# US 2024/0100361 A1 · Methods of use of ultra-high dose rate radiation and therapeutic agent

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- Number: US 2024/0100361 A1
- Document ID: US20240100361A1
- Status: Published application
- Kind: A1
- Application number: 18/455,506
- Filed: 2023-08-24
- Published: 2024-03-28
- Earliest claimed: 2017-07-21
- Assignees: Varian Medical Systems, Inc.
- Applicants: Varian Medical Systems, Inc.
- Inventors: Renate PARRY; Eric ABEL; Swati GIRDHANI; Stanley MANSFIELD; Patrick KUPELIAN; Deepak KHUNTIA
- Web page: https://patentgrep.com/patent/US20240100361A1

## CPC

- A61N 5/1031: {using a specific method of dose optimization}
- A61K 9/0009: {involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis}
- A61K 9/141: {Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers ((co) spray-dried products A61K9/16, (co) lyophilised products A61K9/19; the carrier being chemically bound to the active ingredient A61K47/50)}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 33/242: Gold; Compounds thereof
- A61K 33/244: Lanthanides; Compounds thereof (medicinal preparations containing radioactive lanthanides for use in therapy or testing in vivo A61K51/00)
- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/103: {Treatment planning systems}
- A61N 5/1042: {with spatial modulation of the radiation beam within the treatment head}
- A61N 5/1084: {for delivering multiple intersecting beams at the same time, e.g. gamma knives}
- A61P 35/00: Antineoplastic agents
- G16H 20/40: relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
- A61N 5/1043: {Scanning the radiation beam, e.g. spot scanning or raster scanning}
- A61N 5/1045: {using a multi-leaf collimator, e.g. for intensity modulated radiation therapy or IMRT}
- A61N 2005/1087: {Ions; Protons}
- A61N 2005/1088: {generated by laser radiation}
- A61N 2005/1089: {Electrons}
- A61N 2005/109: {Neutrons}
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- Y02A 90/10: Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Methods for treating tumors by administering FLASH radiation and a therapeutic agent to a patient with cancer are disclosed. The methods provide the dual benefits of anti-tumor efficacy plus normal tissue protection when combining therapeutic agents with FLASH radiation to treat cancer patients. The methods described herein also allow for the classification of patients into groups for receiving optimized radiation treatment in combination with a therapeutic agent based on patient-specific biomarker signatures. Also provided are radiation treatment planning methods and systems incorporating FLASH radiation and therapeutic agents.

## Claims

### Claim at position 1

-23. (canceled)

### Claim 24

A method of identifying a subject with cancer as a candidate for a treatment comprising ultra-high-dose-rate radiation (FLASH RT), the method comprising:
(a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker, a tumor cell marker, a circulating marker, an imaging marker, and any combination thereof;
(b) comparing the expression level of the one or more biomarkers in the tumor sample to an expression level of the one or more biomarkers in a normal tissue sample; and
(c) classifying the subject as a candidate for a treatment comprising FLASH RT if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level of the one or more biomarkers in the normal tissue sample.

### Claim 25 (depends on 24)

The method of claim 24, wherein the one or more biomarkers is CD44, MMP9, ALDH1A1, Vimentin, hyaluronan, beta-catenin, MFG-E8, CD68, TGFβ, or a TGFβ-pathway related biomarker.

### Claim 26 (depends on 24)

The method of claim 24, wherein the tumor sample is a biopsy comprising tumor cells.

### Claim 27 (depends on 24)

The method of claim 24, wherein the normal tissue sample comprises non-tumor cells from the same tissue type as the subject's cancer.

### Claim 28 (depends on 24)

The method of claim 24, wherein the subject is classified as a candidate for a treatment comprising FLASH RT if the expression level of CD44 is increased and/or the −009/C02US expression level of MFG-E8 is decreased in the tumor sample relative to the expression level in a normal or control sample.

### Claim 29 (depends on 24)

The method of claim 24, wherein the subject is classified as a candidate for a treatment comprising FLASH RT if the expression level of CD68 is increased in the tumor sample relative to the expression level in a normal or control tissue sample.

### Claim 30

A method of selecting a treatment for a subject with cancer, the method comprising:
(a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker, a tumor cell marker, a circulating marker, and any combination thereof;
(b) comparing the expression level of the one or more biomarkers in the tumor sample to an expression level of the one or more biomarkers in a normal tissue sample; and
(c) administering a treatment comprising an effective amount of FLASH RT if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level of the one or more biomarkers in the normal tissue sample.

### Claim 31 (depends on 30)

The method of claim 30, wherein the one or more biomarkers is CD44, MMP9, ALDH1A1, Vimentin, hyaluronan, beta-catenin, MFG-E8, CD68, TGFβ, or a TGFβ-pathway related biomarker.

### Claim 32 (depends on 30)

The method of claim 30, wherein the tumor sample is a biopsy comprising tumor cells.

### Claim 33 (depends on 30)

The method of claim 30, wherein the normal tissue sample comprises non-tumor cells from the same tissue type as the subject's cancer.

### Claim 34 (depends on 30)

The method of claim 30, wherein an effective dose of FLASH RT is increased from a current effective dose if the subject is already undergoing a radiation therapy for a tumor.

### Claim 35 (depends on 30)

The method of claim 30, wherein an effective dose of FLASH RT administered to a tumor is increased if the expression level of the one or more biomarkers described herein is elevated in the tumor environment.

### Claim 36 (depends on 30)

The method of claim 30, wherein the treatment comprising FLASH RT comprises protons or consists of protons.

### Claim 37 (depends on 30)

The method of claim 30, wherein the effective amount of FLASH radiation is 10 to 200 gray (Gy).

### Claim 38 (depends on 30)

The method of claim 30, wherein the effective amount of FLASH radiation is 5 to 500 gray (Gy).

### Claim 39 (depends on 30)

The method of claim 30, wherein the effective amount of FLASH radiation is administered in multiple fractions of 3 Gy to 20 Gy per fraction.

### Claim 40 (depends on 30)

The method of claim 30, wherein the effective amount of FLASH radiation is administered at a dose per pulse of at least 0.1 Gy.