, stress keratin 17 (K17). Therefore, we hypothesize that TANs modulate ICB response and will also affect TRT. To assess their role, however, requires that we first understand TAN phenotypes and their heterogeneity in the context of ICB and TRT. This will open the door to exploring the potential for targeting neutrophils with the goal of increasing the responsiveness of tumors to these cancer treatments.
Randy Kimple, MD, PhD
Associate Professor
Department of Human Oncology
Metabolic inhibitors to enhance radiotherapy and overcome immune resistance
Abstract
Immune checkpoint inhibitors (ICIs) have shown great promise for treatment of many cancers. Treatments targeting the cytotoxic T lymphocyte antigen 4 (CTLA4) receptor, programmed cell death 1 (PD1) receptor, or its ligand, PD ligand 1 (PDL1), are ICIs that are used in the care of cancer patients. Despite these substantial advancements, the majority of ICIs recipients either do not benefit at all, or eventually develop resistance to the therapy highlighting the importance of continued therapeutic advances.
Our group has established expertise in targeting metabolic alterations in cancer. We have recently begun targeting lactate dehydrogenase (LDH) to target cancer cell glycolysis. LDH inhibitors (LDHI) alter patterns of energy metabolism in the tumor microenvironment resulting in alterations in extracellular pH and modulating immune cells. We have shown that two LDHIs, oxamate and NHI2, suppress proliferation of B78/D14 melanoma cell lines. Treatment with both oxamate and NHI2 or either in combination with external beam radiotherapy (EBRT), resulted in improved efficacy. In a pilot study, mice bearing B78 tumors treated with LDHI+ICI+EBRT demonstrated decreased tumor burden compared to those without LDHI. At the end of the trial, 4/7 mice in the LDHI+ICI+EBRT group were tumor-free and 3/7 had significantly delayed tumor growth as compared to the EBRT, ICI+EBRT and LDHI+EBRT groups.
In this application we propose using targeted radionuclide therapy (TRT) approach pioneered by Dr. Hernandez to replace EBRT in our LDHI+ICI treatment regimen. We hypothesize that TRT will extend the radiation exposure time to the primary tumor and deliver radiation to areas of metastatic disease. First, we will evaluate the effects of free 90Y-, 177Lu-, and 225Ac radionuclides in a melanoma model cell line, B78/D14. We will examine cell proliferation, apoptosis, and metabolism with and without LDHI. Next, in vivo research will be carried out with the addition of ICI to the regimen utilizing the B78 dual tumor model. The proposed research will provide important insights into the possibilities of LDHI-driven
disruption of cancer cell metabolism and TME improvement to obtain better outcomes from TRT and/or ICI treatments in primary tumor and metastases. This study will help in the design of improved combination strategies to enable more effective responses to eradicate cancers not responsive to ICI therapy alone.
2021 awards
Christian Capitini, MD
Associate Professor
Department of Pediatrics
Combination CAR T cell and MTRT therapy for pediatric solid tumors
Abstract
Neuroblastoma is the most common solid tumor that occurs in children outside of the brain. For children with tumors that have high risk features or that has spread to multiple organs, survival is poor despite an aggressive treatment regimen that involves chemotherapy, surgery, radiation, stem cell transplant and immunotherapy. We believe treating these children with genetically modified killer cells called CAR T cells that can recognize a molecule on the cell surface of the neuroblastoma can improve anti-tumor activity. The purpose of this research is to develop a treatment approach that will be novel, safe, effective and rapidly translatable to the clinic. Using preclinical models, we will test the effects of engineering T cells to recognize and kill neuroblastoma when combined with a radioactive chemical. We will test the combination of CAR T cells and radioactive chemical in a petri dish and in animals with human tumors. We hope to show that the chemical makes the CAR T cells more potent and durable than conventional products. Completion of this proposal will provide important advances in the treatment of neuroblastoma that could be moved quickly into clinical testing.