用于高效有效地向实体瘤递送治疗药物的Intellipulse平台

The Intellipulse ® system is a next generation user-friendly platform for safe and controlled delivery of therapeutics to solid tumors. One issue with delivering therapeutics is being able to get the agent where it is needed without unwanted adverse effects related to clearance of a carrier or off-target events. The second issue with any nucleic acid delivery is having confidence that delivery has occurred. We have demonstrated the utility of this platform by delivering two plasmids encoding immune modifiers directly to melanoma tumors to induce a robust immune response. We previously demonstrated that the intratumor delivery of a plasmid encoding interleukin-12 (pIL-12) resulted in a significant increase in T effector cells and a reduction in T regulatory cells and myeloid derived suppressor cells within the TME, inducing a robust systemic immune response that was amplified when combined with ICIs. The key to make this an effective therapy is to deliver these agents in a manner that has minimal adverse and off target effects while still inducing the desired response. We have designed a novel approach to efficiently deliver multiple plasmids directly to solid tumors. The rationale was based on the premise that by performing intratumor delivery, stimulation would be directed against the specific antigens within the TME to produce an effective local response while stimulating a systemic response, resulting in an abscopal effect. This delivery utilizes a next generation electrotransfer device that enables the use of significantly reduced voltages and includes a means to monitor when successful delivery has occurred. We tested this concept in the B16.F10 mouse melanoma model. Intratumor delivery of pIL-12 resulted in effective control of the treated tumor in over 90% of the mice and generated resistance to challenge. To fully test this approach, we next evaluated a combination therapy delivering both pIL-12 combined with a plasmid encoding the extracellular domain of the PD1 protein, as an alternative form of checkpoint inhibitor. The therapy was tested in a multi-tumor model which included a subcutaneous tumor and intraperitoneal injection of tumor cells. The plasmids were delivered to the subcutaneous tumor; tumors generated by intraperitoneal injection were untreated. Peritoneal tumor growth was not affected by single plasmid delivery or when both plasmids were delivered using other delivery approaches or older electrotransfer technology. Delivery of the plasmids with the Intellipulse® platform resulted in two significant results. Binding of the expressed PD1 peptide to PDL1 on tumor cells was observed by immunohistochemistry and flow cytometry. In addition, complete regression in 90% of the treated mice of the subcutaneous tumor and blockage of peritoneal tumor growth as assessed via in vivo imaging was observed. Work is continuing to explore the treatment of other tumor types.