Method for predicting an effective Anti-cancer drug combination

Abstract

The present disclosure relates to methods of using biomarkers in cancer patients to predict responsiveness of the cancer patients to treatment.

Description

Case Ref. P256WO IPTector® Method for predicting an effective anti-cancer drug combination Technical Field

[0001] The present disclosure relates to methods of using biomarkers in cancer patients to predict 5 responsiveness of the cancer patients to treatment. Background

[0002] DNA microarrays have long been utilized to measure gene expression in tumor samples from patients, aiding in the diagnosis and understanding of cancer. This technology allows for the 10 identification of the presence, type, stage, and origin of cancer based on gene expression profiles. Moreover, gene expression data have shown potential in predicting the efficacy of cancer therapies, offering a glimpse into personalized treatment plans. Over the past decades, the National Cancer Institute (NCI) has played a pivotal role in this field by testing the effects of various cancer therapeutics on 60 human cancer cell lines and analyzing their gene expression with DNA microarrays. This 15 extensive dataset has enabled researchers to explore the intricate relationship between gene expression profiles and therapeutic responses, laying the groundwork for precision oncology. Despite these advancements, the current cancer treatment landscape often involves a trial-and-error approach to identify an effective therapy, during which valuable time is lost, and cancer cells may develop resistance to previously effective treatments. This highlights a critical need for early detection 20 of therapeutic resistance to improve patient outcomes and underscores the importance of precision medicine in oncology.

[0003] In recent years, the emergence of immunotherapy, particularly PD-1 and PD-L1 inhibitors, has revolutionized cancer treatment, offering hope for durable responses in various cancer types. However, not all patients benefit from these therapies, and there is a pressing need to predict which 25 patients will respond favorably. Recent developments in genomics, proteomics, and bioinformatics have led to the identification of biomarkers and gene expression signatures that can predict responsiveness to PD-1 / PD-L1 inhibitors. These innovations offer a pathway toward more tailored and effective cancer treatment strategies, reducing the reliance on trial and error and facilitating the early identification of therapeutic resistance. 30

[0004] Consequently, there is an acute demand for advanced methods, devices, and kits capable of accurately predicting a cancer patient's responsiveness to medical treatments, including the latest immunotherapies. This need extends beyond traditional diagnostic and prognostic tools, embracing the potential of precision medicine to transform cancer care by ensuring that patients receive the - 1 -Case Ref. P256WO IPTector® most appropriate and effective treatments from the outset. Summary

[0005] The present invention relates to a predictive method for determining the responsiveness of 5 patients to a combination therapy of PD-1 / PD-L1 inhibitors and cisplatin (or carboplatin or LiPlaCis), in the treatment of cancer, in particular lung cancer, head and neck cancer, and bladder cancer. For PD-1 inhibitor treatments globally, approximately half is in combination with cisplatin. The present combination therapy exploits the synergy between PD-1 inhibitors and cisplatin, where cisplatin converts immunologically "cold" tumors into "hot" tumors, thereby enhancing PD-1-mediated cell 10 killing. This synergy has shown unprecedented success in lung cancer treatment, though it benefits only up to half of the treated population. The efficacy of the cisplatin and PD-1 inhibitor combination is contingent upon the effectiveness of cisplatin.

[0006] The present disclosure introduces a method capable of predicting the success of cisplatin (or carboplatin or LiPlaCis) and PD-1 / PD-L1 inhibitor therapy across all PD-1 / PD-L1 inhibitors. This 15 synergistic predictor can in some embodiments assist in identifying the part (~50%) the patient population where the combination therapy would be successful.

[0007] In particular, the present inventors have now found an mRNA-based predictor of combined responsiveness to i) cisplatin, carboplatin, LiPlaCis, and to ii) inhibitors of PD1 and PD-L1 interaction.

[0008] In a first aspect, an in-vitro method is provided for testing expression in a cancer-tissue from 20 a cancer patient of one or more biomarkers of sensitivity or resistance to an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD-L1 / PD-L2 inhibitor, the method comprising: obtaining a tumor sample comprising the cancer-tissue, and a. i) determining a level of expression in said tumor sample of one or more biomarkers of sensitivity selected from Table 1 or a complement thereof, wherein sensitivity refers to responsiveness of a 25 cell or tissue to cisplatin, carboplatin or LiPlacis; and ii) determining a level of expression in said tumor sample of one or more biomarkers of sensitivity selected from Table 5 or a complement thereof, wherein sensitivity refers to responsiveness of a cell or tissue to the PD1 / PD-L1 / PD-L2 inhibitor; and / or b. i) determining a level of expression in said tumor sample of one or more biomarkers of resistance 30 selected from Table 3 or a complement thereof, wherein resistance refers to non-responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis; and ii) determining a level of expression in said tumor sample of one or more biomarkers of resistance selected from Table 4 or a complement thereof, wherein resistance refers to non-responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis. - 2 -Case Ref. P256WO IPTector®

