Safe and effective treatment of spontaneous neoplasms with interleukin 12 electro-chemo-gene therapy.

Electroporation improves the anti-tumour efficacy of chemotherapeutic and gene therapies. Combining electroporation-mediated chemotherapeutics with interleukin 12 (IL-12) plasmid DNA produces a strong yet safe anti-tumour effect for treating primary and refractory tumours. A previously published report demonstrated the efficacy of a single cycle of IL-12 plasmid DNA and bleomycin in canines, and, similarly, this study further demonstrates the safety and efficacy of repeated cycles of chemotherapy plus IL-12 gene therapy for long-term management of aggressive tumours. Thirteen canine patients were enrolled in this study and received multiple cycles of electro-chemo-gene therapy (ECGT) with IL-12 pDNA and either bleomycin or gemcitabine. ECGT treatments are very effective for inducing tumour regression via an antitumour immune response in all tested histotypes except for sarcomas, and these treatments can quickly eradicate or debulk large squamous cell carcinomas. The versatility of ECGT allows for response-based modifications which can overcome treatment resistance for affecting refractory lesions. Importantly, not a single severe adverse event was noted even in animals receiving the highest doses of chemotherapeutics and IL12 pDNA over multiple treatment cycles. This report highlights the safety, efficacy and versatility of this treatment strategy. The data reveal the importance of inducing a strong anti-tumour response for successfully affecting not only the treated tumours, but also non-treated metastatic tumours. ECGT with IL12 pDNA plus chemotherapy is an effective strategy for treating multiple types of spontaneous cancers including large, refractory and multiple tumour burdens.

Long-term remission and survival in dogs with high-grade, B cell lymphoma treated with chemotherapy with or without sequential low-dose rate half-body irradiation.

BACKGROUND: Standard of care for dogs with high-grade lymphoma, multiagent chemotherapy, achieves good initial responses but long-term remissions are infrequent; previous studies using half-body irradiation suggest improved long-term outcomes. HYPOTHESIS: The addition of low-dose rate half-body irradiation would improve outcomes in dogs with B-cell lymphoma. ANIMALS: Client-owned dogs with stage III or higher, substage a, B-cell lymphoma that achieved complete remission after 4 doses of multiagent chemotherapy. METHODS: A case-controlled design comparing 2-year remission and survival rates between dogs treated with CHOP-based chemotherapy and those treated with chemotherapy and sequential low-dose rate half-body irradiation. RESULTS: Thirty-eight dogs were enrolled with 18 included in final analysis, 9 prospectively-enrolled dogs and 9 case-matched historical controls. The irradiation cohort's 2-year disease-free rate was 56% whereas median duration exceeded the 730-day study period compared with 0% and 261 days in the chemotherapy only group. Remission duration significantly differed between cohorts (P < .01), hazard ratio 0.218 (95% CI: 0.06-0.77). The irradiation cohort's 2-year survival rate was 78% with median overall survival duration exceeding the 730 day study period compared with 11% and 286 days in the chemotherapy only group. Overall survival time significantly differed between cohorts (P < .02), hazard ratio 0.173 (95% CI: 0.03-0.839). CONCLUSIONS AND CLINICAL IMPORTANCE: The improved long-term outcome achieved by dogs administered sequential low-dose rate half-body irradiation in this study is similar to previous observational studies. Where long-term remission is sought in dogs with B-cell lymphoma low-dose rate half-body irradiation could be considered in addition to standard chemotherapy.

Safety and efficacy of tumor-targeted interleukin 12 gene therapy in treated and non-treated, metastatic lesions.

The ability to control the immune system to actively attack tumor tissues will be a marvelous weapon to combat the persistent attack of cancer. Unfortunately, safe and effective methods to gain this control are not yet available as cancer therapies. To overcome the impediments to this control, tumor-targeted (tt) Interleukin 12 (IL-12) plasmid DNA can be safely delivered to accessible tumors, and these treatments can induce antitumor immune responses in both the treated and untreated tumors. Here, electroporationmediated ttIL-12 pDNA treatments are shown to be safe and well tolerated in a dose escalation study in canines bearing naturally-occurring neoplasms. The final patient in the dose-escalation study received up to 3,800 µg pDNA distributed among five separate squamous cell carcinoma tumors in doses equivalent to those administered in a Phase I trial with wildtype IL-12 pDNA. Not a single severe adverse event occurred in any patient at any of the five dose levels, and only minor, transient changes were noted in any tested parameter. Clinical response analysis and immune marker mRNA detection of treated and non-treated lesions suggest that ttIL-12 pDNA treatments in only a few tumors can elicit antitumor immune responses in the treated lesions as well as distant metastatic lesions. These observations and results demonstrate that ttIL-12 pDNA can be safely administered at clinical levels, and these treatments can affect both treated and nontreated, metastatic lesions.

Managing local swelling following intratumoral electro-chemo-gene therapy.

Delivering genes and other materials directly into the tumor tissue causes specifically localized and powerfully enhanced efficacy of treatments; however, these specific effects can cause rapid, drastic changes in the appearance, texture, and consistency of the tumor. These changes complicate clinical response measurements which can confound the results and render recurring treatments difficult to perform and clinical response measurements nearly impossible to obtain accurately. One of the complicating issues is local swelling. Here, we demonstrate how swelling caused by intratumoral gene treatments can confound the clinical results and impede further treatments, and we demonstrate an easy technique to help overcome this potential hurdle.