# Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

> **NIH NIH U01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $765,000

## Abstract

ABSTRACT
 We are developing a combined modality therapeutic approach to eradicating metastatic cancers that are
immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). Using an “in situ vaccine”
regimen consisting of 12 Gy focal external beam radiation therapy (EBRT) and intratumoral (IT) injection of
tumor-specific antibody (mAb) + IL2, we have eradicated solitary, large, cold syngeneic tumors in mice. This in
situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation resulting in
increased T-cell infiltration and potent T-cell memory. However, the presence of an identical but untreated
second tumor (2°) on a mouse’s opposite flank inhibits the effect of this treatment, preventing eradication of the
primary (1°) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2° tumor causes tumor-
specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1° tumor. We refer to this as concomitant
immune tolerance (CIT). We can overcome CIT, and eliminate both tumors by giving IT mAb-IL2 to the 1°
tumor and EBRT to both the 1° and 2° tumors. Delivering as little as 2 Gy EBRT to the 2° tumor can overcome
CIT. Clinically, delivery of EBRT (even low dose) to all sites of metastatic disease is problematic, but this can
effectively be achieved using molecular targeted radiation therapy (MTRT). MTRT is increasingly entering
clinical oncology practice and our UW team has led preclinical and clinical testing of a novel class of MTRT
using alkylphosphocholine (APCh) analogs that selectively deliver radiation to cancers in vivo. These show
tumor-selective uptake in virtually all mammalian tumor cells and tumor locations tested (including > 90 tumor
lines and in patients across various clinical trials). In a syngeneic murine melanoma model, we have observed
a potent synergy between systemically administered ICI and MTRT delivered using our next-generation APC
analog, 90Y-NM600. In a project that builds upon the ongoing collaborative progress of our multidisciplinary
team, we will now systematically optimize the potency of combining MTRT with immunotherapy to enhance
the immune response against immunologically cold tumors. In murine models, we will: 1) expand on
preliminary data showing potent synergy with the combination of MTRT and ICI, 2) evaluate the capacity of
MTRT to overcome CIT and enhance systemic anti-tumor immune response in the setting of multiple tumors
where one is treated with in situ vaccine (EBRT + IT mAb-IL2) alone or in combination with ICI. Because
murine models do not replicate the size and spatial distribution of human metastatic cancer and because these
factors strongly influence the dosimetry of MTRT, we will test the immunomodulatory effects of MTRT + in situ
vaccine in large breed companion canines (pet dogs) with naturally occurring metastatic melanoma. The
insights and treatment regimens developed in these studies should enable rapid translation to clinical
testing...

## Key facts

- **NIH application ID:** 10476396
- **Project number:** 5U01CA233102-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zachary Scott Morris
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $765,000
- **Award type:** 5
- **Project period:** 2018-09-18 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476396

## Citation

> US National Institutes of Health, RePORTER application 10476396, Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies (5U01CA233102-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10476396. Licensed CC0.

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