[0009] In a further aspect, a method of treating cancer in a patient is provided comprising administering an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD- L1 / PD-L2 inhibitor to the patient wherein the patient has been determined to be responsive to the anti-cancer treatment according to a method comprising: 5 a. contacting a tumor sample from the subject comprising nucleic acid molecules with a first device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of sensitivity towards cisplatin, carboplatin, or LiPlaCis selected from Table 1 or a complement thereof, and single-stranded nucleic acid molecules capable of 10 specifically hybridizing with nucleotides of biomarkers of resistance towards cisplatin, carboplatin, or LiPlaCis selected from Table 2 or a complement thereof; and b. contacting the tumor sample from the subject comprising nucleic acid molecules with a second device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides 15 of biomarkers of sensitivity towards the PD1 / PD-L1 / PD-L2 inhibitor selected from Table 5 or a complement thereof; and c. detecting a level of expression of the biomarkers of sensitivity and the biomarkers of resistance; and d. calculating a difference score for the patient by subtracting a mean of the level of expression of 20 the biomarkers of resistance from a mean of the level of expression of the biomarkers of sensitivity, wherein the difference score is above a cutoff value.

[0010] In a further aspect, the present disclosure provides an algorithm running on a computer compiling (i) data from one or more mRNA transcriptomes of a first library of cancer cells; (ii) data from one or more mRNA transcriptomes of a first library of cancer cell lines; and (iii) cytocidal and / or 25 cytostatic effect data for an anti-cancer treatment comprising i) cisplatin, carboplatin, or LiPlaCis and ii) a PD1 / PD-L1 / PD-L2 inhibitor on the first library of cancer cell lines, said algorithm upon subjecting data from one or more mRNA transcriptomes of a patient’s cancer cells to the algorithm it predicts whether the an anti-cancer treatment has cytocidal and / or cytostatic effects against the patients cancer cells. 30 Incorporation by reference

[0011] All publications, patents, and patent applications referred to herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict - 3 -Case Ref. P256WO IPTector® between a term herein and a term in an incorporated reference, the term herein prevails and controls. Detailed Description

[0012] The features and advantages of the present invention is readily apparent to a person skilled 5 in the art by the below detailed description of embodiments and examples of the invention with reference to the figures and drawings included herein. Predictive method

[0013] In some embodiments, the present disclosure provides an in-vitro method for testing 10 expression in a cancer-tissue from a cancer patient of one or more biomarkers of sensitivity or resistance to an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD- L1 / PD-L2 inhibitor, the method comprising: obtaining a tumor sample comprising the cancer-tissue, and a. i) determining a level of expression in said tumor sample of one or more biomarkers of sensitivity 15 selected from Table 1 or Table 3 or Table 4 or a complement thereof, wherein sensitivity refers to responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis; and ii) determining a level of expression in said tumor sample of one or more biomarkers of sensitivity selected from Table 5 or a complement thereof, wherein sensitivity refers to responsiveness of a cell or tissue to the PD1 / PD-L1 / PD-L2 inhibitor; and / or 20 b. i) determining a level of expression in said tumor sample of one or more biomarkers of resistance selected from Table 2 or a complement thereof, wherein resistance refers to non-responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis; and ii) determining a level of expression in said tumor sample of one or more biomarkers of resistance selected from Table 4 or a complement thereof, wherein resistance refers to non-responsiveness of a cell or tissue to 25 cisplatin, carboplatin or LiPlacis.

[0014] In some embodiments, the method is for predicting sensitivity or resistance of the cancer- tissue to the anti-cancer treatment, and the method further comprises a step c) of predicting sensitivity or resistance to the anti-cancer treatment.

[0015] In some embodiments, the tumor sample comprises a mRNA transcriptome. 30

[0016] In some embodiments, the mRNA transcriptome comprises long non-coding RNA sequences.

[0017] In some embodiments, the mRNA transcriptome comprises mRNA from at least 50 expressed genes in the cancer-tissue, such as at least 60, 70, 80, 90 or 100 expressed genes.

[0018] In some embodiments, the method is provided wherein: a. the results of step a, i) are determined to be substantially similar to the level of expression of said - 4 -Case Ref. P256WO IPTector® one or more biomarkers of sensitivity in a reference cell or tissue known to have sensitivity wherein said sensitivity is based on GI50 data of NCI 60 cell lines; or b. the results of step b, i) is determined to be substantially similar to the level of expression of said one or more biomarkers of resistance in a reference cell or tissue known to have resistance 5 wherein said resistance is based on GI50 data of NCI 60 cell lines. Biomarkers

[0019] In some embodiments, the method is provided wherein said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis is not C1QR1 (SEQ ID NO: 13), SLA (SEQ ID NO: 48), 10 PTPN7 (SEQ ID NO: 77), CENTB1 (SEQ ID NO: 37), IFI16 (SEQ ID NO: 17 or 261), ARHGEF6 (SEQ ID NO: 36 or 294), CD3D (SEQ ID NO: 81), ARHGAP15 (SEQ ID NO: 30), HCLS1 (SEQ ID NO: 16 or 259), CD53 (SEQ ID NO: 282), PTPRCAP (SEQ ID NO: 8), or PTPRC (SEQ ID NO: 10, 18, 25, or 243).

