Immuno-targeting of pancreatic cancer stem cells: A new therapeutic strategy against a devastating disease?

2012·0.34 MB·English

by  Cioffi, Michele

OncoImmunology1:4,560–562;July2012;G2012LandesBioscience
Immuno-targeting of pancreatic cancer stem cells
A new therapeutic strategy against a devastating disease?
Michele Cioffi and Christopher Heeschen*
StemCells&CancerGroup;ClinicalResearchProgramme;SpanishNationalCancerResearchCentre(CNIO);Madrid,Spain
Keywords: pancreatic cancer, cancer stem cells, bispecific antibody, xenograft, CD133, EpCAM
Abbreviations: PDAC, pancreatic ductal adenocarcinoma; CSC, cancer stem cell; EpCAM, epithelial cell adhesion molecule;
PBMC, peripheral blood-derived mononuclear cells
Pancreatic cancer is a highly aggressive and deadly disease harboring a distinct population of cancer stem cells (CSC)
that is not affected by conventional therapies. A new therapeutic approach using the EpCAM/CD3-bispecific antibody
MT110iscapableofactivatingandredirectingcytotoxicTcellstoeliminateprimaryhumanpancreaticcancerstemcells,
whichresulted inlong-term survival ofpreclinical xenografts models.
© 2012 Landes Bioscience.
Pancreaticductaladenocarcinoma(PDAC), at the top of the hierarchy are driving genetic and epigenetic alterations.
the most frequent form of pancreatic metastasis and are resistant to chemother- Immuno-based treatment strategies are a
cancer, is the deadliest solid cancer and apy.4 If sufficient amounts of gemcitabine newly emerging therapeutic modality for
currently the fourth most frequent cause are delivered to the cancer cells in vivo, PDAC, where immune effector mech-
of cancer-related deaths.1 PDAC is char- which can be achieved by concomitant anismcanbeinducedanddirectedtoward
Do not distribute.
acterized by late diagnosis due to lack of administration of stroma-targeting agents antigens preferentially expressed by tumor
early symptoms, extensive metastasis, and such as inhibitors of the hedgehog path- cells including CSC.
highresistancetochemotherapyandradia- way, the bulk of the tumor cells can Several antigens have been identified
tion. Despite expanding research activities indeed be successfully erased as evidenced in the past years to target tumor cells. A
in the field of pancreatic tumor and by tumor shrinkage. However, as this recent study by Visus and colleagues took
vascular biology, there has been little initial success is only followed by relapse, advantage of the ALDH activity as a
therapeutic progress regarding clinical a plausible explanation is that surviving marker to identify and selectively target
endpoints over the past decades. Since CSCs are the source of treatment resist- theCSCpopulationusingseveralcelllines
the 1990s, the anti-metabolite gemcita- anceandshouldatleastinpartaccountfor including pancreatic cancer cells.7 The
bine emerged as the gold standard for the dismissal prognosis of these patients. authors generated in vitro ALDH1A1-
treating patients with PDAC but with a Initial studies from our groups are now specificCD8+Tcellsinordertoeliminate
5-y survival rate of 1–4% and a median providing increasing evidence that direct ALDHbright CSC in preclinical models of
survival period of 4–6 mo, the prognosis targeting of pancreas CSCs in combina- human tumor xenografts and observed
of patients with advanced PDAC remains tion with elimination of the more differ- growth inhibition and reduced metastasis.
extremely poor.2 entiated tumor cells bears therapeutic However, a major concern for this appro-
Since the establishment of the cancer value as this significantly prolonged sur- ach represents the fact that ALDH1A1-
stemcell(CSC)hypothesisforleukemiain vival in preclinical xenograft models.5,6 specific CD8+ T cells will most likely also
1994,3 convincing evidence has also While these studies were based on the targetnormalALDHbrightstemcells,which
emerged for solid tumors that, like adult inhibition of key regulatory pathways that can for example be found in the hemato-
tissues, are sustained and promoted by are crucially relevant for the self-renew poietic system.
cellsthatexhibitfeaturesofstemcellssuch capacity of CSC, more recently, we have In our recent work,8 we evaluated the
asunlimitedself-renewalcapacity.Weand alsoaskedaboutthecapabilityofimmune- therapeutic value of the bispecific anti-
others have recently provided conclusive based therapy to target pancreatic CSC. bodyMT110targetingtheT-cell receptor
