University of Wisconsin-Madison Archives

2019

Scholar Grant

Mario Otto

Madison, WI

Title: Targeted radiotherapy with alkyl phosphocholine analogs for refractory childhood leukemia

Executive Summary:
Advances in diagnosis and available treatments, including CAR-T cell therapy, have led to overall excellent survival rates for most pediatric leukemia patients. Achieving cure in multiply relapsed or refractory disease, and in patients who fail CAR-T cell therapy remains a challenge. Chemoresistance often prevents achieving a state of minimal residual disease burden to allow to proceed to potentially curative hematopoietic stem cell transplantation (HSCT). Leukemia cells are commonly radiosensitive, even when chemoresistant. In this proposal, we will test the efficacy of molecular targeted radiotherapy (TRT) with a leukemia-targeting radiopharmaceutical, 90Y-NM600, in mouse models. 90Y-NM600 is injected intravenously and could kill leukemia cells almost everywhere in the body. The sister molecule 86Y-NM600 can be used for positron-emission tomography (PET) and allows to assess for organ-specific dose-effect relationships, and in future clinical trials for dosimetry and personalized medicine approaches. We hypothesize that 90Y-NM600 can be a useful component of re-induction therapy in preparation for HSCT, and potentially at other stages of leukemia treatment as well. Our specific aims are: 1. Assess biodistribution and perform pre-treatment dosimetry of 90Y-NM600 in murine xenograft models of pediatric leukemia. 2. Investigate the anti-leukemic effect of 90Y-NM600 in mouse models, without and with chemotherapy. The goal of this translational work is to provide crucial pre-clinical dosimetry and efficacy data geared towards regulatory approval for clinical testing of TRT with 90Y-NM600 in refractory pediatric leukemia.

In brief:
• Acute leukemia is the most common blood cancer in children and adolescents
• While the cure rate is overall high, unfortunately there are still many patients that relapse and in whom the leukemia does not go away with chemotherapy
• Radiation can kill leukemia cells. But since leukemia cells often are spread all over the body, radiotherapy delivered with a machine from outside the body would be too harmful.
• 90Y-NM600 is a new drug that carries a radioactive substance directly to leukemia cells via the bloodstream to kill them.
• In this project we will explore how well 90Y-NM600 can reduce the leukemia burden in mouse models of leukemia, either alone or in combination with other forms of therapy, such as chemotherapy. Eradicating most leukemia cells in patients is crucial because it would allow patients to receive a potentially life-saving therapy called bone marrow transplant.
• We also want to investigate how much of the injected 90Y-NM600 dose gets to the parts of the body where leukemia cells commonly hide, and how much goes to healthy organs. This will help tailor the 90Y-NM600 therapy dose to the need of patients in future clinical trials, and minimize side effects.
• The overall goal is to provide pre-clinical data supporting the rationale to move our concept from the laboratory to patient trials.

2019

Young Investigator

Nicholas Pytel

Madison, WI

Executive Summary:
Medulloblastoma (MB), the most common malignant childhood brain cancer, requires a multimodal treatment approach including surgery, radiotherapy, and chemotherapy to achieve cure. Currently, external beam radiation therapy (EBRT) plays a pivotal role in the treatment of MB. However, EBRT also leads to long-term neurocognitive and other sequelae, due to off-target effects on the developing, healthy brain. Targeted radionuclide therapy (TRT) might lead to a reduction in EBRT dose necessary to achieve tumor control. In addition, TRT has immunomodulatory effects that could be exploited therapeutically.

In this proposal, we will explore the anti-tumor effects of a novel TRT agent, 90Y-NM600, in preclinical models of MB, and investigate its effects on the tumor immune microenvironment. Our specific aims are: 1. To investigate the therapeutic response of single agent 90Y-NM600 TRT in a genetically engineered mouse model (GEMM) of MB. We will confirm tumor development by MRI and uptake and biodistribution of 90Y-NM600 utilizing the positron-emitting 86Y-NM600 as surrogate, and will evaluate dose-dependent anti-tumor effects of 90Y-NM600 treatment. 2. To investigate the immunological effects of high and low dose TRT in GEMM of MB on the tumor microenvironment and systemic immune effects. We hope to provide first preclinical efficacy data and evaluate potential adverse effects, and identify perturbations in the immune microenvironment that allow for additional immunotherapeutic intervention. Our ultimate goal is to improve the outcomes of patients by providing a new tool in the armamentarium against childhood medulloblastoma that could have an impact on other brain tumors as well.

Lay summary:
• Medulloblastoma (MB) is the most common childhood brain cancer.
• Radiotherapy is an important component of therapy, but since unfortunately healthy, developing brain tissue is radiated as well, this treatment often leads to long-term side effects such as trouble with memory, speech, academic performance and other brain functions.
• Targeted radionuclide therapy (TRT) using 90Y-NM600 offers a tumor specific approach to bring radiation directly to cancer cells and avoid radiation of healthy tissues. TRT is injected into a vein, and carried to the tumor via the blood stream.
• TRT may provide additional therapeutic benefit in MB by engaging the body’s own immune system to fight the cancer.
• In this project, we will explore the anti-cancer effects of TRT with 90Y-NM600 in mouse models of medulloblastoma.
• We will explore how much drug and radiation dose can be delivered to the tumor.
• We will also investigate to what extent TRT with 90Y-NM600 can trigger the immune system to attack the tumor, and identify immune mechanisms which could be exploited using immunotherapies.
• The overall goal is to provide pre-clinical data supporting the rationale to move our concept from the laboratory to patient trials.