[0020] In some embodiments, the method is provided wherein said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis is (a) selected from one or more of COL5A2 (SEQ ID NO: 15 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID NO: 14 or 28), CBFB (SEQ ID NO: 15), SFRS7 (SEQ ID NO: 19 or 54), and CAP350 (SEQ ID NO: 20 or 61); or (b) COL5A2 (SEQ ID NO 73 or 211) and ITGA4 (SEQ ID NO: 1); or 20 (c) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), and MSN (SEQ ID NO: 2); or (d) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), and FAM46A (SEQ ID NO: 3 or 280); or (e) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), and DOCK2 (SEQ ID NO: 5 or 223); or 25 (f) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), and EVL (SEQ ID NO: 6); or (g) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), and SACS (SEQ ID NO: 7); or 30 (h) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), and PTPRCAP (SEQ ID NO: 8); or (i) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), - 5 -Case Ref. P256WO IPTector® PTPRCAP (SEQ ID NO: 8), and EBI2 (SEQ ID NO: 9); or (j) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), and PTPRC (SEQ ID NO: 10, 18, 25, or 243); or 5 (k) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), and ANP32E (SEQ ID NO: 11); or (l) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 10 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), and SFPQ (SEQ ID NO: 12, 38 or 272); or (m)COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), 15 PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), and C1QR1 (SEQ ID NO: 13); or (n) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID 20 NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), C1QR1 (SEQ ID NO: 13), and FNBP1 (SEQ ID NO: 14 or 28); or (o) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID 25 NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), C1QR1 (SEQ ID NO: 13), FNBP1 (SEQ ID NO: 14 or 28), and CBFB (SEQ ID NO: 15); or (p) COL5A2 (SEQ ID NO: 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID NO: 14 30 or 28), CBFB (SEQ ID NO: 15), and SFRS7 (SEQ ID NO: 19 or 54); or (q) COL5A2 (SEQ ID NO: 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID NO: 14 or 28), CBFB (SEQ ID NO: 15), SFRS7 (SEQ ID NO: 19 or 54), and CAP350 (SEQ ID NO: 20 or 61). - 6 -Case Ref. P256WO IPTector®

[0021] In some embodiments, the method is provided wherein said one or more biomarkers of resistance is: (a) selected from one or more of SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ 5 ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), MGAT4B (SEQ ID NO: 110), DSG2 (SEQ ID NO:111 or 312), LRP5 (SEQ ID NO: 112), KRT18 (SEQ ID NO: 108 or 306), DSG2 (SEQ ID NO: 111 or 312), SOX9 (SEQ ID NO: 121, 315, or 319), and IER3 (SEQ ID NO: 127 or 317); or 10 (b) SFN (SEQ ID NO: 96 or 324) and LISCH7 (SEQ ID NO: 97); or (c) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), and EPB41L4B (SEQ ID NO: 98); or (d) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), and MST1R (SEQ ID NO: 99); or (e) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 15 99), and ITGB4 (SEQ ID NO: 100); or (f) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), and DBNDD2 (SEQ ID NO: 102 or 365); or (g) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), and TACSTD1 (SEQ ID NO: 104); or 20 (h) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), and MISP (SEQ ID NO: 105); or (i) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ 25 ID NO: 105), and KRT8 (SEQ ID NO: 106); or (j) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), and JUP (SEQ ID NO: 107 or 400); or (k) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 30 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), and KRT18 (SEQ ID NO: 108 or 306); or (l) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ - 7 -Case Ref. P256WO IPTector® ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), and FA2H (SEQ ID NO: 109); or (m)SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP 5 (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), and MGAT4B (SEQ ID NO: 110); or (n) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), 10 FA2H (SEQ ID NO: 109), MGAT4B (SEQ ID NO: 110), and DSG2 (SEQ ID NO:111 or 312); or (o) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), MGAT4B (SEQ ID NO: 110), DSG2 (SEQ ID NO:111 or 312), and LRP5 (SEQ ID 15 NO: 112); or (p)KRT18 (SEQ ID NO: 108 or 306); or (q)(q) KRT18 (SEQ ID NO: 108 or 306) and DSG2 (SEQ ID NO: 111 or 312); or (r) KRT18 (SEQ ID NO: 108 or 306),DSG2 (SEQ ID NO: 111 or 312), and SOX9 (SEQ ID NO: 121, 315, or 319); or 20 (s) KRT18 (SEQ ID NO: 108 or 306), DSG2 (SEQ ID NO: 111 or 312), SOX9 (SEQ ID NO: 121, 315, or 319), and IER3 (SEQ ID NO: 127 or 317).

[0022] In some embodiments, the method is provided wherein the one or more biomarkers of sensitivity to a PD-1 / PD-L1 / PD-L2 inhibitor is selected from Table 5 disclosed herein. Exemplary biomarkers are gene: PDCD1 for PD-1, CD274 for PD-L1, PDCD1LG2 for PD-L2 sensitivity. 25

[0023] In some embodiments, the method is provided wherein the one or more biomarkers of sensitivity or resistance are detectable or quantifiable from transcriptomic data generated using RNAseq and / or NanoString.

