# US 12,179,037 B2 · Radiotherapies and uses thereof

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- Number: US 12,179,037 B2
- Document ID: US12179037B2
- Status: Granted
- Kind: B2
- Application number: 17/312,802
- Filed: 2019-12-09
- Published: 2022-03-03
- Granted: 2024-12-31
- Earliest claimed: 2018-12-11
- Assignees: Board of Regents, The University of Texas System
- Applicants: Board of Regents, The University of Texas System
- Inventors: James Welsh; Maria Angelica Cortez; David Hong; Hampartsoum Berj Barsoumian
- Web page: https://patentgrep.com/patent/US12179037B2

## CPC

- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 16/2818: {against CD28 or CD152}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- 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

Provided are methods for sequential radiotherapies, such as XRT. In some embodiments, a higher dosage of an XRT may first be administered to a subject, optionally in combination with an immunotherapy, and subsequently a lower dosage XRT is administered to the subject to treat a cancer. Separating the dosage and intensity of the radiotherapies can be used to achieve improved therapeutic responses, such as improved anti-cancer responses, survival times, and/or abscopal effects.

## Claims

### Claim 1

A method of treating a cancer in a mammalian subject comprising: administering a first radiotherapy to the subject, wherein the radiotherapy comprises a dose of from about 10 cGy to about 170 cGy per fraction, in combination with:
a second radiotherapy, wherein the second radiotherapy is a higher dose than the first radiotherapy;
wherein the first radiotherapy is administered to the subject after the second radiotherapy;
wherein the second radiotherapy is administered to a primary tumor in the mammalian subject, and
wherein the first radiotherapy is administered to a secondary tumor or a metastatic tumor in the mammalian subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the first radiotherapy is an external-beam radiation therapy (XRT).

### Claim 3 (depends on 2)

The method of claim 2, wherein the first radiotherapy comprises administering a dosage of 20-160 cGy per fraction or per day.

### Claim 4 (depends on 1)

The method of claim 1, wherein the first radiotherapy comprises administering a final dose of about 0.1-12 Gy.

### Claim 5 (depends on 4)

The method of claim 4, wherein the first radiotherapy comprises administering a final dose of about 1-9 Gy.

### Claim 6 (depends on 1)

The method of claim 1 wherein the second radiotherapy comprises administering a final dose of from about 20 to about 80 Gy; wherein the second radiotherapy is an external-beam radiation therapy (XRT).

### Claim 7 (depends on 6)

The method of claim 6, wherein the second radiotherapy comprises administering a final dose of from about 60 Gy to about 70 Gy.

### Claim 8 (depends on 1)

The method of claim 1, wherein the first radiotherapy is administered to the subject from about 3 days to about 3 months, or from about 1-4 weeks after the second radiotherapy.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method further comprises administering an immunotherapy to the subject.

### Claim 10 (depends on 9)

The method of claim 9, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 11 (depends on 10)

The method of claim 10, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 12 (depends on 11)

The method of claim 11, wherein the immunotherapy is ipilimumab.

### Claim 13 (depends on 10)

The method of claim 10, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 14 (depends on 10)

The method of claim 10, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 15 (depends on 9)

The method of claim 9, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 16 (depends on 9)

The method of claim 9, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 17 (depends on 16)

The method of claim 16, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 18 (depends on 9)

The method of claim 9, wherein the method further comprises administering a third anti-cancer therapy to the subject, and wherein the third anti-cancer therapy is a chemotherapeutic, an intratumoral injection, or a surgery.

### Claim 19 (depends on 9)

The method of claim 9, wherein the method further comprises administering a third anti-cancer therapy to the subject, wherein the third anti-cancer therapy is a chemotherapeutic or a surgery.

### Claim 20 (depends on 1)

The method of claim 1, wherein the first radiation therapy results in abscopal effects or systemic immune responses in the subject.

### Claim 21 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 22 (depends on 1)

The method of claim 1, wherein the cancer is in the lung, head, neck, abdomen, or pelvis.

### Claim 23 (depends on 1)

The method of claim 1, wherein the cancer is a lung cancer, a brain cancer, a breast cancer, a head and neck cancer, a cervical cancer, prostate cancer, a cancer of the eye, a liver cancer, or a thyroid cancer.

### Claim 24 (depends on 1)

The method of claim 1, comprising administering the immunotherapy to the subject.

### Claim 25 (depends on 24)

The method of claim 24, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 26 (depends on 25)

The method of claim 25, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 27 (depends on 26)

The method of claim 26, wherein the immunotherapy is ipilimumab.

### Claim 28 (depends on 25)

The method of claim 25, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 29 (depends on 24)

The method of claim 24, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 30 (depends on 24)

The method of claim 24, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 31 (depends on 30)

The method of claim 30, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 32 (depends on 24)

The method of claim 24, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 33 (depends on 1)

The method of claim 1, wherein the method further comprises administering an engineered cell therapy or a cell therapy to the subject.

### Claim 34 (depends on 33)

The method of claim 33, wherein the engineered cell therapy or cell therapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 35 (depends on 34)

The method of claim 34, wherein the engineered cell therapy or a cell therapy comprises administering exogenously expanding immune cells to the subject.

