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Emerging Techniques and Technologies for Treatment of Solid Tumors

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

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  1. 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

  2. Challenges for Treating Solid Tumors V Vector engineering Efflux inhibition Vector delivery

  3. Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy

  4. 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

  5. Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy

  6. Conventional delivery ? Enhanced delivery

  7. Vector Delivery • Catheter design • Therapeutic Vectors • Radio-immunotherapy • Vector engineering • Cell delivery therapies • Gene delivery techniques

  8. Catheter & Stent Construction • Drug-eluting stents • Seeking oncological applications • Endovascular in vivo bioengineering • Gene delivery into endothelial cells • Why not take advantage of angiogenesis?

  9. Vector Delivery • Catheter design • Therapeutic Vectors • Radioimmunotherapy • Vector engineering • Cell delivery therapies • Gene delivery techniques

  10. 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!

  11. 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

  12. Vector Engineering avb3 • Immunoliposomes: • Phage display technology • Multi-targeted probes • Tumor receptors: • Proteases, MMP’s & growth factors • VEGF: diagnostic & therapeutic Doxo Gad

  13. Targeting tumor-associated cells: • Tumor-recruited systemic macrophages • Therapeutic macrophage recruitment

  14. Tumor permeability • Sterically-stabilized liposomes

  15. 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

  16. Cell recruitment • Image-guided MCF delivery • RFA recruits macrophages • Depots for drug and gene delivery

  17. RF-recruited intratumoral macrophages Liposomal Doxorubicin delivery and release

  18. Adoptive immunotherapy: • Lymphokine-activated killer cells • Tumor-infiltrating lymphocytes (TIL’s) aCEA aCEA cDNA

  19. Tumor-directed tumor-infiltrating lymphocytes

  20. Gene-Based Therapies • Tissue-specific promoters: • VEGF: activated by angiogenesis • Inducible enhancers: • Heat, hypoxia or ultrasound

  21. Inducible enhancers of gene expression Enhancer subunit Promoter subunit

  22. Inducible enhancers of gene expression • Hypoxia enhances gene expression (VEGF) Hypoxia-inducible factors + Enhancer subunit VEGF gene

  23. 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?

  24. Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy

  25. Enhance Delivery • Drugs to modulate microvascular permeability • Mechanical delivery enhancers

  26. 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

  27. RF-induced tumor permeability

  28. MTC Delivery to Target Tissue/Organ Body Surface Magnetic Field

  29. Magnetic Targeted Carriers Potentiation of effects of RF ablation by iron

  30. Cooperative Therapies • RF recruitment of targetable macrophages • P53 radiation sensitization • Radiation-inducible promoters • Thermally-activated vectors • In vivo electroporation • RF & liposomal chemotherapy

  31. Combined RF/Doxil ChemotherapyDestruction of Blood Supply Immediately after ablation 2 weeks after ablation

  32. 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

  33. Biomaterial • (Antibodies) Structural Polymer (US degraded) • Drug or Gene Sonoporation

  34. Local release of gene inside a tumor Liposome

  35. Hepatic ultrasound-delivered Doxorubicin No ultrasound Ultrasound

  36. Hepatic ultrasound-delivered Doxorubicin Liver Tumor No ultrasound Ultrasound

  37. Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy

  38. Efflux inhibitors • Pharmacological inhibitors • ATP-dependent membrane pumps • P-glycoprotein MDR pump • Cyclosporin; verapamil • MDR-associated proteins • Mechanical inhibitors • Catheter design

  39. Inhibition of Doxorubicin efflux by Cyclosporin A CX1 human colon cancer cell

  40. Enhancing Payload Efficacy • Deliver • Deposit • Detain • Destroy

  41. 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

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