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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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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 V Vector engineering Efflux inhibition Vector delivery
Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy
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 Efficacy • Deliver • Deposit • Detain • Destroy
Conventional delivery ? Enhanced delivery
Vector Delivery • Catheter design • Therapeutic Vectors • Radio-immunotherapy • Vector engineering • Cell delivery therapies • Gene delivery techniques
Catheter & Stent Construction • Drug-eluting stents • Seeking oncological applications • Endovascular in vivo bioengineering • Gene delivery into endothelial cells • Why not take advantage of angiogenesis?
Vector Delivery • Catheter design • Therapeutic Vectors • Radioimmunotherapy • Vector engineering • Cell delivery therapies • Gene delivery techniques
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!
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 avb3 • Immunoliposomes: • Phage display technology • Multi-targeted probes • Tumor receptors: • Proteases, MMP’s & growth factors • VEGF: diagnostic & therapeutic Doxo Gad
Targeting tumor-associated cells: • Tumor-recruited systemic macrophages • Therapeutic macrophage recruitment
Tumor permeability • Sterically-stabilized liposomes
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
Cell recruitment • Image-guided MCF delivery • RFA recruits macrophages • Depots for drug and gene delivery
RF-recruited intratumoral macrophages Liposomal Doxorubicin delivery and release
Adoptive immunotherapy: • Lymphokine-activated killer cells • Tumor-infiltrating lymphocytes (TIL’s) aCEA aCEA cDNA
Gene-Based Therapies • Tissue-specific promoters: • VEGF: activated by angiogenesis • Inducible enhancers: • Heat, hypoxia or ultrasound
Inducible enhancers of gene expression Enhancer subunit Promoter subunit
Inducible enhancers of gene expression • Hypoxia enhances gene expression (VEGF) Hypoxia-inducible factors + Enhancer subunit VEGF gene
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 Efficacy • Deliver • Deposit • Detain • Destroy
Enhance Delivery • Drugs to modulate microvascular permeability • Mechanical delivery enhancers
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 Body Surface Magnetic Field
Magnetic Targeted Carriers Potentiation of effects of RF ablation by iron
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 ChemotherapyDestruction of Blood Supply Immediately after ablation 2 weeks after ablation
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
Biomaterial • (Antibodies) Structural Polymer (US degraded) • Drug or Gene Sonoporation
Local release of gene inside a tumor Liposome
Hepatic ultrasound-delivered Doxorubicin No ultrasound Ultrasound
Hepatic ultrasound-delivered Doxorubicin Liver Tumor No ultrasound Ultrasound
Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy
Efflux inhibitors • Pharmacological inhibitors • ATP-dependent membrane pumps • P-glycoprotein MDR pump • Cyclosporin; verapamil • MDR-associated proteins • Mechanical inhibitors • Catheter design
Inhibition of Doxorubicin efflux by Cyclosporin A CX1 human colon cancer cell
Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy
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