“Immune checkpoint intervention” in cancer

1. A method of treating cancer in a subject, wherein said method comprises the following steps:

(a) identifying a subject with cancer who is suitable for treatment with an immune checkpoint intervention by:

(i) determining the number of clonal neo-antigens in one or more cancer cells from said subject; and/or

(ii) determining the ratio of clonal:sub-clonal neoantigens and/or sub-clonal neoantigen fraction in more than one cancer cell from said subject;

(b) detecting a higher number of clonal neoantigens, and/or a higher ratio of clonal:sub-clonal neoantigens, or lower sub-clonal neoantigen fraction, in comparison to a reference sample; and

(c) treating said subject with an immune checkpoint intervention that comprises an immune checkpoint inhibitor antibody.

2. The method according to claim 1 , wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody that interacts with CTLA4, PD-1, PD-L1, Lag-3, Tim-3, TIGIT or BTLA.

3. The method according to claim 2 , wherein the immune checkpoint intervention is pembrolizumab, nivolumab, atezolizumab or ipilimumab.

4. The method according to claim 1 , wherein the cancer is selected from bladder cancer, gastric cancer, oesophageal cancer, breast cancer, colorectal cancer, cervical cancer, ovarian cancer, endometrial cancer, kidney cancer, lung cancer, brain cancer, melanoma, lymphoma, small bowel cancers, leukemia, pancreatic cancer, hepatobiliary tumours, germ cell cancers, prostate cancer, head and neck cancers, thyroid cancer and sarcomas.

5. The method according to claim 4 , wherein the cancer is lung cancer or melanoma.

6. The method according to claim 5 , wherein the cancer is non-small cell lung cancer (NSCLC).

7. The method according to claim 1 , wherein the subject is a mammal.

8. The method according to claim 7 , wherein the subject is a human.

9. The method according to claim 1 ,

wherein steps (a) and (b) further comprise:

determining the expression profile of immune checkpoint molecules in cancer cells and/or tumour infiltrating immune cells from said subject, or tumour type, and

detecting differential immune checkpoint molecule expression in the cancer cells and/or the tumour infiltrating immune cells, in comparison to a reference sample.

10. The method according to claim 9 , wherein determining the expression profile of immune checkpoint molecules is performed by a transcriptome-wide differential gene expression analysis to identify differentially expressed immune checkpoint-related genes.

11. The method according to claim 1 , wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody that interacts with CTLA4, PD-1, or PD-L1.

12. The method according to claim 2 , wherein the immune checkpoint intervention is pembrolizumab, nivolumab, atezolizumab or ipilimumab.

13. A method of treating cancer in a subject which comprises treating a subject with cancer with an immune checkpoint intervention, wherein the subject has been determined to have:

(i) a higher number of clonal neo-antigens; and/or

(ii) a higher ratio of clonal:sub-clonal neo-antigens, or lower sub-clonal neo-antigen fraction in comparison to a reference sample, and

wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody.

14. The method according to claim 13 , wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody that interacts with CTLA4, PD-1, PD-L1, Lag-3, Tim-3, TIGIT or BTLA.

15. The method according to claim 14 , wherein the immune checkpoint intervention is pembrolizumab, nivolumab, atezolizumab or ipilimumab.

16. The method according to claim 13 , wherein the subject has further been determined to have a differential immune checkpoint molecule expression in comparison to a reference sample.

17. The method according to claim 16 , wherein the expression profile of immune checkpoint molecules has been performed by a transcriptome-wide differential gene expression analysis to identify differentially expressed immune checkpoint-related genes.

18. The method according to claim 13 , wherein the cancer is selected from bladder cancer, gastric cancer, oesophageal cancer, breast cancer, colorectal cancer, cervical cancer, ovarian cancer, endometrial cancer, kidney cancer, lung cancer, brain cancer, melanoma, lymphoma, small bowel cancers, leukemia, pancreatic cancer, hepatobiliary tumours, germ cell cancers, prostate cancer, head and neck cancers, thyroid cancer and sarcomas.

19. The method according to claim 18 , wherein the cancer is lung cancer or melanoma.

20. The method according to claim 19 , wherein the cancer is a non-small cell lung cancer (NSCLC).

21. The method according to claim 13 , wherein the subject is a mammal.

22. The method according to claim 21 , wherein the subject is a human.

23. The method according to claim 13 , wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody that interacts with CTLA4, PD-1, or PD-L1.

24. The method according to claim 13 , wherein the immune checkpoint intervention comprises an immune checkpoint inhibitor antibody that interacts with CTLA4, PD-1, or PD-L1.

25. A method of treating cancer with checkpoint inhibitor interventions in a plurality of subjects with cancer in a targeted fashion, wherein said method comprises:

(a) identifying at least one human subject from a plurality of human subjects with cancer who are suitable for treatment with an immune checkpoint intervention by:

(i) determining the number of clonal neo-antigens in one or more cancer cells from each of said human subjects; and/or

(ii) determining the ratio of clonal:sub-clonal neoantigens and/or sub-clonal neoantigen fraction in more than one cancer cell from each of said human subjects;

(b) detecting a higher number of clonal neoantigens, and/or a higher ratio of clonal:sub-clonal neoantigens, or lower sub-clonal neoantigen fraction, in comparison to a reference sample in the at least one of said human subjects; and

(c) treating the at least one human subject with the higher number of clonal antigens or the higher ratio of the clonal:sub-clonal neoantigens with an immune checkpoint intervention that comprises an immune checkpoint inhibitor antibody.