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H ARVARD MEDICAL SCHOOL B ETH I SRAEL D EACONESS M EDICAL C ENTER Emerging Techniques and Technologies for Treatment of Solid Tumors Jonathan B. Kruskal, M.D., Ph.D. Director, Abdominal Imaging Challenges for Treating Solid Tumors V Vector engineering Efflux inhibition

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emerging techniques and technologies for treatment of solid tumors

HARVARD

MEDICAL

SCHOOL

BETH ISRAEL DEACONESS

MEDICAL CENTER

Emerging Techniques and Technologies for Treatment of Solid Tumors

Jonathan B. Kruskal, M.D., Ph.D.

Director, Abdominal Imaging

challenges for treating solid tumors
Challenges for Treating Solid Tumors

V

Vector engineering

Efflux inhibition

Vector delivery

enhancing payload efficacy
Enhancing Payload Efficacy
  • Deliver
  • Deposit
  • Detain
  • Destroy
innovations in solid tumor treatment
Innovations in Solid Tumor Treatment
  • Endovascular advances
    • Vector engineering
    • Gene & cell-based therapies
    • Catheter construction
  • Interstitial treatments
    • Thermal ablation (RF, MW, cryo, HIFU)
  • Efflux inhibition
    • Interstitial pressure & MDR blockade
enhancing payload efficacy5
Enhancing Payload Efficacy
  • Deliver
  • Deposit
  • Detain
  • Destroy
slide6

Conventional delivery

?

Enhanced delivery

slide7
Vector Delivery
    • Catheter design
  • Therapeutic Vectors
    • Radio-immunotherapy
    • Vector engineering
    • Cell delivery therapies
    • Gene delivery techniques
catheter stent construction
Catheter & Stent Construction
  • Drug-eluting stents
    • Seeking oncological applications
  • Endovascular in vivo bioengineering
    • Gene delivery into endothelial cells
    • Why not take advantage of angiogenesis?
slide10
Vector Delivery
    • Catheter design
  • Therapeutic Vectors
    • Radioimmunotherapy
    • Vector engineering
    • Cell delivery therapies
    • Gene delivery techniques
radioimmunotherapy
Radioimmunotherapy
  • Selective Internal Radiation Therapy
    • 90-Yttrium microspheres (32mm; resin)
    • Intra-arterial delivery to tumors
    • Preferential deposition in vascular tissue
    • Therapeutic dose to tumor, not organ
    • Greater radiation exposure than XRT
    • But, lets optimize this technology!
slide12
I131-CEA monoclonal antibody
    • Antibodies target CEA on cell surface
    • Deliver I131 to surface of tumor cell (& colon)
    • Are internalization techniques needed?

RFA/heat

Sonoporation

UV light

vector engineering
Vector Engineering

avb3

  • Immunoliposomes:
    • Phage display technology
    • Multi-targeted probes
  • Tumor receptors:
    • Proteases, MMP’s & growth factors
    • VEGF: diagnostic & therapeutic

Doxo

Gad

slide14
Targeting tumor-associated cells:
      • Tumor-recruited systemic macrophages
      • Therapeutic macrophage recruitment
slide15
Tumor permeability
    • Sterically-stabilized liposomes
cell based therapies
Cell-Based Therapies
  • Cell transplantation:
    • Persistent expression by transduced cells
    • Fibroblasts and dendritic cells
    • Await techniques for improved targeting
    • Intrasplenic hepatocytes
  • Cell recruitment
  • Adoptive immunotherapy
slide17
Cell recruitment
    • Image-guided MCF delivery
    • RFA recruits macrophages
    • Depots for drug and gene delivery
slide18

RF-recruited intratumoral macrophages

Liposomal Doxorubicin delivery and release

slide19
Adoptive immunotherapy:
    • Lymphokine-activated killer cells
    • Tumor-infiltrating lymphocytes (TIL’s)

aCEA

aCEA cDNA

gene based therapies
Gene-Based Therapies
  • Tissue-specific promoters:
    • VEGF: activated by angiogenesis
  • Inducible enhancers:
    • Heat, hypoxia or ultrasound
slide22

Inducible enhancers of gene expression

Enhancer subunit

Promoter subunit

slide23

Inducible enhancers of gene expression

    • Hypoxia enhances gene expression (VEGF)

Hypoxia-inducible factors

+

Enhancer subunit

VEGF gene

slide24

Inducible promoters of gene expression

    • Ultrasound induces heat shock protein expression

Targeted US results in local heat delivery

US waves

Promoter subunit activated by HSP

What about other local sources of heat?

enhancing payload efficacy25
Enhancing Payload Efficacy
  • Deliver
  • Deposit
  • Detain
  • Destroy
enhance delivery
Enhance Delivery
  • Drugs to modulate microvascular permeability
  • Mechanical delivery enhancers
slide27
Pretargeting & endoluminal enhancement:
    • VEGF to increase endothelial pore size
    • Transient permeability enhancers: vasoactive peptides (IF-b, RMP-7, TNF-a, LT C4)
    • Platelet activating factor, FGF, Bradykinin
    • Osmotic endothelial disruption with mannitol
    • Mechanical enhancement:
      • RF ablation and electroporesis/iontophoresis
mtc delivery to target tissue organ
MTC Delivery to Target Tissue/Organ

Body

Surface

Magnetic Field

slide30

Magnetic

Targeted

Carriers

Potentiation of effects of RF ablation by iron

slide31

Cooperative Therapies

  • RF recruitment of targetable macrophages
  • P53 radiation sensitization
  • Radiation-inducible promoters
  • Thermally-activated vectors
  • In vivo electroporation
  • RF & liposomal chemotherapy
combined rf doxil chemotherapy destruction of blood supply
Combined RF/Doxil ChemotherapyDestruction of Blood Supply

Immediately after ablation

2 weeks after ablation

slide34
In situ activation of expression:
    • Induce local liberation of contents
      • Photoactivation, radiation, US or RFA
    • Heat sensitive (LTS) or neutral liposomes
      • In situ reduction & redistribution
    • Sonoporation of liposomes or contrast agents
      • US induces gene uptake & expression
slide35

Biomaterial

  • (Antibodies)

Structural

Polymer

(US degraded)

  • Drug or Gene

Sonoporation

slide36

Local release of gene

inside a tumor

Liposome

slide38

Hepatic ultrasound-delivered Doxorubicin

Liver Tumor

No ultrasound

Ultrasound

enhancing payload efficacy39
Enhancing Payload Efficacy
  • Deliver
  • Deposit
  • Detain
  • Destroy
efflux inhibitors
Efflux inhibitors
  • Pharmacological inhibitors
    • ATP-dependent membrane pumps
    • P-glycoprotein MDR pump
      • Cyclosporin; verapamil
    • MDR-associated proteins
  • Mechanical inhibitors
    • Catheter design
enhancing payload efficacy42
Enhancing Payload Efficacy
  • Deliver
  • Deposit
  • Detain
  • Destroy
summary
Summary
  • For treatment of solid tumors, a variety of emerging techniques & technologies exist:
    • Many opportunities available for technical optimization, including combination therapies
    • In order to progress:
      • Await good quality peer-reviewed science
      • Need randomized prospective clinical trials