evidence for a hierarchical organization of Immune-based therapies could bear the CD3 complexandEpithelial celladhesion
human PDAC and, even more impor- putative advantage of targeting CSC molecule (EpCAM; CD326). EpCAM is
tantly, demonstrated that pancreatic CSC irrespective of potentially very diverse frequently overexpressed and functionally
*Correspondenceto:ChristopherHeeschen;Email:[email protected]
Submitted:01/13/12;Accepted:01/13/12
http://dx.doi.org/10.4161/onci.19368
560 OncoImmunology Volume1Issue4
AUTHOR'SVIEW
altered in epithelial cancer cells, including
CSC,9andthereforeisbecomingaccessible
onthesurfaceofthesecells.Incontrast,in
normalepithelialcellsandembryonicstem
cells, EpCAM is sequestered within inter-
cellular boundaries. Therefore, EpCAM
representsapromisingtargetforimmuno-
therapy of EpCAM-expressing cancer cells
including tumorigenic CSCs.
We first evaluated the effect of MT110
using a dose escalation and time depend-
ent approach in three different primary
PDAC cells isolated from human cancer
tissue samples. We observed that T cells
reach maximal activity for inducing apop-
tosis of cancer cells at a concentration of
100 ng/ml MT110, as demonstrated by
flow cytometry analysis for early T-cell
activation marker CD69 and late activa-
tion marker CD25. Subsequent flow
© 2012 Landes Bioscience.
cytometry analysis for CSC markers iden-
tifiedbyexpressionofCD133andSSEA1,
respectively, showed a significant reduc-
tion in the CSC population implying that Figure1.ActivationofTcellsbyMT110againstcancercellsandcancerstemcells.
they are not spared from the cytotoxic
activityofactivatedTcells.Moreover,asa
Do not distribute.
surrogate assay for the self-renewal capa- analysis of harvested tumors, which provideanexplanationforourobservation
city of CSCs, we examined the sphere revealed a depletion for cells expressing that A6L was less responsive to MT110
formation capacity of the cells following CD133, SSEA-1, and CXCR4 as well treatment.
treatment with MT110. As predicted, as significantly reduced sphere-formation MT110 is currently tested in a dose-
primary cancer cells exposed to MT110 capacityintheMT110groupascompared escalating Phase I clinical trial enrolling
for 7 d showed a significant decline in with tumors harvested from mice treated patients with diverse epithelial cancers
sphere formation. with control BiTE. (lung, colon, gastric). Low toxicity and
The most defining feature of CSC is Apparently, the efficacy of this treat- early signs of biological activity have
their ability to exclusively form tumors in ment approach is dependent on the level been observed at clinically well-tolerated
vivo. Indeed, CSC treated for 7 d with of EpCAM expression. In our model doses of MT110 in this first-in-human
MT110 and then implanted into mice system, we compared 185 cells, which clinical trial. Our results derived from
had completely lost their in vivo tumor- were derived from a primary PDAC, and preclinical PDAC models now suggest
igenicity. Finally and most importantly, A6L cells,whichwere derived fromaliver that this treatment regimen could also
we then studied the treatment effects metastasis. Flow cytometry revealed that represent a new opportunity for patients
of MT110 in vivo using a model of 185 cells were all EpCAM positive, while with PDAC. It is important to note,
established primary human PDAC co- A6L cells also harbored an EpCAM- however, that the strong fibroblastic
implanted with healthy donor-derived negative subpopulation, which could be nature of PDAC results in poor tumor
PBMC. After administration of MT110 further enriched during sphere formation. vascularization and may therefore require
we observed a complete stall in tumor Spheres derived from EpCAM-negative simultaneous targeting of the stroma,
growth over the entire follow-up period cells are invasive CSC that probably e.g., by the addition of hedgehog path-
indicating that the tumors were depleted underwent epithelial-to-mesenchymal way inhibitors for sufficient delivery of
for tumorigenic/tumor-promoting CSC. transition (EMT).10 The presence of this MT110 to the cancer cells including the
Thiswasalsoconfirmedbyflowcytometry EpCAM negative subpopulation may CSC subpopulation.6
www.landesbioscience.com OncoImmunology 561
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