### Claim 36

A method of treating a cancer in a mammalian subject comprising: administering a first radiotherapy to the subject, wherein the radiotherapy comprises a dose of from about 10 cGy to about 170 cGy per fraction, in combination with:
a second radiotherapy, wherein the second radiotherapy is a higher dose than the first radiotherapy,
wherein the second radiotherapy is an external-beam radiation therapy (XRT);
and wherein the second radiotherapy comprises administering a final dose of from about 50 Gy to about 70 Gy;
wherein the second radiotherapy is administered to a primary tumor in the mammalian subject, and
wherein the first radiotherapy is administered to a secondary tumor or a metastatic tumor in the mammalian subject.

### Claim 37 (depends on 36)

The method of claim 36, wherein the first radiotherapy is an external-beam radiation therapy (XRT).

### Claim 38 (depends on 37)

The method of claim 37, wherein the first radiotherapy comprises administering a dosage of 20-160 cGy per fraction or per day.

### Claim 39 (depends on 36)

The method of claim 36, wherein the first radiotherapy comprises administering a final dose of about 0.1-12 Gy.

### Claim 40 (depends on 39)

The method of claim 39, wherein the first radiotherapy comprises administering a final dose of about 1-9 Gy.

### Claim 41 (depends on 36)

The method of claim 36, wherein the first radiotherapy is administered to the subject after the second radiotherapy.

### Claim 42 (depends on 41)

The method of claim 41, wherein the first radiotherapy is administered to the subject from about 3 days to about 3 months, or from about 1-4 weeks after the second radiotherapy.

### Claim 43 (depends on 36)

The method of claim 36, wherein the first radiotherapy is administered to the subject before the second radiotherapy.

### Claim 44 (depends on 43)

The method of claim 43, wherein the first radiotherapy is administered to the subject from about 3 days to about 3 months, or from about 1-4 weeks before the second radiotherapy.

### Claim 45 (depends on 36)

The method of claim 36, wherein the method further comprises administering an immunotherapy to the subject.

### Claim 46 (depends on 45)

The method of claim 45, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 47 (depends on 46)

The method of claim 46, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 48 (depends on 47)

The method of claim 47, wherein the immunotherapy is ipilimumab.

### Claim 49 (depends on 46)

The method of claim 46, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 50 (depends on 46)

The method of claim 46, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 51 (depends on 45)

The method of claim 45, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 52 (depends on 45)

The method of claim 45, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 53 (depends on 52)

The method of claim 52, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 54 (depends on 45)

The method of claim 45, wherein the method further comprises administering a third anti-cancer therapy to the subject, and wherein the third anti-cancer therapy is a chemotherapeutic, an intratumoral injection, or a surgery.

### Claim 55 (depends on 45)

The method of claim 45, wherein the method further comprises administering a third anti-cancer therapy to the subject, wherein the third anti-cancer therapy is a chemotherapeutic or a surgery.

### Claim 56 (depends on 36)

The method of claim 36, wherein the first radiation therapy results in abscopal effects or systemic immune responses in the subject.

### Claim 57 (depends on 36)

The method of claim 36, wherein the subject is a human.

### Claim 58 (depends on 36)

The method of claim 36, wherein the cancer is in the lung, head, neck, abdomen, or pelvis.

### Claim 59 (depends on 36)

The method of claim 36, wherein the cancer is a lung cancer, a brain cancer, a breast cancer, a head and neck cancer, a cervical cancer, prostate cancer, a cancer of the eye, a liver cancer, or a thyroid cancer.

### Claim 60 (depends on 36)

The method of claim 36, comprising administering the immunotherapy to the subject.

### Claim 61 (depends on 60)

The method of claim 60, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 62 (depends on 61)

The method of claim 61, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 63 (depends on 62)

The method of claim 62, wherein the immunotherapy is ipilimumab.

### Claim 64 (depends on 61)

The method of claim 61, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 65 (depends on 60)

The method of claim 60, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 66 (depends on 60)

The method of claim 60, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 67 (depends on 66)

The method of claim 66, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 68 (depends on 60)

The method of claim 60, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 69 (depends on 36)

The method of claim 36, wherein the method further comprises administering an engineered cell therapy or a cell therapy to the subject.

### Claim 70 (depends on 69)

The method of claim 69, wherein the engineered cell therapy or cell therapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 71 (depends on 70)

The method of claim 70, wherein the engineered cell therapy or a cell therapy comprises administering exogenously expanding immune cells to the subject.

### Claim 72

A method of treating a cancer in a mammalian subject comprising: administering a first radiotherapy to the subject, wherein the radiotherapy comprises a dose of from about 10 cGy to about 170 cGy per fraction, in combination with:
a second radiotherapy, wherein the second radiotherapy is a higher dose than the first radiotherapy, and
wherein the first radiotherapy is administered to the subject from about 3 days to about 3 months, or from about 1-4 weeks before the second radiotherapy.

### Claim 73 (depends on 72)

The method of claim 72, wherein the first radiotherapy is an external-beam radiation therapy (XRT).

