# Novel Molecular Targeted Radionuclide Therapies for Dosimetry-Guided Immunomodulation

> **NIH NIH P01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $351,029

## Abstract

PROJECT SUMMARY – PROJECT 1: Mounting preclinical and clinical evidence demonstrates that external
beam radiation therapy (EBRT) can enhance the systemic anti-tumor response to immunotherapies (ImmRx) by
modifying the tumor microenvironment (TME) in ways that enhance tumor immune susceptibility. Others and we
have observed that in the setting of multifocal or metastatic disease this capacity of focal EBRT to elicit in situ
vaccination (optimal at doses of 8-12 Gy) may be further enhanced by delivering low dose radiation (RT; 2-4 Gy)
to all tumor sites. In this capacity, low dose RT may play a critical role in overcoming tumor-specific immune
suppression from RT-sensitive immune lineages [e.g. regulatory T cells (Tregs)] and may also enhance the
immune susceptibility of tumor cells at these disseminated sites by cGAS/STING activation of a type I interferon
(IFN) response. The limited ability of EBRT to target all tumor sites without considerable risk of toxicity is a major
hurdle that limits the capacity of EBRT to modulate the collective TME in this manner. In the setting of
microscopic or metastatic disease, it is not possible to treat all TMEs with EBRT at the doses required for
immunomodulation without also incurring lymphopenia. Consequently, a radiotherapy modality is needed that
can deliver immunomodulatory RT doses to all tumor sites without triggering systemic immunosuppression. To
meet this need, we hypothesize that molecularly targeted radionuclide therapy (TRT), a systemic form of
radiotherapy combining a tumor-selective vector with a therapeutic radioisotope, will deliver immunomodulatory
RT to all metastatic tumor sites resulting in significant tumor responses without systemic immune suppression.
 To effectively study these broad mechanisms requires a TRT agent with 1) selective uptake across a breadth
of malignancy, 2) a theranostic capacity for delivery of paired isotopes that can be used for therapy and
diagnostic imaging (e.g. 90Y and 86Y, respectively) to facilitate personalized dosimetry, and 3) the ability to bind
and deliver diverse radionuclides to study the differential capacity of these to immunomodulate the TME of micro-
and macro-metastases. Current FDA-approved TRTs are limited in their capacity to achieve this vision. We have
developed a novel TRT vector, NM600, which is optimally suited for this broad application in dose-dependent
immunomodulation and which has produced many complete responses including tumor specific immune memory
induction in syngeneic murine tumor models when used in combination with checkpoint inhibition (Project 2),
immunocytokine (Project 3), and DNA vaccine (Project 4) immunotherapies. Project 1 will investigate how the
properties of different TRT vectors and radionuclides (e.g. linear energy transfer (LET), dose rate, and dose
distribution) influence the TME and the host immune system in syngeneic mouse models relevant to each Project
and also in companion canine cancer patients to assess whet...

## Key facts

- **NIH application ID:** 10416045
- **Project number:** 5P01CA250972-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** JAMEY P WEICHERT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,029
- **Award type:** 5
- **Project period:** 2020-09-14 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416045

## Citation

> US National Institutes of Health, RePORTER application 10416045, Novel Molecular Targeted Radionuclide Therapies for Dosimetry-Guided Immunomodulation (5P01CA250972-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10416045. Licensed CC0.

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