Methods of use of ultra-high dose rate radiation and therapeutic agent

1. A method for treating a tumor in a subject with cancer, the method comprising:

administering an effective amount of ultra-high-dose-rate (FLASH) radiation and a therapeutic agent to the tumor,

wherein the therapeutic agent comprises an immune modulator, a senolytic agent, or a radiosensitizer.

2. The method of claim 1 , wherein administering the effective amount of ultra-high-dose-rate (FLASH) radiation comprises:

administering the effective amount of ultra-high-dose-rate (FLASH) radiation at a dose rate equal to or greater than 40 Gy/sec, or

administering the effective amount of ultra-high-dose-rate (FLASH) radiation at a dose in 1 second or less, and in a single pulse or in multiple pulses.

3. The method of claim 1 , wherein the ultra-high-dose-rate (FLASH) radiation comprises protons or consists of protons.

4. The method of claim 1 , wherein the therapeutic agent comprises a mitotic spindle inhibitor, a DNA damage repair and response inhibitor, a MAPK pathway inhibitor, an epithelial to mesenchymal (EMT) inhibitor, an activator of T helper type 1 (TH1) lymphocytes, an activator of the PTEN pathway, and inhibitor of the TGF-beta pathway, an activator of the type-1 interferon signaling pathway, an activator of dendritic cell maturation, an inhibitor of CD47/SIRP-alpha, or an inhibitor of the Aryl Hydrocarbon Receptor (ahR).

5. The method of claim 4 , wherein the mitotic spindle inhibitor is selected from the group consisting of: a CDK4/6 inhibitor, an AURKA inhibitor, a TPX2-AURKA complex inhibitor, or a taxane.

6. The method of claim 4 , wherein the DNA damage repair and response inhibitor is selected from the group consisting of: a PARP inhibitor, a RAD51 inhibitor, or an inhibitor of a DNA damage response kinase selected from the group consisting of: CHCK1, ATM, or ATR.

7. The method of claim 4 , wherein the MAPK pathway inhibitor comprises an inhibitor of EGFR, MEK, BRAF, or ERK.

8. The method of claim 4 , wherein the EMT inhibitor comprises a TGFβ-pathway inhibitor selected from the group consisting of: a compound, small molecule, antibodies or fragments thereof that bind TGF-beta.

9. The method of claim 4 , wherein the activator of T helper type 1 (TH1) lymphocytes comprises a cytokine, a toll-like receptor agonist, a STAT3 modulator, compounds derived from inactivated bacteria or parasites or derivatives thereof that trigger interferon gamma or IL-12 production, staphylococcus enteroxin B, unmethylated CpG nucleotides, or bacterial or virus based gene expression systems that lead to a production of IL2, IL-12 and IFN-gamma when injected at a tumor site.

10. The method of claim 4 , wherein the activator of the PTEN pathway comprises an mTOR inhibitor selected from the group consisting of: rapamycin, temsirolimus, everolimus, sirolimus or AP-2357 Ublituximab, Rituximab, Sunitinib, Trastuzumab, Pertuzumab, Resistin, Simvastatin, Lovastatin, Rosiglitazone, NVP-AEW541, an Src inhibitor, or PP1 Herbimycin.

11. The method of claim 4 , wherein the activator of the type-1 interferon signaling pathway comprises a STING agonist, an Toll-like receptor (TLR) agonist, or a MAVS agonist.

12. The method of claim 4 , wherein the activator of dendritic cell maturation comprises a synthetic peptide vaccine, and the inhibitor of CD47/SIRP-alpha is selected from the group consisting of: an antibody or fragment thereof, or a small molecule compound that inhibits the CD47/DSIRP-alpha interaction.

13. The method of claim 4 , wherein the inhibitor of the Aryl Hydrocarbon Receptor (ahR) comprises SR1, CH-223191, UM729, or Galangin.

