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2. Outline:
Stem cell for therapeutic delivery
Creating anti cancer stem cells
Genetic modification of SC to secrete anticancer proteins
Genetic modification of stem cells to induce cancer cell death
Stem cell as a nanoparticle carriers
Stem cells loaded with oncolytic virus
Potential stem cell efficacy
Enhancing innate stem cells behavior
genetic manipulation of SC
 immune evasion: non-genetic modification
enhancing tumor tropism
Enhancing stem cell efficacy using combination therapies: to sensitize or synergize
Novel development of stem cells: encapsulation
Therapeutic stem cells in clinical trial
Why is there a paucity of clinical trials using these cells
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3. Three methods for treating cancer
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The major drawback
the lack of selectivity

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Many adult stem cells show intrinsic tumor-tropic properties
Attractive candidate for the targeted delivery of anticancer biological agents
The strategy is twofold
Site-specific delivery: SCs can disseminate solid tumors and migrate towards micrometastatic
lesions
SCs can be modified to stably express or release various
anticancer agents
SCs as a new candidate for cancer treatment

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The development of preclinical SC therapies remain voracious
Translating the most promising into the clinic necessitates much technical
and regulatory traversal
SC research as an interesting field
There is a need to separate the hope from the hype

6. Problems that are associated with anticancer agents delivery
Unfavorable pharmacokinetics: short half-life and biotransformation
Difficulty in producing sustained and officious concentrations in the vicinity of the tumor
In brain cancer: BBB
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7. The use of SCs as cellular delivery agents has been posed as a novel means to
tackle these challenges
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8. To maximize the therapeutic impact of SC therapy
SC should evade the host immune system and home toward malignant foci
SCs have immunosupressive property
The migratory capacity of NSCs and neural progenitors was initially shown in xenograft mouse models
by their ability to home to
intracranial brain tumors
and
non-neural tumors in other regions of body
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9. Signaling pathways that have a major role in the SCs migration
SDF1-CXCR4
PI3K
Urokinase-type plasminogen activator(uPA)-uPA receptor
VEGEFR2
Matrix metalloproteinase1-proteinase activated receptor
The degree of SC migration
Nature of the SC
Culture condition
Expression of migratory factors
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SDF1

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Creating anti cancer stem cells
Genetic modification of SC to secrete anticancer proteins
SCs modified by viral transduction to express transgens encoding secretable effector proteins
Pro-apoptotic protein TRAIL that binds to death receptor DR4 and DR5
SC- expression of biological agents that block the binding of endogenous ligand to their receptor
Such as Proteins that bind to EGFR or EGFRvIII
Cytokines such as IFN beta or alpha
They act Directly on malignant cells or on supporting cells of tumor

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Indirect effectors
Inhibition of angiogenesis
TSP1 and PEX
Secretion of immunomodulatory molecules
Secretion of IL-12 or IL-18 by MSC: renal cell carcinoma, cervical tumors and glioblastoma

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TSP1
And
A fragment of MMP-2, which comprises the
C-terminal hemopexin-like domain, termed
PEX

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Genetic modification of stem cells to induce cancer cell death
SC engineered to express an enzyme that converts a non-toxic prodrug into a cytotoxic drug
5-flurouracil
A: 5-fluroCytosine
cytosine deaminas
B:Granciclovir(GCK)
GCK-monophosphate
HSV-tK
C:irinotecan Potent topoisomerase inhibitor
SN-38
carboxylestrase
A:NSC and MSC/in mouse model for brain tumors
C: Preclinical models of ovarian and lung cancer
B:Animal models of glioblastoma ,breast and prostat cancer

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Nanoparticle carriers
High concentration of chemotherapeutic reagents
Protecting them from degradation
Modification of their surface to alter
Stability
Solubility
Targeting
Disadvantage:
Inefficient clearance and dissemination in solid tumors
Failure to target micrometastatic lesions
One approach to overcome these barriers is to use SCs as
nanoparticle delivery agents

