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Combination thymidine kinase and interleukin-2 gene therapy for head and neck cancer in a murine model
Otolaryngology Head and Neck Surgery Volume 115 Number 2
Scientific Sessions Monday -
metastasis, and clinical progression of the disease. The use of elF-4E in distinguishing radiation necrosis from recurrent tumor and its possible role in identifying resection margins during surgery are being evaluated. 11:30 AM
Combination Thymidine Kinase and Interleukin-2 Gene Therapy for Head and Neck Cancer in a Murine Model BERTW. O'MALLEY, Jr., MD (presenter), and KEARYA. COPE, Baltimore, Md,, and Pittsburgh, Pa.
Combination therapy with use of adenovirus-mediated transfer of the herpes thymidine kinase (HSV-tk) and interleukin-2 (IL-2) genes was used to treat head and neck cancer in C3H/HeJ mice. Tumors were generated by direct injection of 5 x 105 murine squamous carcinoma cells into the floor of the mouth of these syngeneic mice. One week after tumor implantation, recombinant adenoviral vectors containing both therapeutic genes and control genes alone and in combination were injected directly into the established tumors, and subsequently all mice were administered ganciclovir twice daily (25 mg/kg) for 6 days. Animals treated with either HSV-tk alone or HSV-tk + IL-2 demonstrated significant tumor regression compared with those receiving IL-2 alone or a control vector (p < 0.008). Mice receiving combination HSV-tk + IL-2, however, also demonstrated a significantly greater regression of tumors compared with single agent HSV-tk alone (p < 0.008), indicating a synergistic effect of the combination gone therapy. This synergism was confirmed in survival studies as mice treated with HSV-tk + IL-2 showed increased survivals (p = 0.0002). Clinical and microscopic examination of regional surrounding tissues and distant organs showed no evidence of cytotoxicity for representative animals in each experimental group. These studies demonstrate efficacy of combination HSV-tk and IL-2 gene therapy and may provide a powerful new modality for the treatment of head and neck cancer. 11:45 AM Optimizing an Adenoviral-Mediated "Suicide Gene" Strategy for the Treatment of Head and Neck Cancer DUANE A. SEWELL, MD (presenter), DAQING LI, MD, and BERTW. O'MALLEY, Jr., MD, Baltimore, Md.
The most effective suicide gene therapy strategy in experimental studies to date uses the herpes simplex virus thymidine kinase gene (HSV-tk) to sensitize tumors to the cytotoxic effects of ganciclovir administration. Previous reports with highly efficient adenoviral vectors carrying HSV-tk to treat established tumors in animal models have focused on utilizing the highest possible viral titers. Also, high levels (not compatible with accepted human dosing) of ganciclovir in the range of 100 to 150 mg/kg twice daily have been used to confer cytotoxicity to the tumors in vivo. In the following studies we investigate tumor regression
-
P 73
in an oral squamous cell carcinoma animal model as a function of variable adenoviral titer and ganciclovir dosing. In multiple experiments using adenoviral titers ranging from i.3 x 10g plaque forming units (pfu) to 2.6 x 109 pfu to treat oral tumors, we found no statistical difference in tumor regression among the different viral doses. Each treatment group, however, demonstrated a significant effect to tumor regression when compared with controls treated with saline solution (p = 0.010 to p = 0.028). Furthermore, we were able to reduce the level of ganciclovir administration to 10 mg/kg twice daily while maintaining significant antitumoral responses to the HSV-tk therapy. The optimization of this suicide gone therapy strategy is imperative to minimize theoretical and known viral vector toxicities while establishing a foundation upon which to design appropriate and effective clinical trials.
SESSION B: Auditory System ( R o o m 21 -
WCC) M. CHARLES LIBERMAN, PhD, J. CHRISTOPHER POST, MD, and DEBARA L. TUCCI, M D (moderators), Boston, Mass., Pittsburgh, Pa., and Durham, N.C. 8:00 AM
Histopathology Findings in Human Temporal Bones Following Radiation Treatment, Cisplatinum Treatment, and C o m b i n e d Radiation and Cisplatinum Treatment DICK L. HOISTAD, MD (presenter), FRANK G, ONDREY, MD, PhD, GEORGE L. ADAMS, MD, FACS, and MICHAEL M. PAPARELLA, MD, Minneapolis, Minn., and Bethesda, Md.
Organ preservation with multimodal therapy has become a treatment strategy for head and neck squamous cell carcinoma (SCCa). Radiation and cisplatinum are two commonly used modalities that can have acute and delayed ototoxic effects to the temporal bone, causing decreased or total hearing loss. Thirteen patients were included in this project: four normal, five who received radiation treatment, two who received cisplatinum treatment, and two who received radiation and cisplatinum combined. Histopathologic findings were then compared amongst the patients. All patients who underwent radiation received 5500 rads or greater and demonstrated not only inner and outer hair cell loss, decreased spiral ganglion cell population, and stria vascularis changes, but small arteriole and venule intimal hypertrophy and fibrosis. These small vessel changes were not found in the cisplatinum group or normal group. We conclude that hearing loss experienced by patients undergoing organ preservation protocol could be a result not only of direct inner ear end organ injury but also vascular injury in the temporal bone as a result of radiation. As a result, prophylactic treatment to prevent small vessel injury may play a role in maintaining hearing in patients undergoing organ preservation protocol.