14. The method of claim 1 , wherein the immune modulator is selected from the group consisting of an inhibitor to an inhibitory checkpoint molecule, an activator of a stimulatory checkpoint molecule, a chemokine inhibitor, an inhibitor of macrophage migration inhibitory factor (MIF), a growth factor, a cytokine, an interleukin, an interferon, an antibody that binds to an immune system cell, a cellular immune modulator, a vaccine, an oncolytic virus, and any combination thereof.

15. The method of claim 14 , wherein:

the inhibitor to the inhibitory checkpoint molecule comprises a small molecule drug, or an antibody or a fragment thereof that specifically binds to the inhibitory checkpoint molecule and inhibits its activity;

the activator of the stimulatory checkpoint molecule comprises a small molecule drug, polypeptide-based activator, or polynucleotide-based activator that specifically binds to the stimulatory checkpoint molecule and increases its activity;

the chemokine inhibitor comprises a small molecule drug, or antibody or fragment thereof that specifically binds to the chemokine (or its receptor) and inhibits a chemokine activity; or

the inhibitor of MIF comprises a small molecule drug, or antibody or fragment thereof that specifically binds to MIF and inhibits an MIF activity.

16. The method of claim 15 , wherein:

the inhibitory checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, BTLA, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, CD47, CD48, CD160, CD244 (2B4), CHK1, CHK2, CGEN-15049, ILT-2, ILT-4, LAG-3, VISTA, gp49B, PIR-B, TIGIT, TIM1, TIM2, TIM3, TIM4, and KIR, and ligands thereof;

wherein the stimulatory checkpoint molecule is selected from the group consisting of B7-1 (CD80), B7-2 (CD86), 4-1BB (CD137), OX40 (CD134), HVEM, inducible costimulator (ICOS), glucocorticoid-induced tumor necrosis factor receptor (GITR), CD27, CD28, CD40, and ligands thereof; or

the chemokine inhibitor binds to a chemokine receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR, 4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, and CXCR7.

17. A computer-implemented method of radiation treatment planning for treating a tumor in combination with an immune modulator, the method comprising:

determining a prescribed dose of ultra-high-dose-rate (FLASH) radiation to be delivered into and across a tumor target, wherein the prescribed dose is determined based on a response of the tumor to a therapeutic agent;

accessing values of parameters comprising a number of beams in a plurality of beams to be directed into sub-volumes in the tumor target, directions of the plurality of beams, and beam energies for the plurality of beams, wherein each of the plurality of beams comprises a plurality of beam segments;

identifying overlapping beams in the plurality of beams that have respective beam paths that overlap outside the tumor target;

determining a maximum beam energy for each beam in the plurality of beams and determining beam energies for a plurality of beam segments of each beam in the plurality of beams as a percentage of the maximum beam energy for each beam in the plurality of beams; and

for each overlapping beam of the identified overlapping beams that overlap outside the tumor target, reducing beam intensities for beam segments of the identified overlapping beams by a dose calculation factor, wherein beam intensities for beam segments for the plurality of beams are determined such that a cumulative dose delivered to the tumor target satisfies the prescribed dose.

18. A non-transitory computer-readable storage medium having computer-executable instructions for causing a computing system to perform a method of ultra-high-dose-rate (FLASH) radiation treatment planning for treating a tumor in combination with a therapeutic agent, the method comprising:

accessing values of parameters from a memory of the computing system, wherein the parameters comprise directions of beams to be directed into sub-volumes in a target and beam energies for the beams;

accessing information that specifies limits for the ultra-high-dose-rate (FLASH) radiation treatment plan, wherein the limits are based on a dose threshold and comprise a limit on an irradiation time for each sub-volume outside the target;

wherein the information that specifies limits comprises information about treatment of the tumor with a therapeutic agent; and

adjusting the values of the parameters that affect a calculated amount of a dose to be delivered by the beams until differences between respective total values for the sub-volumes in the target satisfy a threshold value.