### Claim 74 (depends on 73)

The method of claim 73, wherein the first radiotherapy comprises administering a dosage of 20-160 cGy per fraction or per day.

### Claim 75 (depends on 72)

The method of claim 72, wherein the first radiotherapy comprises administering a final dose of about 0.1-12 Gy.

### Claim 76 (depends on 75)

The method of claim 75, wherein the first radiotherapy comprises administering a final dose of about 1-9 Gy.

### Claim 77 (depends on 72)

The method of claim 72, wherein the second radiotherapy comprises administering a final dose of from about 20 to about 80 Gy; wherein the second radiotherapy is an external-beam radiation therapy (XRT).

### Claim 78 (depends on 77)

The method of claim 77, wherein the second radiotherapy comprises administering a final dose of from about 60 to about 70 Gy.

### Claim 79 (depends on 72)

The method of claim 72, wherein the method further comprises administering an immunotherapy to the subject.

### Claim 80 (depends on 79)

The method of claim 79, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 81 (depends on 80)

The method of claim 80, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 82 (depends on 81)

The method of claim 81, wherein the immunotherapy is ipilimumab.

### Claim 83 (depends on 80)

The method of claim 80, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 84 (depends on 80)

The method of claim 80, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 85 (depends on 79)

The method of claim 79, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 86 (depends on 79)

The method of claim 79, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 87 (depends on 86)

The method of claim 86, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 88 (depends on 79)

The method of claim 79, wherein the method further comprises administering a third anti-cancer therapy to the subject, and wherein the third anti-cancer therapy is a chemotherapeutic, an intratumoral injection, or a surgery.

### Claim 89 (depends on 79)

The method of claim 79, wherein the method further comprises administering a third anti-cancer therapy to the subject, wherein the third anti-cancer therapy is a chemotherapeutic or a surgery.

### Claim 90 (depends on 72)

The method of claim 72, wherein the first radiation therapy results in abscopal effects or systemic immune responses in the subject.

### Claim 91 (depends on 72)

The method of claim 72, wherein the subject is a human.

### Claim 92 (depends on 72)

The method of claim 72, wherein the cancer is in the lung, head, neck, abdomen, or pelvis.

### Claim 93 (depends on 72)

The method of claim 72, wherein the cancer is a lung cancer, a brain cancer, a breast cancer, a head and neck cancer, a cervical cancer, prostate cancer, a cancer of the eye, a liver cancer, or a thyroid cancer.

### Claim 94 (depends on 72)

The method of claim 72, comprising administering the immunotherapy to the subject.

### Claim 95 (depends on 94)

The method of claim 94, wherein the immunotherapy is an antibody or comprises an antibody variable domain.

### Claim 96 (depends on 95)

The method of claim 95, wherein the immunotherapy is an anti-PD1 immunotherapy, an anti-PD-L1 immunotherapy, an anti-CTLA-4 immunotherapy, an anti-TGF-β immunotherapy, an OX40 agonist, a 4-1BB agonist, an IDO inhibitor, an anti-GITR immunotherapy, an anti-LAG3 immunotherapy, an anti-TIM3 immunotherapy, an anti-TIGIT immunotherapy, an anti-MERTK immunotherapy, an intratumoral injection, a STING-targeted immunotherapy, a NLRP3-targeted immunotherapy, a TLR9-targeted immunotherapy, a CPG-targeted immunotherapy, a TLR4-targeted immunotherapy, a TLR7/8-targeted immunotherapy, a OX40-targeted immunotherapy, a MER-TK-targeted immunotherapy, an oncolytic virus immunotherapy, an anti-CTLA-4 immunotherapy, an anti-PD1 immunotherapy, an anti-PDL1 immunotherapy, an anti-CD40 immunotherapy, a FLT-3-ligand immunotherapy, or a IL-2 cytokine immunotherapy.

### Claim 97 (depends on 96)

The method of claim 96, wherein the immunotherapy is ipilimumab.

### Claim 98 (depends on 95)

The method of claim 95, wherein the immunotherapy is alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, or rituximab.

### Claim 99 (depends on 94)

The method of claim 94, wherein the immunotherapy is a checkpoint inhibitor.

### Claim 100 (depends on 94)

The method of claim 94, wherein the immunotherapy comprises an engineered cell therapy or a cell therapy.

### Claim 101 (depends on 100)

The method of claim 100, wherein the immunotherapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 102 (depends on 94)

The method of claim 94, wherein the immunotherapy is administered to the subject after the first radiotherapy.

### Claim 103 (depends on 72)

The method of claim 72, wherein the method further comprises administering an engineered cell therapy or a cell therapy to the subject.

### Claim 104 (depends on 103)

The method of claim 103, wherein the engineered cell therapy or cell therapy comprises administering a chimeric antigen expressing T-cell (CAR-T), T-cell receptor (TCR), natural killer cell (NK), or dendritic cell (DC) therapy to the subject.

### Claim 105 (depends on 104)

The method of claim 104, wherein the engineered cell therapy or a cell therapy comprises administering exogenously expanding immune cells to the subject.