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Stem cells as nanoparticle carriers
Loading with nanoparticles and administered in vivo
Migrate to malignancies and deposit it
Its successful implementation requires Much technical consideration Including
Establishing an efficient means to load SC without affecting their intrinsic properties
Controlling the release of nanoparticle From the SCs to ensure sustained targeted therapy
Loading the cell membrane of MSC with porous silica ‘nanorattles’ containg
doxorubicin
Induce apoptosis in intracranial tumorous more efficiently than injection of
doxorubicin

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Stem cells loaded with oncolytic virus
Oncolytic viruses have the ability to selectively replicate and kill tumor cells
Clearance by the host immune system
Insufficient viral distribution following intraumoural administration
oncolytic adenoviruses
Ovarian cancer in Murine models
Different SC types have been used as host cells for the transportation and local release of intact replicating
 MSC as carrier for measles virus to ovarian tumor
Oncolytic HSV has been modified for tumor-selective replication and is inherently neurotropic, which
makes it a promising candidate for brain tumor
MSC loaded with OHSV
Increasing antitumor efficacy in a clinically relevant glioblastoma models
Challenge:
To ensure absolute safety of the viral system to avoid complications in it’s clinical translation

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Bio Vex Inc, T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1
designed to selectively replicate within tumors and to produce GM-CSF
to enhance systemic antitumor immune responses
With the announcement of positive results in March 2013, T-VEC is the first oncolytic virus to be proven
effective in a Phase III clinical trial, melanoma
DNAtrix’s lead product, DNX-2401, is a conditionally-replicative oncolytic adenovirus that has been
engineered to specifically target a large number of tumor cell types.
Multiple genetic modifications have been made to the virus so that DNX-2401 selectively infects and kills
tumor cells while sparing normal healthy cell
Phase I, Glioblastoma

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Enhancing innate stem cells behavior
1- genetic manipulation of SC
Maximize the success of SC-based therapies, it is crucial that they survive in vivo until the entire cancer has been eliminated and that they
successfully migrate towards malignancies
Torikai et al
Used zinc finger nuclease to genetically edit HLAI in ESCs :these cells could escape lysis from HLA-resticted cytotoxic T Cells
To prevent immune rejection of ESC-derived allograftes,CTLA-4- Ig and PDL1 knock –in human ESCs

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2- immune evasion: non-genetic modification
Surface binding or intracellular loading of SCs with effectors moieties
MSCs can be loaded with micro particles containing chemicals that impart particular cellular characteristics to the
targeted cells
Cell-penetrating peptides (CPPs)
short peptides
facilitate cellular uptake of various molecular cargo
(from nanosize particles to small chemical molecules
and large fragments of DNA)
The function of the CPPs
to deliver the cargo into cells
CPPs hold great potential as in vitro and in vivo
delivery vectors for use in research and medicine.
 Current use is limited by
a lack of cell specificity in CPP-mediated cargo delivery
insufficient understanding of the modes of their uptake

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3-enhancing tumor tropism
HDAC inhibitors for MSC
Upregulation uPA/enhancimg
tumor-tropic behaviors
Cationic for HSC
Enhancing their mobilization
In low SDF1 gradients
Over expressing of
Chemokine receptor
Enhancing their migratoion

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Enhancing stem cell efficacy using combination therapies
Bimodal SC or bifunctional molecules
Bimodal SC
HSV-tK therapy with TRAIL in glioblastoma models
CD with IFN beta in glioblastoma,breast cancer models

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Novel development of stem cells: encapsulation

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Therapeutic stem cells in clinical trials
Geexin, inc
NCT02079324
MSC expressing IL-12(GX-051)
Advanced head and neck cancer
Garcia-Castro
ICOVIR-5:Auologous MSC loaded with oncolytic adenovirus
In 4 Childerens with metastatic neuroblastoma
Allogenic immortalized NSCs expressing CD
Recurrent glioblastoma
NCT01172946
Modified NSCs with leucovorin:NCT02015819
Or with irinotecan hydrochloride:NCT02055196
Surgical resection/injection of modified NSCs+oral prodrug 5-FC

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