Predictive biomarkers for CTLA-4 blockade therapy and for PD-1 blockade therapy
Biomarkers are described for predicting the efficacy, risk of relapse, risk of an immune related adverse event (irAE), or combination thereof for a CTLA-4 blockade treatment, such as ipilimumab, in a subject with melanoma. Biomarkers are also described for predicting the efficacy and clinical benefit for a PD-1 blockade treatment, such as a PD-1 blocking antibody, in a subject with melanoma.
1. A method comprising
(1) assaying peripheral blood mononuclear cells (PBMCs) from a subject diagnosed with melanoma for expression of (a) CD8, Ki67, and eomesodermin (EOMES); (b) CD8 and EOMES; or (c) CD4, Ki67, and EOMES,
wherein the frequency of Ki67+EOMES+CD8+ T cells in the PBMCs is inversely proportional with the risk of relapse after CTLA-4 blockade treatment,
wherein the frequency of EOMES+CD8+ T cells in CD8+ T cells in the PBMCs is inversely proportional with the risk of relapse after CTLA-4 blockade treatment,
wherein the frequency of Ki67+EOMES+CD4+ T cells in CD4+ T cells in the PBMCs is inversely proportional with the risk of an immune related adverse event (irAE) after CTLA-4 blockade treatment,
(2) treating the subject with a CTLA-4 blockade treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is at least 2.2%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is at least 56%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is at least 0.45%.
2. A method comprising
assaying peripheral blood mononuclear cells (PBMCs) from a subject diagnosed with melanoma for expression of (a) CD8, Ki67, and eomesodermin (EOMES); (b) CD8 and EOMES; or (c) CD4, Ki67, and EOMES; and
treating the subject with a treatment other than a CTLA-4 blockade treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is less than 2.11%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is less than 55.6%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is less than 0.446%.
3. A method comprising
assaying peripheral blood mononuclear cells (PBMCs) from a subject diagnosed with melanoma for expression of (a) CD8, Ki67, and eomesodermin (EOMES); (b) CD8 and EOMES; or (c) CD4, Ki67, and EOMES; and
treating the subject with both a CTLA-4 blockade treatment and a different treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is less than 2.11%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is less than 55.6%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is less than 0.446%.
4. The method of claim 1 further comprising selecting a subject for CTLA-4 blockade treatment, after the step of assaying and prior to the step of treating, if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is at least 2.2%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is at least 56%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is at least 0.45%.
5. The method of claim 2 further comprising selecting a subject for a treatment, after the step of assaying and prior to the step of treating, other than a CTLA-4 blockade treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is less than 2.11%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is less than 55.6%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is less than 0.446%.
6. The method of claim 3 further comprising selecting a subject for treatment, after the step of assaying and prior to the step of treating, with both a CTLA-4 blockade treatment and a different treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is less than 2.11%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is less than 55.6%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is less than 0.446%.
7. A method comprising
assaying peripheral blood mononuclear cells (PBMCs) from a subject diagnosed with melanoma for expression of (a) CD8, Ki67, and eomesodermin (EOMES); (b) CD8 and EOMES; or (c) CD4, Ki67, and EOMES,
wherein the subject is treated with a CTLA-4 blockade treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is at least 2.2%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is at least 56%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is at least 0.45%, and
wherein the subject is not treated with a CTLA-4 blockade treatment if (a) the frequency of Ki67+EOMES+CD8+ T cells in PBMCs of the subject is less than 2.11%, (b) the frequency of EOMES+CD8+ T cells in PBMCs of the subject is less than 55.6%, or (c) the frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is less than 0.446%.
8. A method of treating a subject diagnosed with melanoma comprising treating the subject with a CTLA-4 blockade treatment when (a) the measured frequency of Ki67+EOMES+CD8+ T cells in peripheral blood mononuclear cells (PBMCs) of the subject is at least 2.2%, (b) the measured frequency of EOMES+CD8+ T cells in PBMCs of the subject is at least 56%, or (c) the measured frequency of Ki67+EOMES+CD4+ T cells in PBMCs of the subject is at least 0.45%.
9. The method of claim 1 , wherein the CTLA-4 blockade treatment is treatment with ipilimumab or tremelimumab.
10. The method of claim 1 , wherein the CTLA-4 blockade treatment is treatment with ipilimumab.
11. The method of claim 1 , wherein the subject is treated with a CTLA-4 blockade treatment if the measured frequency of Ki67+EOMES+CD8+ T cells in peripheral blood mononuclear cells (PBMCs) of the subject is at least 2.2%.
12. The method of claim 8 , wherein the CTLA-4 blockade treatment is treatment with ipilimumab or tremelimumab.
13. The method of claim 8 , wherein the subject is treated with a CTLA-4 blockade treatment if the measured frequency of Ki67+EOMES+CD8+ T cells in peripheral blood mononuclear cells (PBMCs) of the subject is at least 2.2%.
14. The method of claim 7 , wherein the CTLA-4 blockade treatment is treatment with ipilimumab or tremelimumab.