Methods and devices for stimulating an immune response using nanosecond pulsed electric fields

Inventors

NUCCITELLI, Richard Lee • Nuccitelli, Pamela S. • Lum, Joanne • Lui, Kaying • Athos, Brian G. • Kreis, Mark P. • Mallon, Zachary R. • Berridge, Jon

Assignees

Pulse Biosciences Inc

Abstract

Nanosecond pulsed electric field (nsPEF) treatments of a tumor are adjusted based on a size and type of the tumor to stimulate an immune response against the tumor and other tumors in the subject. Calreticulin expression on tumor cells can be detected to confirm treatment. An immune response biomarker can be measured, and further nsPEF treatments can be performed if needed to stimulate or further stimulate the immune response. Cancers that have metastasized may be treated by directly treating a tumor that is most accessible. The treatment can be combined with CD47-blocking antibodies, doxorubicin, CTLA-4-blocking antibodies, and/or PD-1-blocking antibodies. Electrical characteristics of nsPEF treatments can be based on the size, type, and/or strength of tumors and/or a quantity of tumors in the subject.

Core Innovation

The invention provides a method of stimulating an immune response to a disease in a subject by positioning a set of electrodes in proximity to diseased tissue and applying sub-microsecond pulsed electric fields to the diseased tissue sufficient to stimulate an immune response within one or more cells of the diseased tissue. Immune stimulation is then confirmed using a level or a presence of one or more biomarkers.

The disclosure centers immune response activation as a treatment readout by using immune response biomarkers obtained after applying sub-microsecond pulsed electric fields. A key biomarker readout described is calreticulin on the surface membranes of tumor cells, including calreticulin translocation or expression on tumor cell surface membranes, and confirmation can include comparing pre-treatment measurement with post-treatment measurement.

The disclosure further describes implementing nsPEF-based immunogenic treatment in the context of tumors by adjusting electrical parameters based on tumor size, type, and sensitivity, and by monitoring immune biomarkers to confirm immune activation. It also describes immune stimulation readouts such as immune cell infiltration and secondary tumor monitoring, including reduced secondary tumor growth alongside immune biomarker labeling such as calreticulin labeling.

Claims Coverage

The independent claim covers electrode positioning near diseased tissue, applying sub-microsecond pulsed electric fields to stimulate an immune response within cells of the diseased tissue, and confirming immune response stimulation using a level or a presence of one or more biomarkers. The dependent refinements in the provided claim set further specify confirmation biomarkers and add adjunct immune interventions and parameter and tissue selection features.

Across the provided independent and dependent claim content, the claim strategy is to stimulate an immune response by applying sub-microsecond pulsed electric fields delivered via electrodes near diseased tissue and then to confirm immune stimulation using biomarker levels or presence, including calreticulin on tumor cell surface membranes, with further refinements that select field characteristics based on diseased tissue properties and optionally add CD47-blocking antibodies and pre- and post-treatment biomarker comparison.

Stated Advantages

Documented Applications