Project Summary/Abstract:
Immunotherapy for the treatment of various human cancers has drawn great attention, and many immune
checkpoint inhibitors are in clinical trials. However, immune checkpoint blockade-based therapy has yet to be
fully successful, mainly due to a lack of cancer specificity and immunotherapy-associated side effects. These
problems can be overcome by loco-regional delivery of therapeutics and a tumor site–specific immune
checkpoint blockade. The primary objective of the present research is to develop a cancer-targeted immune
checkpoint blockade therapy for lung cancer by applying a non-toxic nanoparticle-based gene therapy with a
novel PD-L1 inhibitory peptide (PD-L1ip) secretory gene. Recently, novel PD-L1ip genes that inhibit the
complexation of PD-L1 and PD-1 were generated and effective gene expression was demonstrated in tumor
cells as well as significant enhancement of cytotoxic T cell activity in cancer cell growth inhibition in vitro.
Independently, in orthotopic mouse models of both murine and human lung cancer, it was demonstrated that
intratracheally (IT) administered cell penetrating peptide (CPP) nanoparticle containing genes such as
endogenous apoptosis inducer genes (TRAIL and angiotensin II type 2 receptor (AT2R)) or firefly luciferase
gene by an aerosolizer caused high expressions of genes in lung tumor cells; relatively lower expression was
detected in normal lung epithelial cells. The pulmonary gene therapy with AT2R or TRAIL gene significantly
attenuated the growth of lung carcinoma grafts without showing any side effects. These studies suggest that
local pulmonary gene delivery effectively distributes CPP nanoparticle containing gene throughout the lung and
causes cancer-targeted gene expression. Therefore, it is suggested that the pulmonary delivery of PD-L1ip
gene by CPP nanoparticle vector should be an effective local immunotherapy modality for lung cancer.
Accordingly, the investigators hypothesize that pulmonary administration of the CPP and PD-L1ip gene
complex by an aerosolizer is a feasible, safe and effective treatment for primary and metastatic lung cancer.
The specific objectives of the proposed study are; 1) to further study the inhibitory peptide structure and the
binding thermodynamics and kinetics with PD-L1 by computational modeling, as well as the function of the
peptide in CD8+ T cell-dependent cancer cell lysis in vitro, 2) to evaluate the therapeutic efficacy and adverse
event profile of the PD-L1ip gene administered via intratracheal spray in murine models of both murine primary
and metastatic lung cancer, 3) to demonstrate the safety and feasibility of intratracheal administration of CPP-
PD-L1ip gene complex using normal and lung tumor bearing mice. The proposed study will evaluate the
therapeutic and safety profiles of this CPP nanoparticle-based pulmonary immunotherapy, and contains ample
training opportunity for graduate/undergraduate students. This pulmonary immunotherapy strategy would be
applicable to human patients with primary and/or metastatic lung cancer.