[0024] In some embodiments, the method is provided wherein: a. the level of expression of said one or more biomarkers of sensitivity in said sample is determined 30 by collecting nucleic acid molecules from said sample and, detecting the level of expression of said one or more biomarkers using a device to which one or more single-stranded nucleic acid molecules are attached, wherein said nucleic acid molecule specifically hybridizes to said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis, selected from Table 1 or Table 3 or Table 4; or - 8 -Case Ref. P256WO IPTector® b. the level of expression of said one or more biomarkers of resistance in said sample is determined by collecting nucleic acid molecules from said sample and, detecting the level of expression of said one or more biomarkers using a device to which one or more single-stranded nucleic acid molecules are attached, wherein said nucleic acid molecule specifically hybridizes to said one or 5 more biomarkers of resistance to cisplatin, carboplatin, or LiPlaCis, selected from Table 2.

[0025] In some embodiments, the method is provided wherein: a. said device is a microarray or is for performing a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR); and b. said one or more single-stranded nucleic acid molecules of said device have a length in the range 10 of 10 to 100 nucleotides in length; and c. said one or more single-stranded nucleic acid molecules are labeled or immobilized on a solid substrate.

[0026] In some embodiments, the method is provided wherein said one or more of said single- stranded nucleic acid molecules have a length in the range of 20 to 60 nucleotides. 15

[0027] In the following tables 1-4, an overview of mRNA biomarkers is provided for cisplatin, carboplatin or Liplacis. Further, table 5 below present the sensitivity biomarkers for PD-1, PD-L1 and PD-L2 inhibition. Table 1. mRNA biomarkers of sensitivity to cisplatin. Dashes mean that the Affymetrix probeset has 20 not been mapped to a specific gene. Affymetrix IDs refer to the array type HG-U133A.25 30 - 9 -(Table 1 continued)(Table 1 continued)Case Ref. P256WO IPTector®Table 2. mRNA biomarkers of resistance to cisplatin. Dashes mean that the Affymetrix probeset has not been mapped to a specific gene. Affymetrix IDs refer to the array type HG-U133A.5 - 12 -Case Ref. P256WO IPTector®Table 3. mRNA biomarkers of sensitivity to cisplatin. Dashes mean that the Affymetrix probeset has not been mapped to a specific gene. Affymetrix IDs refer to the array type HG-U133A.5 - 15 -Case Ref. P256WO IPTector®Table 4. mRNA biomarkers of sensitivity to cisplatin. Dashes mean that the Affymetrix probeset has not been mapped to a specific gene. Affymetrix IDs refer to the array type HG-U133A.- 18 -Case Ref. P256WO IPTector®Table 5. mRNA biomarkers of sensitivity to PD-1 inhibition (PD-1 inhibitor or PD-L1 or PD-L2 inhibitors). Affymetrix IDs refer to the array type HG-U133A.5 Treatment

[0028] In some embodiments, the present disclosure provides a method of treating cancer in a patient comprising administering an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD-L1 / PD-L2 inhibitor to the patient wherein the patient has been determined 10 to be responsive to the anti-cancer treatment according to a method comprising: a. contacting a tumor sample from the subject comprising nucleic acid molecules with a first device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of sensitivity towards cisplatin, carboplatin, or LiPlaCis selected from Table 1 or 15 Table 3 or Table 4 or a complement thereof, and single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of resistance towards cisplatin, carboplatin, or LiPlaCis selected from Table 2 or a complement thereof; and b. contacting the tumor sample from the subject comprising nucleic acid molecules with a second - 22 -Case Ref. P256WO IPTector® device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of sensitivity towards the PD1 / PD-L1 / PD-L2 inhibitor selected from Table 5 or a complement thereof; and 5 c. detecting a level of expression of the biomarkers of sensitivity and the biomarkers of resistance; and d. calculating a difference score for the patient by subtracting a mean of the level of expression of the biomarkers of resistance from a mean of the level of expression of the biomarkers of sensitivity, wherein the difference score is above a cutoff value. 10

[0029] In some embodiments, the method comprises administering cisplatin, carboplatin, or LiPlaCis and the PD1 / PD-L1 / PD-L2 inhibitor sequentially.

[0030] In some embodiments, the method comprises administering cisplatin, carboplatin, or LiPlaCis and the PD1 / PD-L1 / PD-L2 inhibitor simultaneously.

[0031] In some embodiments, the method comprises administering carboplatin. In some 15 embodiments, the method comprises administering carboplatin wherein the cancer is breast cancer, such as metastatic breast cancer. Anti-cancer agents

[0032] In some embodiments, the PD1 / PD-L1 / PD-L2 inhibitor is selected from the group consisting 20 of: Nivolumab, Pembrolizumab, Cemiplimab, Sintilimab, Tislelizumab, Toripalimab, Camrelizumab, Dostarlimab, Penpulimab, Geptanolimab, Sugemalimab, Serplulimab, Atezolizumab, Durvalumab, Avelumab, Bintrafusp alfa, Balstilimab, Enoblituzumab, Kn046, Oportuzumab monatox, Envafolimab, HBM9161, and SHR-1316. 25 Cancers

[0033] In some embodiments, the method is provided wherein the cancer is selected from the group consisting of: lung cancer, such as non-small cell lunger cancer, head and neck cancer, such as throat and mouth cancer, ovarian cancer, testicular cancer, bladder cancer, cervical cancer, endometrial cancer, small cell lung cancer, cholangiocarcinoma, breast cancer, sarcomas, Hodgkin and non- 30 hodgkin lymphomas, skin cancer, esophageal cancer, cervical cancer.

