Nano-Pulse Stimulation Therapy in Oncology

Abstract

Background: Nano-Pulse Stimulation (NPS) therapy applies electric pulses in the nanosecond domain to initiate regulated cell death in the treated tissues. This nonthermal therapy has been used to treat a wide range of murine tumors and has been shown to activate the immune system to inhibit the growth of rechallenge tumors, as well as untreated, abscopal tumors when accompanied by the injection of immune system stimulants into the treated tumors. Clinical trials have begun using NPS to treat basal cell carcinoma and hepatocellular carcinoma.

Methods: Murine tumors can be easily imaged when the tumor cells are injected intradermally so that they grow within the mouse skin. Pulling the skin over a translucent light post shines light through the skin and makes it easy to treat the tumor and identify the treatment zone.

Results: Original research using murine tumor models is described, including melanoma, squamous cell carcinoma, lung carcinoma, breast carcinoma, and pancreatic carcinoma. The energy required to ablate these tumors has been determined with pancreatic carcinoma and lung carcinoma exhibiting 90% ablation with 240 mJ/mm³, lung carcinoma and squamous cell carcinoma requiring 360 mJ/mm³, and melanoma requiring 480 mJ/mm³. NPS therapy initiated a variable immune response indicated by the rejection of injected rechallenge tumor cells with melanoma and hepatocellular carcinoma exhibiting the strongest response and lung carcinoma, the weakest response. Following the original research data, a review of human clinical trials using NPS therapy is presented.

Conclusions: NPS therapy offers a nonthermal, drug-free approach for oncology, which is limited only by applying energy to the tumor. This new immunogenic modality is just beginning to be applied in the clinic. The 87% efficacy of the first large clinical trial conducted by several medical personnel is impressive and indicates that NPS is an effective new modality for cancer treatment.

Keywords: cryoablation; nano-pulse stimulation; nanosecond; nanosecond pulsed electric fields; radiofrequency ablation; regulated cell death.

FIG. 1.

Previously unpublished method for treating the entire murine tumor. (A) Photo of lighted silicone post over which the skin encapsulating the tumor is stretched. The white ring is placed over the skin to hold it once the tumor is in position. (B) Photo of mouse with skin stretched over the post for transillumination; (C) Image of a melanoma tumor after treatment with two rows of bipolar needle electrodes. Holes indicate the position of the two rows of electrodes. (D) COMSOL Multiphysics model of the electric field distribution between the two rows of needle electrodes (black dots) indicating the uniformity of the applied electric field.

FIG. 2.

B16 murine melanoma clearance following the application of the indicated treatment energy with a bipolar applicator (error bars represent SEM.) (taken with permission from McDaniel et al.).

FIG. 3.

Previously unpublished growth of B16 melanoma tumors injected on day 0 and treated on day 5 with 30 kV/cm pulses with the indicated NPS energy. (A) 60 mJ/mm³ treatment ablated 2 of the 10 tumors treated; (B) 120 mJ/mm³ ablated 4 of the 10 tumors treated; (C) 240 mJ/mm³ ablated 7 of the 10 tumors treated; (D) 480 mJ/mm³ ablated 9 of the 10 tumors treated. NPS, Nano-Pulse Stimulation.

FIG. 4.

Previously unpublished growth of 4T1 breast tumors injected on day 0 and treated on day 5 with the indicated NPS energy. (A) 60 mJ/mm³ treatment did not ablate any tumors; (B) 120 mJ/mm³ ablated 3 of the 12 treated tumors; (C) 240 mJ/mm³ ablated 10 of the 12 treated tumors; (D) 360 mJ/mm³ ablated 11 of the 12 treated tumors.

FIG. 5.

Previously unpublished growth of Lewis lung carcinomas (LLC) injected on day 0 and treated on day 5 with the indicated NPS energy. (A) In the sham control, none of the 10 treated tumors was ablated; (B) 60 mJ/mm³ treatment ablates none of the 12 treated tumors; (C) 120 mJ/mm³ ablates three of the 10 tumors treated; (D) 240 mJ/mm³ treatment ablated all 10 of the 10 treated tumors.

FIG. 6.

Previously unpublished growth of squamous cell carcinomas (SCCVII) injected on day 0 and treated on day 5 with the indicated NPS energy. (A) Untreated tumors all grow well with no ablation; (B) 180 mJ/mm³ treatment ablated 15 of the 20 treated tumors; (C) 240 mJ/mm³ treatment ablated 9 of the 10 treated tumors; (D) 360 mJ/mm³ treatment ablated 11 of the 13 tumors treated. We suspect that these two were not completely covered by the NPS treatment, resulting in the continued growth.

FIG. 7.

Previously unpublished growth of pancreatic (Pan02) tumors injected on day 0 and treated with NPS on day 11. (A) Sham tumor growth with electrodes inserted around tumor without delivering energy; (B) 60 mJ/mm³ treatment ablated 6 of the 10 tumors treated; (C) 120 mJ/mm³ treatment ablated 9 of the 10 tumors treated; (D) 240 mJ/mm³ treatment ablated 9 of the 10 tumors treated.

FIG. 8.

The percentage of rechallenge tumors that were inhibited in six different tumor types, indicating varying degrees of immune stimulation (previously unpublished).