Method for the Identification of Immunotherapy-Drug Combinations Using a Network Approach

• US 20170218068A1
• Filed: 07/31/2015
• Published: 08/03/2017
• Est. Priority Date: 07/31/2014
• Status: Active Grant

• Current Assignee: University of Western Australia
• Original Assignee: Telethon Kids Institute, University of Western Australia
• Inventors: LESTERHUIS, Willem Joost, LAKE, Richard Andrew, BOSCO, Anthony
• Granted Patent: US 11,186,640 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/409 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine hemin, hematin A61K31/555
• CPC Class Codes: A61K 31/4415 Pyridoxine, i.e. Vitamin B6 pyridoxal phosphate A61K31/675
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 39/3955 : against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: G16B 20/00 : ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 : Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 5/00 : ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks

Abstract

This invention relates to systems and methods for evaluating the differentiality of a set of discrete random variables between two or more conditions, such as a malignant condition responding to treatment regime and one that is not. It also provides for the identification and selection of drugs that act in coordinated manner to phenocopy a genetic network of a malignant condition that responds to at least an immune checkpoint blockade agent.

Claims

1. A computer-implemented method for identifying or evaluating relationships between gene molecular interaction networks to identify genetic modules and more specifically genetic hubs that govern the response to immune checkpoint blockade, the method comprising the steps of:

a) receiving a target set of genetic materials from a plurality of animals, each either responding or non-responding to immunotherapy of cancer conditions;

b) evaluating and searching for gene pairs that are expressed in a correlated fashion (positive or negative) over many samples in a dataset;

c) identifying dependency network structures for the plurality of genes for each condition; and

d) defining genetic modules and or hubs that serve as intervention points in treatment efficacy.

2. A method according to claim 1 further comprising the steps of:

a) interrogating publicly available databases of drug-treated cell lines with genetic module data derived from the method of claim 1; and

b) selecting those therapeutic agents that influence a response (positive or negative) associated with at least a module that governs and or dominates a response to immunotherapy by animals that respond to a treatment.

3. A method according to claim 1 further comprising the steps of:

a) interrogating publicly available drug databases with hub data derived from the method of claim 1; and

b) selecting at least one therapeutic agent that is capable of influencing the biological activity of a hub that is pivotal to the genetic activity and or equilibrium of a malignant condition.

6. A method according to claim 1 wherein the immunotherapy targets or works in association a pathway associated with at least one of the following molecules:

cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1), PD1 ligand, glucocorticoid-induced TNFR related protein (GITR), T cell membrane protein 3, LAG3, lymphocyte activation gene 3, T-cell immunoglobulin domain and mucin domain 3, TIM3;

B- and T lymphocyte attenuator, BTLA, OX40, B7-H3 or B7-H4.

7. A method according to claim 1 wherein the immunotherapy is an immune checkpoint blockade agent.

8. A method according to claim 7 wherein the immune checkpoint blockade agent targets cytotoxic T-lymphocyte-associated antigen 4.

9. A method according to claim 7 wherein the immune checkpoint blockade agent targets programmed cell death protein 1.

10. A method according to claim 7 wherein the immune checkpoint blockade agent targets PD1 ligand.

11. A method according to claim 7 wherein the immune checkpoint blockade agent targets glucocorticoid-induced TNFR-related protein.

12. A method according to claim 7 wherein the immunotherapy is selected from at least one of the following agents:

ipilimumab, tremelimumab, nivolumab, pidilizumab, pembrolizumab, MPDL-3280A, MED/4736 TRX518 or MK4166.

20. A method of treating a patient with a malignant condition, said method comprising the steps of:

a) identifying one or more therapeutic agents that work in a coordinated manner with immune checkpoint modulating agents to phenocopy a network of responding tumours, using the method of claim 2; and

b) administering to said patient a combination of at least an immune checkpoint modulating agent and the therapeutic agent.

26. A method of treating a patient with a malignant condition, said method comprising the steps of:

a) identifying one or more therapeutic agents that work in a coordinated manner with immune checkpoint modulating agents to phenocopy a network of responding tumours, using the method of claim 3; and

b) administering to said patient a combination of at least an immune checkpoint modulating agent and the therapeutic agent.