Scientific Sessions Monday -
metastasis, and clinical progression of the disease. The use of elF-4E in distinguishing radiation necrosis from recurrent tumor and its possible role in identifying resection margins during surgery are being evaluated. 11:30 AM
Combination Thymidine Kinase and Interleukin-2 Gene Therapy for Head and Neck Cancer in a Murine Model BERTW. O'MALLEY, Jr., MD (presenter), and KEARYA. COPE, Baltimore, Md,, and Pittsburgh, Pa.
Combination therapy with use of adenovirus-mediated transfer of the herpes thymidine kinase (HSV-tk) and interleukin-2 (IL-2) genes was used to treat head and neck cancer in C3H/HeJ mice. Tumors were generated by direct injection of 5 x 105 murine squamous carcinoma cells into the floor of the mouth of these syngeneic mice. One week after tumor implantation, recombinant adenoviral vectors containing both therapeutic genes and control genes alone and in combination were injected directly into the established tumors, and subsequently all mice were administered ganciclovir twice daily (25 mg/kg) for 6 days. Animals treated with either HSV-tk alone or HSV-tk + IL-2 demonstrated significant tumor regression compared with those receiving IL-2 alone or a control vector (p < 0.008). Mice receiving combination HSV-tk + IL-2, however, also demonstrated a significantly greater regression of tumors compared with single agent HSV-tk alone (p < 0.008), indicating a synergistic effect of the combination gone therapy. This synergism was confirmed in survival studies as mice treated with HSV-tk + IL-2 showed increased survivals (p = 0.0002). Clinical and microscopic examination of regional surrounding tissues and distant organs showed no evidence of cytotoxicity for representative animals in each experimental group. These studies demonstrate efficacy of combination HSV-tk and IL-2 gene therapy and may provide a powerful new modality for the treatment of head and neck cancer. 11:45 AM Optimizing an Adenoviral-Mediated "Suicide Gene" Strategy for the Treatment of Head and Neck Cancer DUANE A. SEWELL, MD (presenter), DAQING LI, MD, and BERTW. O'MALLEY, Jr., MD, Baltimore, Md.
The most effective suicide gene therapy strategy in experimental studies to date uses the herpes simplex virus thymidine kinase gene (HSV-tk) to sensitize tumors to the cytotoxic effects of ganciclovir administration. Previous reports with highly efficient adenoviral vectors carrying HSV-tk to treat established tumors in animal models have focused on utilizing the highest possible viral titers. Also, high levels (not compatible with accepted human dosing) of ganciclovir in the range of 100 to 150 mg/kg twice daily have been used to confer cytotoxicity to the tumors in vivo. In the following studies we investigate tumor regression
-
P 73
in an oral squamous cell carcinoma animal model as a function of variable adenoviral titer and ganciclovir dosing. In multiple experiments using adenoviral titers ranging from i.3 x 10g plaque forming units (pfu) to 2.6 x 109 pfu to treat oral tumors, we found no statistical difference in tumor regression among the different viral doses. Each treatment group, however, demonstrated a significant effect to tumor regression when compared with controls treated with saline solution (p = 0.010 to p = 0.028). Furthermore, we were able to reduce the level of ganciclovir administration to 10 mg/kg twice daily while maintaining significant antitumoral responses to the HSV-tk therapy. The optimization of this suicide gone therapy strategy is imperative to minimize theoretical and known viral vector toxicities while establishing a foundation upon which to design appropriate and effective clinical trials.
SESSION B: Auditory System ( R o o m 21 -
WCC) M. CHARLES LIBERMAN, PhD, J. CHRISTOPHER POST, MD, and DEBARA L. TUCCI, M D (moderators), Boston, Mass., Pittsburgh, Pa., and Durham, N.C. 8:00 AM
Histopathology Findings in Human Temporal Bones Following Radiation Treatment, Cisplatinum Treatment, and C o m b i n e d Radiation and Cisplatinum Treatment DICK L. HOISTAD, MD (presenter), FRANK G, ONDREY, MD, PhD, GEORGE L. ADAMS, MD, FACS, and MICHAEL M. PAPARELLA, MD, Minneapolis, Minn., and Bethesda, Md.
Organ preservation with multimodal therapy has become a treatment strategy for head and neck squamous cell carcinoma (SCCa). Radiation and cisplatinum are two commonly used modalities that can have acute and delayed ototoxic effects to the temporal bone, causing decreased or total hearing loss. Thirteen patients were included in this project: four normal, five who received radiation treatment, two who received cisplatinum treatment, and two who received radiation and cisplatinum combined. Histopathologic findings were then compared amongst the patients. All patients who underwent radiation received 5500 rads or greater and demonstrated not only inner and outer hair cell loss, decreased spiral ganglion cell population, and stria vascularis changes, but small arteriole and venule intimal hypertrophy and fibrosis. These small vessel changes were not found in the cisplatinum group or normal group. We conclude that hearing loss experienced by patients undergoing organ preservation protocol could be a result not only of direct inner ear end organ injury but also vascular injury in the temporal bone as a result of radiation. As a result, prophylactic treatment to prevent small vessel injury may play a role in maintaining hearing in patients undergoing organ preservation protocol.