PD-L2 biomarkers predictive of PD-1 pathway inhibitor responses in esophagogastric cancers
The present invention is based on the identification of novel biomarkers predictive of responsiveness of esophagogastric cancers to inhibitors of the PD-1 pathway.
1. A method of treating an esophagogastric adenocarcinoma in a subject likely to be responsive to a PD-1 pathway inhibitor, the method comprising
a) measuring the copy number, amount, or activity of PD-L2 in a subject sample obtained from a subject having esophagogastric adenocarcinoma;
b) comparing the copy number, amount, or activity of PD-L2 in a control sample, and determining a significantly increased copy number, amount, or activity of PD-L2 in the subject sample relative to the control sample thereby identifying the esophagogastric adenocarcinoma as being likely to be responsive to the PD-1 pathway inhibitor; and
c) administering the PD-1 pathway inhibitor to the subject likely to be responsive to the PD-1 pathway inhibitor.
2. The method of claim 1 , further comprising recommending, prescribing, or administering at least one additional anti-cancer therapy.
3. The method of claim 1 , wherein the control sample is derived from an esophagogastric adenocarcinoma cancerous sample or non-cancerous esophagogastric sample from either the subject or a member of the same species to which the subject belongs.
4. The method of claim 1 , wherein the subject sample and/or the control sample has not been contacted with any anti-esophagogastric adenocarcinoma treatment or PD-1 pathway inhibitor, or wherein the subject has not been administered any anti-esophagogastric adenocarcinoma treatment or PD-1 pathway inhibitor.
5. The method of claim 2 , wherein the at least one additional anti-cancer therapy is an immune checkpoint inhibitor.
6. The method of claim 1 , wherein the amount of PD-L2 is detected using a reagent which specifically binds with PD-L2.
7. The method of claim 1 , wherein PD-L2 is assessed by detecting the presence of a transcribed polynucleotide or portion thereof.
8. The method of claim 1 , wherein the PD-1 pathway inhibitor comprises at least one antibody selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, and combinations thereof.
9. The method of claim 1 , wherein the esophagogastric adenocarcinoma is an esophageal adenocarcinoma, or a gastric adenocarcinoma.
10. The method of claim 1 , wherein the subject is a mammal.
11. The method of claim 1 , wherein the control sample comprises cells or does not comprise cells; or wherein the control sample comprises esophagogastric adenocarcinoma cells known to be responsive or non-responsive to the PD-1 pathway inhibitor.
12. The method of claim 1 , wherein the subject sample is selected from the group consisting of serum, whole blood, plasma, urine, cells, cell lines, resected tissue, and biopsies.
13. The method of claim 1 , wherein the esophagogastric adenocarcinoma in the subject is responsive to PD-1 pathway inhibitor in at least one criteria selected from the group consisting of cellular proliferation, tumor burden, m-stage, metastasis, progressive disease, clinical benefit rate, survival until mortality, pathological complete response, semi-quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST criteria.
14. The method of claim 2 , wherein the anti-cancer therapy is selected from the group consisting of targeted therapy, chemotherapy, radiation therapy, and/or hormonal therapy.
15. The method of claim 1 , wherein the control sample is a cancerous esophagogastric adenocarcinoma or non-cancerous esophagogastric sample from the subject obtained from an earlier point in time than the subject sample; and/or wherein the control sample is obtained before the subject has received PD-1 pathway inhibitor therapy and the subject sample is obtained after the subject has received PD-1 pathway inhibitor therapy.
16. The method of claim 6 , wherein the reagent is selected from the group consisting of an antibody, an antibody derivative, and an antibody fragment.
17. The method of claim 7 , wherein the transcribed polynucleotide is an mRNA or a cDNA.
18. The method of claim 17 , wherein the step of detecting further comprises amplifying the transcribed polynucleotide, and/or wherein the transcribed polynucleotide is detected by identifying a nucleic acid that anneals with the biomarker nucleic acid, or a portion thereof, under stringent hybridization conditions, wherein the stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65° C.
19. The method of claim 8 , wherein the PD-1 pathway inhibitor comprises an anti-PD-L2 antibody.
20. The method of claim 9 , wherein the esophageal adenocarcinoma is metastatic.
21. The method of claim 10 , wherein the mammal is a human, or an animal model of an esophagogastric adenocarcinoma.