# Photodynamic therapy with prior inhibition of epidermal growth factor receptor to stimulate antitumor innate immune response

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $444,397

## Abstract

Inhibition of epidermal growth factor receptor (EGFR) prior to the delivery of photodynamic therapy 
(PDT) can remarkably improve treatment efficacy in animal models of non-small cell lung 
cancer (NSCLC). Currently, clinical use of EGFR tyrosine kinase inhibitors (TKIs) for treatment 
of patients with NSCLC is limited to those with EGFR mutated disease. EGFR-TKI therapy is 
typically continued until time of disease progression since most patients eventually develop 
EGFR-TKI resistant disease. Here, we propose to use EGFR-TKIs as a brief, priming therapy for 
several days rather than as a daily continuous therapeutic. Importantly, as a priming 
therapy, we hypothesize that EGFR-TKI pretreatment will improve the therapeutic efficacy of PDT 
(and ionizing radiotherapy, XRT) through an innate immune response-dependent mechanism. 
Significantly, we posit that the use of EGFR-TKIs as a priming approach to stimulate 
innate immunity is relevant to patients with EGFR wild-type disease. However, its potential 
efficacy may not be apparent in the setting of daily continuous EGFR-TKI therapy due to suppression 
of innate and adaptive immunity by prolonged use of EGFR-TKIs. As a priming therapy, EGFR-TKIs 
could augment responses to PDT and XRT through multiple mechanisms that involve 
cooperation between the EGFR-TKIs and PDT or XRT to promote tumor-directed innate 
immunity. EGFR-TKIs may increase neutrophil activation in tumors receiving PDT or XRT, serving to 
increase vascular damage and/or stimulate other cells of the innate immune system, such 
as innate immune lymphocytes. Indeed, our published data show EGFR-TKI to increase 
vascular damage to PDT, and preliminary data demonstrate increases in tumor-localized 
neutrophil activation when PDT is preceded by EGFR-TKI (EGFR- TKI/PDT). Additionally, EGFR-TKIs and 
PDT or XRT may cooperatively increase numbers of innate immune lymphocytes and the immunologic 
visibility of target cells (e.g., tumor cells or tumor-associated endothelial cells) to 
these lymphocytes. In fact, in preliminary data the efficacy of EGFR-TKI/PDT is 
dependent on the innate immune lymphocytes NK and γδ T cells. We note that the role of 
γδ T cells in response to EGFR-TKI, notwithstanding combinations with PDT or XRT, is 
 a novel area of investigation. Moreover, we uniquely investigate EGFR-TKI priming with 
proton XRT. Knowledge gained from this proposal will guide selection of a clinical approach to 
EGFR-TKI priming with radiation therapy, whether it be with PDT, photon XRT, or proton XRT. Toward 
this goal, we will address the following aims: Aim 1. To define the role of neutrophils in 
promoting vascular damage when PDT is preceded by EGFR-TKI. Aim 2. To ascertain how pretreatment 
with EGFR-TKI augments the response of innate immune lymphocytes to PDT-treated tumors. Aim 3. To 
establish the efficacy and innate immune effects of EGFR-TKIs combined with ionizing radiation therapies (photon and 
proton) and demonstrate appl...

## Key facts

- **NIH application ID:** 10073486
- **Project number:** 5R01CA236362-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Theresa M Busch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $444,397
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073486

## Citation

> US National Institutes of Health, RePORTER application 10073486, Photodynamic therapy with prior inhibition of epidermal growth factor receptor to stimulate antitumor innate immune response (5R01CA236362-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073486. Licensed CC0.

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