[0034] In some embodiments, the cancer is selected from the group consisting of: non-small cell lung cancer, head and neck cancer, endometrial cancer, and bladder cancer.

[0035] In some embodiments, the cancer is endometrial cancer.

[0036] In some embodiments, the cancer is breast cancer, such as metastatic breast cancer, for - 23 -Case Ref. P256WO IPTector® example triple-negative and BRCA-associated breast cancer, ovarian cancer, such as advanced ovarian cancer, and lung cancer. In some embodiments, these cancers are particularly relevant when the treatment comprises carboplatin.

[0037] In some embodiments, the cancer, such as any cancer specified herein, comprises one or more 5 paediatric tumours.

[0038] In some embodiments, the subject or patient is a metastatic breast cancer patient receiving carboplatin and / or gemcitabine Algorithm 10

[0039] In some embodiments, the present disclosure provides an algorithm running on a computer compiling (i) data from one or more mRNA transcriptomes of a first library of cancer cells; (ii) data from one or more mRNA transcriptomes of a first library of cancer cell lines; and (iii) cytocidal and / or cytostatic effect data for an anti-cancer treatment comprising i) cisplatin, carboplatin, or LiPlaCis and ii) a PD1 / PD-L1 / PD-L2 inhibitor on the first library of cancer cell lines, said algorithm upon subjecting 15 data from one or more mRNA transcriptomes of a patient’s cancer cells to the algorithm it predicts whether the an anti-cancer treatment has cytocidal and / or cytostatic effects against the patients cancer cells. Examples 20 Materials and methods

[0040] Chemicals used in the examples herein, e.g. for buffers and substrates, are commercial products of at least reagent grade. Example 1. Predicting Responsiveness to Cisplatin and to Inhibitors of PD1, PD-L1 and PD-L2 25 Interaction in Various Cancer Patient Populations

[0041] An mRNA-based predictor of combined responsiveness to cisplatin and to inhibitors of PD1 and PD-L1 interaction (Programmed cell Death protein 1 receptor, Programmed Death Ligand 1, and Programmed Death Ligand 2, here together called PD-1#s) applies to a number of patients with a variety of cancers. Each patient undergoes a pre-treatment measurement of gene expression with an 30 Affymetrix array. The predicted combined cisplatin and PD-1#s sensitivity for each patient is calculated as the difference between the mean of the levels of the biomarkers of sensitivity (Table 1) and the mean of the levels of the biomarkers of resistance (Table 2). When patients are grouped by cancer types, cancer types predicted to be more responsive to combined cisplatin and PD-1#s are identified. Out of 27 different cancer types, patients with hematological cancer types are predicted to be more - 24 -Case Ref. P256WO IPTector® responsive to the combined cisplatin and PD-1#s treatment than patients with solid tumor cancers. The median of the boxplots serves as a cutoff that can separate patients predicted to be responsive to treatment with combined cisplatin and PD-1#s from patients predicted to be non-responsive. Values above the median indicate patients predicted to be responsive to combined cisplatin and PD- 5 1#s, while values below the median indicate patients predicted to be non-responsive. For a test sample from an individual patient, comparing the test sample to the reference population for the same cancer type is useful. If the test sample is above the median for the reference population of the same cancer type, then the patient is predicted to be responsive to combined cisplatin and PD-1#s treatment. Conversely, if the test sample is below the median for the reference population of the same cancer 10 type, then the patient is predicted to be non-responsive to the treatment. This method for predicting patient responsiveness is also applicable when the reference cancer population consists of only two patients: one responsive to the combined cisplatin and PD-1#s treatment and one non-responsive. Example 2: Validation of a cisplatin response predictor in carboplatin-treated metastatic breast 15 cancer patients Background: Cisplatin and carboplatin are widely used platinum-based chemotherapies in breast cancer, particularly in triple negative breast cancer, but their use is often limited by toxicity and variable efficacy. A cisplatin Drug Response Predictor (DRP) based on a 205-gene mRNA signature has previously demonstrated clinical utility in liposomal cisplatin-treated metastatic breast cancer (MBC) 20 patients (DOI 10.1200 / JCO.2023.41.16_suppl.3130 ; Journal of Clinical Oncology, Volume 41, Number 16_suppl) and in non-small cell lung cancer (NSCLC) patients treated with cisplatin (PMID 29566065). In this example, the clinical relevance of the DRP was assessed in MBC patients receiving carboplatin and gemcitabine. Methods: The cisplatin DRP was applied to tumor gene expression data from 20 MBC patients 25 treated with carboplatin and gemcitabine within a Danish MBC cohort (DBCG) (PMID 31654283), and the scores were scaled from 0 to 100 using the full DBCG cohort (n=803) as background population. Time to progression (TTP) was used as the clinical endpoint and associations between DRP scores and TTP were evaluated using Cox proportional hazards models. A one-sided significance level of 0.05 was used for statistical testing. 30 Results: The median TTP in the carboplatin and gemcitabine-treated patients (n = 20) was 2.1 months, and patients had received a median of four prior lines of therapy. The DRP score was significantly associated with TTP when modeled as a continuous covariate using Cox regression (one- sided p-value = 0.03). A 50-point difference in DRP score corresponded to a hazard ratio (HR) of 0.31 (upper 95% confidence bound = 0.86, p = 0.03, one-sided), indicating a lower risk of progression in - 25 -Case Ref. P256WO IPTector® patients with a higher DRP score. The estimated median TTP was 6.5 months for patients with a DRP score of 75, compared to 2.1 months for those with a score of 25. Conclusion: The previously validated cisplatin DRP was significantly associated with clinical outcomes in carboplatin-treated MBC patients, supporting its applicability to carboplatin in addition 5 to cisplatin. A 50-point increase in DRP score (75 versus 25) was estimated to extend the median TTP by 4.4 months. This difference in median TTP is clinically relevant in the context of advanced breast cancer, given the short median TTP and the heavily pretreated status of the patients. - 26 -

