# US 2014/0155678 A1 · Focused radiation for augmenting immune-based therapies against neoplasms

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- Number: US 2014/0155678 A1
- Document ID: US20140155678A1
- Status: Published application
- Kind: A1
- Application number: 14/127,597
- Filed: 2012-06-19
- Published: 2014-06-05
- Earliest claimed: 2011-06-21
- Assignees: The Johns Hopkins University
- Inventors: Jing Zeng; Charles George Drake; Drew M. Pardoll; Michael Lim
- Web page: https://patentgrep.com/patent/US20140155678A1

## CPC

- A61N 5/1001: {using radiation sources introduced into or applied onto the body; brachytherapy}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 41/00: Medicinal preparations obtained by treating materials with wave energy or particle radiation {; Therapies using these preparations}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/1042: {with spatial modulation of the radiation beam within the treatment head}
- A61P 35/00: Antineoplastic agents
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

An approach combining immune-based therapies with focused radiation, including stereotactic radiation, to treat cancers is disclosed. The use of focused radiation primes the immune system in a similar manner to vaccines to augment immune-based therapies and can counteract the suppressive effects of a tumor. The combination of focused radiation and immune-based therapies, including administration of at least one immunotherapeutic agent, improves survival compared to each therapy alone and can, in some cases, lead to a durable cure. Accordingly, focused radiation can be an adjuvant for immune-based therapies for treating cancers.

## Claims

### Claim at position 1

-20. (canceled)

### Claim 21

A method for treating a tumor in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective dose of focused radiation to treat the tumor in combination with at least one immunotherapeutic agent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the at least one immunotherapeutic agent is an immune checkpoint inhibitor.

### Claim 23 (depends on 21)

The method of claim 21, wherein the focused radiation is selected from the group consisting of stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity-modulated radiation therapy.

### Claim 24 (depends on 23)

The method of claim 23, wherein the focused radiation has a radiation source selected from the group consisting of a particle beam (proton), cobalt-60 (photon), and a linear accelerator (x-ray).

### Claim 25 (depends on 24)

The method of claim 24, wherein the at least one immunotherapeutic agent is selected from the group consisting of monoclonal antibodies, immune effector cells, vaccines, and cytokines.

### Claim 26 (depends on 25)

The method of claim 25, wherein the monoclonal antibody is selected from the group consisting of anti-PD-1 antibody, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab (anti-CTLA-4), ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, KIR antagonist antibodies, anti-4-1BB, anti-OX40, anti-CD27, and CD40 agonist antibodies.

### Claim 27 (depends on 26)

The method of claim 26, further comprising administering at least one adjuvant in combination with the at least one immunotherapeutic agent.

### Claim 28 (depends on 27)

The method of claim 27, wherein the at least one adjuvant is selected from the group consisting of a cytokine, an interleukin, an interferon, a granulocyte-macrophage colony-stimulating factor (GM-CSF), Bacille Clamette-Guérin (BCG), a keyhole limpet memocyanin (KLH), incomplete Freund's adjuvant (IFA), QS-21, DETOX, and dinitrophenyl.

### Claim 29 (depends on 21)

The method of claim 21, wherein the tumor is a tumor associated with a cancer selected from the group consisting of a cancer involving the spine, a lung cancer, a pancreatic cancer, a prostate cancer, a liver cancer, a kidney cancer, a breast cancer, a melanoma, a metastatic orbital tumor, an orbital lymphoma, a benign brain tumor, and combinations thereof.

### Claim 30 (depends on 21)

The method of claim 21, further comprising administering to the subject at least one additional therapeutic agent.

### Claim 31

A method of neoadjuvant therapy for treating cancer in a subject in need of treatment thereof, the method comprising:
(a) administering to the subject a therapeutically effective dose of focused radiation in combination with a therapeutically effective first dose of at least one immunotherapeutic agent;
(b) performing surgery on the subject to remove at least a portion of a tumor associated with the cancer; and
(c) administering to the subject a therapeutically effective dose of focused radiation in combination with a therapeutically effective second dose of at least one immunotherapeutic agent;
wherein steps (a), (b), and (c) can be repeated in series or individually as necessary to treat the cancer in the subject.

### Claim 32 (depends on 31)

The method of claim 31, further comprising administering to the subject additional chemotherapy and or radiation treatment.

### Claim 33 (depends on 32)

The method of claim 32, further comprising administering to the subject adjuvant therapy.

### Claim 34 (depends on 31)

The method of claim 31, further comprising administering to the subject at least one additional immunotherapeutic agent.

### Claim 35 (depends on 31)

The method of claim 31, wherein the at least one immunotherapeutic agent is selected from the group consisting of monoclonal antibodies, immune effector cells, vaccines, and cytokines.

### Claim 36 (depends on 35)

The method of claim 35, wherein the monoclonal antibody is selected from the group consisting of anti-PD-1 antibody, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab (anti-CTLA-4), ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, KIR antagonist antibodies, anti-4-1BB, anti-OX40, anti-CD27, and CD40 agonist antibodies.

### Claim 37 (depends on 33)

The method of claim 33, wherein the at least one adjuvant is selected from the group consisting of a cytokine, an interleukin, an interferon, a granulocyte-macrophage colony-stimulating factor (GM-CSF), Bacille Clamette-Guérin (BCG), a keyhole limpet memocyanin (KLH), incomplete Freund's adjuvant (IFA), QS-1,DETOX, and dinitrophenyl.

### Claim 38 (depends on 31)

The method of claim 31, wherein the tumor is a tumor associated with a cancer selected from the group consisting of a cancer involving the spine, a lung cancer, a pancreatic cancer, a prostate cancer, a liver cancer, a kidney cancer, a breast cancer, a melanoma, a metastatic orbital tumor, an orbital lymphoma, a benign brain tumor, and combinations thereof.