4. A computerized or computer implemented method for identifying therapeutic intervention points for a malignant condition that is influenced by an immunotherapy, said method comprising:

a) receiving, at a first processor, a set of genetic treatment data from a malignant biological system that responds to an immunotherapy, wherein the data set is derived from a plurality of biological entities;

b) receiving, at a second processor, a set of genetic treatment data from a malignant biological system that fails to fully respond to an immunotherapy, wherein the data set is derived from a plurality of biological entities;

c) providing, at a third processor, a computational network model that represents the malignant biological system comprising nodes and modules that represent gene pairs that are expressed in a correlated fashion (positive or negative) over a plurality of samples;

d) calculating, with a fourth processor, activity measures and co-expression relationships, for the nodes, representing dependency network structures for the plurality of genes expressed in the data set of step b and the data set of step a;

e) identifying with a fifth processor, the genetic modules and the hubs that govern and or dominate a response to immune checkpoint blockade from animals that respond to a treatment.

5. A method according to claim 4 wherein the method further comprises a sixth processor which uses the data generated by the fifth processor to interrogate publicly available databases to identify drugs that influence a response (positive or negative) associated with at least a module or hub identified by the fifth processor, that governs and or dominates a response to immune checkpoint blockade from animals that respond to a treatment.

27. A method of treating a patient with a malignant condition, said method comprising the steps of:

a) identifying one or more therapeutic agents that work in a coordinated manner with immune checkpoint modulating agents to phenocopy a network of responding tumours, using the method of claim 4; and

b) administering to said patient a combination of at least an immune checkpoint modulating agent and the therapeutic agent.

13. A therapeutic combination that comprise at least an immune checkpoint blockade agent and a therapeutic agent wherein the combination enhances or represses a patient'"'"'s response associated with a malignant condition.

14. A therapeutic combination according to claim 13 wherein the immune checkpoint blockade agent is selected from an agent that (a) targets the inhibitory T cell molecule CTLA-4, or (b) targets the Programmed Death receptor (PD-1), or (c) targets the PD-1 antagonist, or (d) a glucocorticoid-induced TNFR family related gene (GITR) member.

15. A therapeutic combination according to claim 13 wherein the immune checkpoint blockade agent is selected from the group consisting of:

ipilimumab, tremelimumab, nivolumab, AMP-224, pidilizumab, pembrolizumab, MPDL-3280A, MSB0010718C, MED/4736, TRX518 or MK4166.

17. A therapeutic combination according to claim 13 wherein when the immune checkpoint modulating agent is an anti-CTLA-4 agonist or a glucocorticoid induced TNFR family related gene (GITR) member, the therapeutic agent is selected from the group consisting of:

NOS2 (iNOS), Aurora kinase B, Ect2 or IGF1.

18. A therapeutic combination according to claim 13 wherein when the immune checkpoint modulating agent is an anti-CTLA-4 agonist or a glucocorticoid-induced TNFR family related gene (GITR) member, the therapeutic agent is selected from the group consisting of:

lsosorbide dinitrate (ISDN), lsosorbide dinitrate, JS-K, isosorbide mononitrate or nitroclycerin;

All-trans-retinoid acid (ATRA);

VX-680 (aurora kinase inhibitor);

Meticrane;

Hydrocotarnine;

Fasudil (Rho kinase inhibitor);

Galantamine;

Pyridoxine (vitamin B6);

flavopiridol.

19. A method of treatment of a patient with a malignant condition, said method comprising the step of administering to said patient a combination of at least an immune checkpoint blockade agent and the therapeutic agent of claim 13.

21. A method of treatment according to claim 19 wherein the malignant condition is a mesothelioma, lung cancer, or kidney cancer.

22. A method of treatment according to claim 19 wherein when the therapeutic combination provides a treatment of mesothelioma, the therapeutic agent is a nitric oxide (NO) generator or a retinoid.

23. A method of treatment according to claim 19 wherein the immune checkpoint blockade agent is anti-CTLA4 and the NO generator is selected from isosorbide dinitrate or JS-K.

24. A method of treatment according to claim 19 wherein the immune checkpoint blockade agent is anti-CTLA4 and the retinoid is All-trans retinoic acid.

25. A method of treatment according to claim 19 wherein the immune checkpoint blockade agent is glucocorticoid-induced TNFR family related gene and the therapeutic agent is selected from isosorbide dinitrate or All-trans retinoic acid.

16. (canceled)