Claims

Case Ref. P256WO IPTector® Claims 1. An in-vitro method for testing expression in a cancer-tissue from a cancer patient of one or more biomarkers of sensitivity or resistance to an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD-L1 / PD-L2 inhibitor, the method comprising: obtaining a 5 tumor sample comprising the cancer-tissue, and a. i) determining a level of expression in said tumor sample of one or more biomarkers of sensitivity selected from Table 1 or Table 3 or Table 4 or a complement thereof, wherein sensitivity refers to responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis; and ii) determining a level of expression in said tumor sample of one or 10 more biomarkers of sensitivity to the PD1 / PD-L1 / PD-L2 inhibitor selected from Table 5, such as PD-1; and / or b. i) determining a level of expression in said tumor sample of one or more biomarkers of resistance selected from Table 2 or a complement thereof, wherein resistance refers to non-responsiveness of a cell or tissue to cisplatin, carboplatin or LiPlacis; and 15 ii) determining a level of expression in said tumor sample of one or more biomarkers of resistance to the PD1 / PD-L1 / PD-L2 inhibitor.

2. The method of any one of the preceding claims, wherein the method is for predicting sensitivity or resistance of the cancer-tissue to the anti-cancer treatment, and the method further 20 comprises a step c) of predicting sensitivity or resistance to the anti-cancer treatment.

3. The method of any preceding claim, wherein the tumor sample comprises a mRNA transcriptome. 25 4. The method of any preceding claim, wherein the mRNA transcriptome comprises long non- coding RNA sequences.

5. The method of any preceding claim, wherein the mRNA transcriptome comprises mRNA from at least 50 expressed genes in the cancer-tissue, such as at least 60, 70, 80, 90 or 100 expressed 30 genes.

6. The method of any one of the preceding claims, wherein: a. the results of step a, i) are determined to be substantially similar to the level of expression of said one or more biomarkers of sensitivity in a reference cell or tissue - 27 -Case Ref. P256WO IPTector® known to have sensitivity wherein said sensitivity is based on GI50 data of NCI 60 cell lines; or b. the results of step b, i) is determined to be substantially similar to the level of expression of said one or more biomarkers of resistance in a reference cell or tissue 5 known to have resistance wherein said resistance is based on GI50 data of NCI 60 cell lines.

