METHOD FOR IN-SITU RADIATION-PRIMED T-CELL THERAPY

Abstract

The present invention as described herein is aimed at combining a radiation-induced immunogenic effect with a T-cell therapy technique to markedly improve the therapeutic effectiveness of adoptive T-cell therapy with minimized toxicity. The method of this invention comprises, identifying a target tumor, applying ablative radiation treatment to the tumor in-situ, waiting for the production of CTLs primed by antigen presenting cells (APC), then resecting the target tumor from the patient. The CTLs are harvested and isolated from the tumor and undergo ex-vivo expansion and subsequent treatment of immune checkpoint blockades. The expanded CTLs are then infused back into the patient for systemic treatment of microscopic disease. The primed CTLs that are induced by radiation in-situ, are used as the source of T-cell therapy or other types of cell therapy. The harvested CTLs will have high tumor specificity with a wide range of heterogeneous tumor associated antigens (TAA) presentation.

Claims

1. A method for in-situ radiation primed T-cell harvesting, comprising: identifying and examining a patient with a target tumor for treatment; irradiating the target tumor by pre-operative ablative radiation treatment; waiting for a period of time for antigen priming of cytotoxic T-cells (CTLs) outside of the target tumor; allowing for the build up of CTLs; then resecting the target tumor from the patient; and then harvesting and isolating the CTLs from the target tumor, which CTLs then undergo ex-vivo selection and expansion, followed by the modulation of immune checkpoint blockades, such as anti-PD1.

2. The method as described in claim 1, whereby the expanded and modulated CTLs are infused back into the patient for systemic treatment of microscopic disease.

3. The method as described in claim 1, whereby the expanded and modulated CTLs are infused back into the patient for systemic treatment of metastatic tumors.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] In describing the invention, reference will at times be made to the accompanying drawings in which:

[0008] FIG. 1 is a flow diagram illustrating the steps of the method and process of the present invention.

DESCRIPTION OF THE INVENTION

[0009] Before the subject invention is described further, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the invention. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting.

[0010] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. In the following description, numerous specific details are set forth to provide a thorough understanding of the embodiments. One skilled in the art to which this invention belongs will recognize, however, that the techniques described can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well known structures, materials or operations are not shown or described in detail to avoid obscuring certain aspects.

[0011] In this specification, the singular forms a, an and the include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.

[0012] As shown in FIG. 1, the method of this invention comprises, first, identifying and examining the target tumor of a patient, then irradiating the patient's target tumor by pre-operative ablative radiation treatment. Pre-operative ablative radiation treatment may be accomplished by a variety of methods known to one of ordinary skill in the art to which this invention belongs. Then waiting for a period of time for the antigen priming of the T-cells outside of the tumor (in the lymph nodes). After a certain waiting period post-irradiation, allowing for adequate immune response and the recruitment of primed CTLs, the tumor is resected and the CTLs are harvested and isolated from the resected tumor and the CTLs undergo ex-vivo selection and expansion and modulation by subsequent treatment of immune checkpoint blockades such as anti-PD1. The waiting period post-irradiation may extend for days, but will vary depending on the tumor type, location, and other patient conditions. The expanded and modulated CTLs of therapeutic quantities will then be infused back into the patient by infusion means known to one of ordinary skill in the art to which this invention belongs. This technique as described and practiced is referred to as In-Situ Radiation-Primed T-cell Therapy (ISPT).

[0013] The therapy by this invention may be delivered for systemic treatment of microscopic disease following the removal of the primary tumor with curative intent. It may also be used with curative or palliative intent for treating advanced cancers, whereby, one of the metastatic tumors could be irradiated, resected and used as the source of in-situ primed T-cells which are isolated/harvested, expanded/modulated and then infused back into the patient to shrink and/or eliminate other tumors, wherever located in the patient's body.

[0014] T-cell therapy as prescribed by this invention may be administered as the sole treatment modality or in combination with other synergetic adjuvant therapies to further enhance treatment outcomes.

[0015] The harvested primed T-cell can also be used as the source of other tumor antigen-specific cell therapies.

[0016] Radiation is used as the stimulus for inducing immunogenicity in this invention application. Other physical means such as ultrasound, electroporation, hyperthermia, microwave/radiofrequency/cryo-ablation, radioisotope treatment, tumor treating electrical fields (Novocure), or chemical agents can also serve as stimuli for in-situ induction of immunogenicity, and may be used as an alternative stimuli in this invention.

[0017] As various changes can be made in the above-described subject matter without departing from the scope and the spirit of the invention, it is intended that all subject matter contained in the above description, shown in the accompanying drawings, or defined in the appended claims will be interpreted as descriptive and illustrative, and not in a limiting sense. Many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

EQUIVALENTS

[0018] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the claims.