Research Highlights

PD-L1 Expression in APCs Key to pulmonary tree into the bloodstream and subsequently the myocar-
dium, where the therapeutic cargo is quickly released. Using rodent
Immunotherapy Success models of diabetic heart failure, the researchers showed that inhalation
While immunotherapy has had a big impact on cancer treatment, of CaPs loaded with a therapeutic mimetic peptide, previously shown to
only about a quarter of patients respond to these treatments. A improve myocardial contraction, restored cardiac function. Inhaling
study recently published in the Journal of Clinical Investigation the particles was not toxic to healthy heart tissue in mice or rats. The
offers new clues as to the reasons behind these numbers. The authors also showed that CaPs rapidly accumulated in the heart after
researchers studied mice with colon cancer, ovarian cancer, mela- inhalation in healthy pigs, which have similar respiratory systems to
noma, and lung cancer to understand how expression of PD-L1 humans. According to the authors, further studies are needed to eval-
affects response to its blockade. The researchers found a key link uate the long-term safety of the nanoparticles and determine how
in the antigen presenting cells (APCs)—macrophages and dendritic they cross the pulmonary barrier, but inhalation therapy could reduce
cells found in the tumor microenvironment and in the nearby lymph the doses of active compounds needed to treat heart failure, thanks to
nodes. According to the authors, PD-L1 expression in APCs is rapid and direct drug delivery to cardiac tissue. (Sci Transl Med. 10,
responsible for response to therapy. In 2003, in a paper published eaan6205; https://doi.org/10.1126/scitranslmed.aan6205.)
in Nature Medicine, the research team showed that dendritic cells ex-
press PD-L1 and that its blockade on APCs causes tumor regression Double-Duty Immunotherapy Shows
in model systems. When the FDA approved immunotherapy drugs Promise in Mouse Models
designed to block PD-L1 and PD-1, the indication said patients’
tumors must express PD-L1. But, these therapies have worked in pa- A new cancer therapy that blocks two immune system-suppressing
tients whose tumor cells did not express PD-L1, and they have failed pathways hindered tumor growth, prevented metastasis, and pro-
in patients whose tumor cells do, demonstrating that it is not a reli- longed survival in multiple mouse models, according to a study appear-
able biomarker for response. In the new study, the researchers exam- ing recently in Science Translational Medicine. Targeting two pathways
ined tissue samples from melanoma and ovarian cancer patients with a single molecule has strategic advantages over the traditional
treated with immunotherapies. In both cancers, they found a link be- approach of combining multiple treatment agents, and the double-
tween the percent of APCs expressing PD-L1 and an objective clin- acting immunotherapy can be coupled with conventional chemo-
ical response to treatment. Currently, tumor tissue is tested broadly therapy or radiation. Checkpoint blockade antibodies like avelumab
for PD-L1 expression. Without looking at individual cells within the have transformed cancer treatment by preventing tumors from exploit-
tissue, however, the true source of PD-L1 expression could be ing a built-in immunosuppressive network that dampens T cell activity
masked. The study suggests a more complicated analysis, looking in normal function, which is controlled by the molecules PD-1 and PD-
for additional markers might be more informative in guiding treat- L1. However, only a minority of patients respond to anti-PD-1 or PD-
ment. (J Clin Invest. Published online 16 January, 2018; https://doi. L1 therapies, thus motivating the authors to create a new compound
org/10.1172/JCI96061.) capable of targeting additional immunosuppressive pathways. Because
anti-PD-1 resistance in melanoma has been linked to increased expres-
sion of genes regulated by the protein TGF-b, they generated M7824—
Inhalable Heart Treatment a PD-L1-blocking antibody combined with a TGF-b-binding “trap.”
Scientists have devised an Treatment with M7824 prolonged survival more effectively than
inhalable treatment for heart anti-PD-L1 or the TGF-b trap alone in mouse models of breast and
failure that could help overcome colorectal cancers and also conferred long-term protective anti-tumor
the many limitations of inject- immunity in the animals. When M7824 was used with localized radi-
able or orally administered ation therapy in mouse models of colorectal cancer, the treatment also
therapies. The new drug deliv- shrank unirradiated tumors at secondary sites. M7824 treatment led to
ery approach—consisting of fewer metastases compared with monotherapies, leading the authors to
biocompatible and biodegrad- speculate that PD-L1 might also contribute to cancer invasiveness.
able nanoparticles loaded with M7824 is being further investigated in phase 1 studies evaluating pa-
therapy—quickly targeted heart tissue in mice and pigs, which the au- tients with advanced solid tumors. (Sci Transl Med. 10, eaan5488;
thors say could help make convenient, home-based treatments a reality https://doi.org/10.1126/scitranslmed.aan5488.)
for chronic heart failure patients. The study appeared recently in Sci-
ence Translational Medicine. Cardiovascular disease is the leading cause Cancer-Killing Viruses Render
of death worldwide, claiming roughly 17.5 million lives per year around
the world. Most heart failure drugs are given orally (which can lead to
Immunotherapy More Effective
unreliable absorption) or by intravenous injection (which can cause Two new studies appearing in Science Translational Medicine in early
patient discomfort). The new study shows that inhalation of small January report that treatment with oncolytic viruses can make brain
(<50 nm in diameter) biocompatible and biodegradable calcium phos- and breast cancers susceptible to immune checkpoint inhibitor ther-
phate nanoparticles (CaPs) leads to their rapid translocation from the apy. The new findings could pave the way for combination regimens