7. The method of any one of the preceding claims, wherein said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis is not C1QR1 (SEQ ID NO: 13), SLA (SEQ ID NO: 10 48), PTPN7 (SEQ ID NO: 77), CENTB1 (SEQ ID NO: 37), IFI16 (SEQ ID NO: 17 or 261), ARHGEF6 (SEQ ID NO: 36 or 294), CD3D (SEQ ID NO: 81), ARHGAP15 (SEQ ID NO: 30), HCLS1 (SEQ ID NO: 16 or 259), CD53 (SEQ ID NO: 282), PTPRCAP (SEQ ID NO: 8), or PTPRC (SEQ ID NO: 10, 18, 25, or 243). 15 8. The method of any one of the preceding claims, wherein said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis is (a) selected from one or more of COL5A2 (SEQ ID NO: 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID 20 NO: 14 or 28), CBFB (SEQ ID NO: 15), SFRS7 (SEQ ID NO: 19 or 54), and CAP350 (SEQ ID NO: 20 or 61); or (b) COL5A2 (SEQ ID NO 73 or 211) and ITGA4 (SEQ ID NO: 1); or (c) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), and MSN (SEQ ID NO: 2); or (d) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), and FAM46A 25 (SEQ ID NO: 3 or 280); or (e) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), and DOCK2 (SEQ ID NO: 5 or 223); or (f) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), and EVL (SEQ ID NO: 6); 30 or (g) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), and SACS (SEQ ID NO: 7); or (h) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ - 28 -Case Ref. P256WO IPTector® ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), and PTPRCAP (SEQ ID NO: 8); or (i) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS 5 (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), and EBI2 (SEQ ID NO: 9); or (j) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), and PTPRC (SEQ ID NO: 10, 18, 25, or 243); or 10 (k) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), and ANP32E (SEQ ID NO: 11); or (l) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ 15 ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), and SFPQ (SEQ ID NO: 12, 38 or 272); or (m)COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS 20 (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), and C1QR1 (SEQ ID NO: 13); or (n) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS 25 (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), C1QR1 (SEQ ID NO: 13), and FNBP1 (SEQ ID NO: 14 or 28); or (o) COL5A2 (SEQ ID NO 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS 30 (SEQ ID NO: 7), PTPRCAP (SEQ ID NO: 8), EBI2 (SEQ ID NO: 9), PTPRC (SEQ ID NO: 10, 18, 25, or 243), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), C1QR1 (SEQ ID NO: 13), FNBP1 (SEQ ID NO: 14 or 28), and CBFB (SEQ ID NO: 15); or (p) COL5A2 (SEQ ID NO: 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS - 29 -Case Ref. P256WO IPTector® (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID NO: 14 or 28), CBFB (SEQ ID NO: 15), and SFRS7 (SEQ ID NO: 19 or 54); or (q) COL5A2 (SEQ ID NO: 73 or 211), ITGA4 (SEQ ID NO: 1), MSN (SEQ ID NO: 2), FAM46A (SEQ ID NO: 3 or 280), ITGB2 (SEQ ID NO: 4), DOCK2 (SEQ ID NO: 5 or 223), EVL (SEQ ID NO: 6), SACS 5 (SEQ ID NO: 7), EBI2 (SEQ ID NO: 9), ANP32E (SEQ ID NO: 11), SFPQ (SEQ ID NO: 12, 38 or 272), FNBP1 (SEQ ID NO: 14 or 28), CBFB (SEQ ID NO: 15), SFRS7 (SEQ ID NO: 19 or 54), and CAP350 (SEQ ID NO: 20 or 61).

9. The method of any one of the preceding claims, wherein said one or more biomarkers of 10 resistance is: (a) selected from one or more of SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), MGAT4B 15 (SEQ ID NO: 110), DSG2 (SEQ ID NO:111 or 312), LRP5 (SEQ ID NO: 112), KRT18 (SEQ ID NO: 108 or 306), DSG2 (SEQ ID NO: 111 or 312), SOX9 (SEQ ID NO: 121, 315, or 319), and IER3 (SEQ ID NO: 127 or 317); or (b) SFN (SEQ ID NO: 96 or 324) and LISCH7 (SEQ ID NO: 97); or (c) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), and EPB41L4B (SEQ ID NO: 98); or 20 (d) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), and MST1R (SEQ ID NO: 99); or (e) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), and ITGB4 (SEQ ID NO: 100); or (f) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R 25 (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), and DBNDD2 (SEQ ID NO: 102 or 365); or (g) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), and TACSTD1 (SEQ ID NO: 104); or (h) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R 30 (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), and MISP (SEQ ID NO: 105); or (i) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), and KRT8 (SEQ ID NO: 106); or - 30 -Case Ref. P256WO IPTector® (j) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), and JUP (SEQ ID NO: 107 or 400); or (k) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R 5 (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), and KRT18 (SEQ ID NO: 108 or 306); or (l) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 10 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), and FA2H (SEQ ID NO: 109); or (m)SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 15 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), and MGAT4B (SEQ ID NO: 110); or (n) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), MGAT4B (SEQ ID NO: 110), and DSG2 (SEQ 20 ID NO:111 or 312); or (o) SFN (SEQ ID NO: 96 or 324), LISCH7 (SEQ ID NO: 97), EPB41L4B (SEQ ID NO: 98), MST1R (SEQ ID NO: 99), ITGB4 (SEQ ID NO: 100), DBNDD2 (SEQ ID NO: 102 or 365), TACSTD1 (SEQ ID NO: 104), MISP (SEQ ID NO: 105), KRT8 (SEQ ID NO: 106), JUP (SEQ ID NO: 107 or 400), KRT18 (SEQ ID NO: 108 or 306), FA2H (SEQ ID NO: 109), MGAT4B (SEQ ID NO: 110), DSG2 (SEQ ID 25 NO:111 or 312), and LRP5 (SEQ ID NO: 112); or (p)KRT18 (SEQ ID NO: 108 or 306); or (q)(q) KRT18 (SEQ ID NO: 108 or 306) and DSG2 (SEQ ID NO: 111 or 312); or (r) KRT18 (SEQ ID NO: 108 or 306),DSG2 (SEQ ID NO: 111 or 312), and SOX9 (SEQ ID NO: 121, 315, or 319); or 30 (s) KRT18 (SEQ ID NO: 108 or 306), DSG2 (SEQ ID NO: 111 or 312), SOX9 (SEQ ID NO: 121, 315, or 319), and IER3 (SEQ ID NO: 127 or 317).

10. The method of any one of the preceding claims, wherein the one or more biomarkers of sensitivity or resistance are detectable or quantifiable from transcriptomic data generated - 31 -Case Ref. P256WO IPTector® using RNAseq and / or NanoString.

