# Project 2: Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies.

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $552,100

## Abstract

Project 2 - Summary
Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and
 Proton-Based Mitigation Strategies
There is accumulating evidence across many types of cancers that radiation-induced lymphopenia (RIL) is
common, but it is often ignored as an unavoidable side effect. Severe RIL has been shown to correlate with
poor disease-specific outcomes. Extensive use of radiotherapy (RT) in the curative management of solid
tumors necessitates the development of RIL-mitigation strategies. We have compelling evidence of significant
differences in the lymphocyte-sparing effects of proton therapy (PT) vs. photon (or x-ray) therapy (XRT),
presumably attributable to the differences in their dose distribution patterns. Our work has further
demonstrated that both patient-specific and dosimetric factors contribute to the risk of severe RIL and T-cell
clonality. Our hypotheses are as follows: (1) RIL predictive models that account for individual patient
susceptibilities and dosimetric factors will have clinically significant predictive power; (2) reducing dose to
circulating immune cells and immune structures at risk preserves not only the quantity but, more importantly,
the quality of lymphocytes, which has a direct positive impact on cancer immunity and disease outcomes; (3)
through the utilization of intensity-modulated proton and photon RT (IMPT and IMRT), employing individualized
dosimetric constraints derived from the models, we will be able to select the optimum treatment modality
(protons or photons) and develop patient-specific strategies to substantially mitigate RIL and its consequences.
To test these hypotheses, we propose three specific aims. In Aim 1, we will utilize our large databases of
mainly esophagus, liver and brain cancer patients to improve our understanding of lymphocyte depletion as a
function of dosimetric and patient-specific baseline clinical factors and develop models to accurately predict
individualized severe RIL risk. In Aim 2, we will evaluate the clinical impact of the radiation treatment modality
on T-cell diversity, immune repertoire, and functional immune status. We will test the hypothesis that the
quality of lymphocytes as measured by immune phenotyping, T-cell diversity, and functional immunity after RT
is a major driver of clinical outcomes rather than just the absolute lymphocyte count. In Aim 3, we will assess
the validity of our models using independent retrospective and prospective data. We will also apply the models
to select the optimum treatment modality and technique for a given patient and define the personalized
dosimetric constraints to be used to optimize proton and photon radiation dose distribution patterns to minimize
RIL severity and risk. Upon the completion of this project, we will have a better understanding of how the
baseline clinical characteristics and proton and photon dosimetric factors impact RIL risk and severity, T-cell
diversity, and functional immunity...

## Key facts

- **NIH application ID:** 10491853
- **Project number:** 5P01CA261669-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Steven Hsesheng Lin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $552,100
- **Award type:** 5
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491853

## Citation

> US National Institutes of Health, RePORTER application 10491853, Project 2: Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies. (5P01CA261669-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10491853. Licensed CC0.

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