332 Molecular Therapy Vol. 26 No 2 February 2018

Research Highlights

of oncolytic virus followed by growth. In mouse models of breast cancer, treatment with anti-
immunotherapy to treat multi- TNFR2 antibody enhanced survival, whereas a different Treg-targeting
ple types of tumors that are strategy did not prolong lifespans, and both therapies administered
currently associated with bleak together shrank tumors. The authors say future studies should compare
outcomes. In one study, a phase and combine TNFR2 targeting with other Treg checkpoint inhibitors.
1 clinical trial of nine human pa- (Sci Signal. 11, eaan0790; https://doi.org/10.1126/scisignal.aan0790.)
tients with high-grade glioma,
Samson et al. demonstrated for Biomaterials Fast-Track T Cell Therapies
the first time that the oncolytic virus reovirus can cross the notoriously
difficult-to-penetrate blood-brain barrier after being delivered intra-
venously. Samples taken during planned surgical resections of the pa-
tients’ tumors provided evidence that the oncolytic virus treatment
triggered T cell invasion and elevated PD-L1 expression inside can-
cers—both of which are necessary for checkpoint blockade to effec-
tively unleash the immune system and eliminate malignant cells.
The scientists went on to demonstrate that oncolytic virus treatment
followed by checkpoint blockade prolonged survival in mouse models
of high-grade glioma. A second analysis by Bourgeois-Daigneault and Adoptive cell transfer involves taking T cells from patients, sometimes
colleagues used a different oncolytic virus (the Maraba virus) in genetically modifying them, and then multiplying them in vitro before
conjunction with checkpoint blockade to shrink tumors and prolong returning them to patients so that they can, for example, locate and kill
survival in mouse models of breast cancer. Importantly, Bourgeois- cancer cells. However, these procedures often take weeks to produce
Daigneault et al. observed that Maraba virus treatment before surgical batches of therapeutic T cells that are large and reactive enough to
resection led to long-lasting and personalized anti-tumor immunity in be able to eliminate their target cells. A new study appearing in Nature
the mice, hinting that such therapies could be used to prevent cancer Biotechnology now describes an alternative material-based T cell-
relapse. Both groups of authors advocate for testing oncolytic virus expansion method that could help surmount these obstacles. With
therapy in patients at earlier stages of disease, which might allow an APC-mimetic biomaterial scaffold, the researchers achieved greater
for an even stronger immune response. (Sci Transl Med. 10, expansion of primary mouse and human T cells than with existing
eaam7577; https://doi.org/10.1126/scitranslmed.aam7577 and Sci methods, and they demonstrated the approach’s potential in a mouse
Transl Med. 10, eaao1641; https://doi.org/10.1126/scitranslmed. lymphoma model treated with chimeric antigen receptor-expressing
aao1641.) T cells (CAR-T cells) that are engineered to home in on and destroy
lymphoma cells. To engineer an APC-mimetic scaffold, the team first
loaded tiny mesoporous silica rods (MSRs) with interleukin 2 (IL-2),
Regulatory T Cells: Prime Suspects to an APC-produced factor that prolongs the survival of associated
Increase and Broaden Immunotherapy T cells. The MSRs were then coated with lipids that formed a thin sup-
ported lipid bilayer, which resembles the outer membrane of APCs
Efficacy? and that the researchers then functionalized with a pair of T cell-stim-
Researchers have boosted the antitumor effects of cancer immuno- ulating antibodies that remain mobile in the lipid layer and can bind to
therapy in mice by blocking a protein found on immune cells called receptor/co-receptor molecules on the surface of T cells. In culture me-
TNFR2. Writing in Science Signaling, they say that combining dium, 3D scaffolds spontaneously formed through the settling and
TNFR2 inhibitors with immune-stimulating agents might be a prom- random stacking of the rods, forming pores big enough to allow the
ising treatment strategy for patients with various cancers. One major entry, movement, and accumulation of T cells, thereby signaling
goal for cancer treatment is to overcome tumors’ abilities to evade them to multiply. The team demonstrated that APC-mimetic scaffolds
and suppress the immune system. Some tumors contain large amounts performed better than methods involving commercially available
of strongly immunosuppressive cells called regulatory T cells (Tregs), expansion beads (Dynabeads), which are currently used in clinical
which display TNFR2 on their surfaces. Reasoning that targeting Tregs adoptive cell transfer approaches. An APC-mimetic scaffold that
could prevent the cells from dampening anti-cancer responses, Nie and was engineered to activate a specific type of CAR-T cell was able to
colleagues devised a combination regimen composed of a TNFR2- generate higher numbers of the modified T cells over longer periods
blocking antibody (dubbed M861) and low doses of an immune-stim- of culture than analogously designed expansion beads, and the result-
ulating molecule called CpG ODN. In mouse models of colon cancer, ing cells were similarly effective in killing the lymphoma cells in the
the combination of M861 and CpG ODN potently inhibited tumor mice. After successfully using the material to expand all T cells present
growth, with 80% of treated animals becoming completely tumor- in a sample, the team demonstrated that APC-mimetic scaffolds could
free. Importantly, rodents treated with the dual regimen developed also be used to expand antigen-specific T cell clones from a more com-
long-term immunological memory against colon cancer. When admin- plex mixture of cells. (Nat Biotechnol. Published online 15 January,
istered alone, neither M861 nor CpG ODN effectively stopped tumor 2018; https://doi.org/10.1038/nbt.4047.)

Molecular Therapy Vol. 26 No 2 February 2018 333