11. The method of any one of the preceding claims, wherein the method involves a step of pre- treatment measurement of gene expression with an Affymetrix array. 5 12. The method of any one of the preceding claims, wherein: a. the level of expression of said one or more biomarkers of sensitivity in said sample is determined by collecting nucleic acid molecules from said sample and, detecting the level of expression of said one or more biomarkers using a device to which one or 10 more single-stranded nucleic acid molecules are attached, wherein said nucleic acid molecule specifically hybridizes to said one or more biomarkers of sensitivity to cisplatin, carboplatin, or LiPlaCis, selected from Table 1 or Table 3 or Table 4; or b. the level of expression of said one or more biomarkers of resistance in said sample is determined by collecting nucleic acid molecules from said sample and, detecting the 15 level of expression of said one or more biomarkers using a device to which one or more single-stranded nucleic acid molecules are attached, wherein said nucleic acid molecule specifically hybridizes to said one or more biomarkers of resistance to cisplatin, carboplatin, or LiPlaCis, selected from Table 2. 20 13. The method of claim 12, wherein: a. said device is a microarray or is for performing a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR); and b. said one or more single-stranded nucleic acid molecules of said device have a length in the range of 10 to 100 nucleotides in length; and 25 c. said one or more single-stranded nucleic acid molecules are labeled or immobilized on a solid substrate.

14. The method of any one of claims 12 to 13, wherein said one or more of said single-stranded nucleic acid molecules have a length in the range of 20 to 60 nucleotides. 30 15. A method of treating cancer in a patient comprising administering an anti-cancer treatment comprising i) cisplatin, carboplatin or LiPlacis and ii) a PD1 / PD-L1 / PD-L2 inhibitor to the patient wherein the patient has been determined to be responsive to the anti-cancer treatment according to a method comprising: - 32 -Case Ref. P256WO IPTector® a. contacting a tumor sample from the subject comprising nucleic acid molecules with a first device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with 5 nucleotides of biomarkers of sensitivity towards cisplatin, carboplatin, or LiPlaCis selected from Table 1, Table 3 or Table 4 or a complement thereof, and single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of resistance towards cisplatin, carboplatin, or LiPlaCis selected from Table 2 or a complement thereof; and 10 b. contacting the tumor sample from the subject comprising nucleic acid molecules with a second device comprising: i. single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of biomarkers of sensitivity towards the PD1 / PD-L1 / PD-L2 inhibitor selected from Table 5; and 15 c. detecting a level of expression of the biomarkers of sensitivity and the biomarkers of resistance; and d. calculating a difference score for the patient by subtracting a mean of the level of expression of the biomarkers of resistance from a mean of the level of expression of the biomarkers of sensitivity, wherein the difference score is above a cutoff value. 20 16. The method of claim 15, comprising administering cisplatin, carboplatin, or LiPlaCis and the PD1 / PD-L1 / PD-L2 inhibitor sequentially.

17. The method of claim 15, comprising administering cisplatin, carboplatin, or LiPlaCis and the 25 PD1 / PD-L1 / PD-L2 inhibitor simultaneously.

18. The method according to any one of the preceding claims, wherein the PD1 / PD-L1 / PD-L2 inhibitor is selected from the group consisting of: Nivolumab, Pembrolizumab, Cemiplimab, Sintilimab, Tislelizumab, Toripalimab, Camrelizumab, Dostarlimab, Penpulimab, Geptanolimab, 30 Sugemalimab, Serplulimab, Atezolizumab, Durvalumab, Avelumab, Bintrafusp alfa, Balstilimab, Enoblituzumab, Kn046, Oportuzumab monatox, Envafolimab, HBM9161, and SHR-1316.

19. The method according to any one of the preceding claims, wherein the cancer is selected from the group consisting of: lung cancer, such as non-small cell lunger cancer, head and neck cancer, - 33 -Case Ref. P256WO IPTector® such as throat and mouth cancer, ovarian cancer, testicular cancer, bladder cancer, cervical cancer, endometrial cancer, small cell lung cancer, cholangiocarcinoma, breast cancer, sarcomas, Hodgkin and non-hodgkin lymphomas, skin cancer, esophageal cancer, cervical cancer. 5 20. The method according to any one of the preceding claims, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, head and neck cancer, endometrial cancer, and bladder cancer. 10 21. The method according to claim 19, wherein the cancer is selected from the group consisting of: breast cancer, such as metastatic breast cancer, for example triple-negative and BRCA- associated breast cancer, ovarian cancer, such as advanced ovarian cancer, and lung cancer.

22. The method of claim 21, wherein the anti-cancer treatment comprises carboplatin. 15 23. An algorithm running on a computer compiling (i) data from one or more mRNA transcriptomes of a first library of cancer cells; (ii) data from one or more mRNA transcriptomes of a first library of cancer cell lines; and (iii) cytocidal and / or cytostatic effect data for an anti-cancer treatment comprising i) cisplatin, carboplatin, or LiPlaCis and ii) a PD1 / PD-L1 / PD-L2 inhibitor on the first 20 library of cancer cell lines, said algorithm upon subjecting data from one or more mRNA transcriptomes of a patient’s cancer cells to the algorithm it predicts whether the an anti-cancer treatment has cytocidal and / or cytostatic effects against the patients cancer cells. 25 * * * - 34 -

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