Christopher Larson

Natalie Mendez

Tony Reid

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922 www.moleculartherapy.org  vol. 21  no. 5  may 2013
© The American Society of Gene & Cell Therapycommentary
See page 1096
Targeting Tumors Using 
Nanoparticle Platforms: A 
Phase I Study of a Systemically 
Administered Gene Therapy System
Christopher Larson1, Natalie Mendez2 and Tony Reid1
doi:10.1038/mt.2013.76
1Division of Hematology–Oncology, 
Department of Medicine, University of 
California, San Diego, La Jolla, California, 
USA; 2Department of Materials Science and 
Engineering, University of California, San 
Diego, La Jolla, California, USA
Correspondence: Tony Reid, Division of 
Hematology–Oncology, Department of 
Medicine, University of California, San Diego, 
3855 Health Sciences Drive, La Jolla, California 
92093, USA. 
E-mail: tonyreid@ucsd.edu
The potential for nonviral gene therapy to treat cancer has been limited by the 
difficulty of targeting therapeutic genes to 
tumors. In this issue of Molecular Therapy, 
Senzer et al.1 show evidence of specific tu-
mor targeting as well as clinical efficacy in 
a phase I trial of a nonviral vector. This is 
the first phase I clinical trial to demonstrate 
tumor specificity and uptake by metastatic 
tumors of a systemically delivered liposomal 
nanoparticle. Importantly, the therapeutic 
nanoparticle elicited minimal side effects 
and the majority of patients demonstrated 
stable disease. This phase I trial has shown 
this delivery system to be a safe, stable, effi-
cient, and tumor-specific drug delivery plat-
form for systemic administration.
The study evaluated systemic delivery 
of a liposomal nanoparticle vector 
encoding wild-type p53 (SGT-53), which 
was engineered with the aim of restoring 
the expression and proapoptotic function 
of the latter in tumor tissue (Figure 1). 
The vector comprised cationic lipids in 
complex with plasmid DNA and was 
targeted to tumors using a single-chain 
antibody specific for the transferrin 
receptor covalently linked to the lipids by a 
cysteine–maleimide bond.2 The transferrin 
receptor is highly expressed on cancer cells, 
which renders it an attractive targeting 
moiety.3 Eleven previously treated patients 
suffering from a wide variety of refractory 
cancers with no alternative treatment 
options received SGT-53 intravenously for 
5 weeks. The results demonstrated both 
safety of the therapy with no dose-limiting 
toxicities and dose-dependent presence of 
the transgene in tumors. There was also 
evidence of clinical efficacy, as 7 of the 11 
patients had stable disease at 6 weeks after 
treatment. These results, taken together, 
illuminate a pathway for the treatment of 
cancer with gene therapy vectors delivered 
with targeted nanoparticles.
Although cationic lipids have been 
shown to be effective transfection reagents 
in vitro, their application in vivo has 
been hampered by off-target interactions 
with the reticuloendothelial system and 
anionic extracellular matrix and proteins.4 
They have also been shown to induce 
lymphopenia and elevated levels of liver 
enzymes, which can lead to lethal liver 
damage and mortality.5 In Senzer and 
colleagues’ study, most of the patients had 
mild reactions (predominantly grade 1–2 
transient hypotension and fever); the only 
grade 3 adverse event was fatigue in one 
patient that was attributable to extensive 
tumor necrosis. Because toxicity associated 
with lipoplexes limits their wide-ranging 
application, further clinical testing of the 
SGT-53 formulation for immunogenicity, 
liver toxicity, and damage in other organs 
should provide valuable information 
related to this critical issue.6
Precise selection of the lipid comp-
osition and the targeting ligand are 
important factors for effective nanoparticle 
delivery systems. Bio physical characteriza-
tion of similar complexes using transfer-
rin as the targeting molecule showed that 
although DNA in complex with cationic 
lipids alone forms large (150- to 400-nm) 
structures with a very positively charged 
surface, the addition of transferrin to the 
complexes leads to a more compact (50- 
to 90-nm), electrically neutral structure 
that should prolong its circulation time 
and ability to target tumors.7 In effect, this 
provides the charge neutralization and im-
munoevasive properties of polyethylene 
glycol without the concomitant decreased 
transfection efficiency.
Although the delivery mechanism is 
an important breakthrough in the present 
study, the nature of the transgene effect 
is also intriguing. The clinical correlation 
of p53 status with patient outcome 
continues to be a hotly debated area of 
p53 research.8,9 The challenge derives 
mainly from the inherent complexity of 
the p53 pathway and the large number of 
mutations in different tumor types and 
clinical stages.10 The p53 database includes 
mutations or variations in the p53 gene 
(encoding p53) that have been reported 
in the literature since 1989.11 There have 
been encouraging findings regarding 
survival correlations with p53 mutations; 
for instance, studies have shown that 
cancers of the breast, head and neck, liver, 
hematopoietic, and lymphoid systems 
show an association of p53 mutation 
with worsened survival, whereas cancers 
of the pancreas, prostate gland, rectum, 
and stomach did not.10 Although p53 is 
an intracellular protein that might be 
expected to kill only transfected cells, there 
is evidence that this is not necessarily the 
case. In a mouse model of breast cancer, 
therapeutic efficacy was observed even at 
transfection efficiencies of less than 5%.12 
Inhibition of angiogenesis was implicated 
as a possible explanation for this bystander 
effect. Controlled phase II and phase 
III studies stratified for p53 status and 
that evaluate the metabolic activity of 
treatment will help elucidate the impact 
of p53 restoration therapy and identify 
responding subgroups of patients.
Although these experiments demon-
strated plasmid DNA delivery to the 
tumors, technical difficulties prevented 
assessment of DNA uptake into the 
nucleus or expression of vector-derived 
Molecular Therapy  vol. 21  no. 5  may 2013 923
© The American Society of Gene & Cell Therapy commentary
messenger RNA or protein. Consequently, 
it is difficult to distinguish whether the 
therapeutic effect was due to expression 
of the p53 transgene or whether 
efficient tumor targeting of high levels 
of the cationic lipids lead to nonspecific 
cytotoxicity. Previous preclinical studies 
offer evidence that the therapeutic effects 
observed in this study did not arise 
simply as a result of cytopathic effects of 
the cationic lipids. For example, similar 
nanoparticles carrying control plasmids 
that do not encode p53 did not cause 
cytotoxicity in vitro, and nanoparticles 
carrying a plasmid encoding green 
fluorescent protein (GFP) were injected 
intravenously into nude mice and 
induced GFP expression in tumor 
xenografts but not normal tissue.13 
However, confirming this distinction is 
critical given the important implications 
regarding the feasibility of using this 
system in a wider array of applications. 
For example, treating cancer by delivering 
therapeutic genes to be highly expressed 
and secreted for a wide bystander effect (e.g., 
a prodrug convertase or immuno stimulatory 
cytokine), or treating hemophilia by 
using a single-chain antibody targeting 
normal cells and delivering a plasmid 
encoding clotting factors, would depend 
on achieving high expression levels of the 
transgene with minimal cytotoxicity in 
the transfected cells.
SGT-53 is intended for use in 
combination with standard radiation 
treatment or chemotherapy modalities. 
The loss of p53 function correlates 
with resistance to standard treatments, 
and restoration of p53 has resulted in 
sensitization of tumors to chemotherapy 
and radiation therapy.14 In vivo studies 
have shown that combination therapy 
results in significant tumor regression;15 
therefore, clinical studies that evaluate the 
effect of systemically administered SGT-
53 in combination with chemotherapy 
and/or radiotherapy should be assessed.
The study by Senzer at al. clearly 
shows that the transferrin receptor is a 
promising target for gene therapy delivery 
specifically to cancer and is effective 
when targeted by a nonviral vector. 
Wider application of this technology 
for nonviral gene therapy of diseases 
other than cancer, for which systemic 
gene delivery mediated by a virus16 
could have undesirable effects, may be 
possible by targeting a molecule whose 
role is comparable to that played by the 
transferrin receptor for delivery to cancer.
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Figure 1 p53 gene delivery with nanoparticles targeted to the transferrin receptor. 
SGT-53 selectively transfects cancer cells (below) relative to normal cells (above) due to high 
expression of the transferrin receptor. (Inset): Liposomal nanoparticle vector encoding wild-type 
p53 targeted with a single-chain antibody specific for the transferrin receptor.


Targeting Tumors Using Nanoparticle Platforms: A Phase I Study of a Systemically Administered Gene Therapy System

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Targeting Tumors Using Nanoparticle Platforms: A Phase I Study of a Systemically Administered Gene Therapy System

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