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Last Updated: April 25, 2024

Claims for Patent: 9,863,935

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Summary for Patent: 9,863,935

Title:	Predictive biomarkers for CTLA-4 blockade therapy and for PD-1 blockade therapy
Abstract:	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.
Inventor(s):	Weber; Jeffrey S. (Tampa, FL), Wang; Wenshi (Tampa, FL), Yu; Bin (Tampa, FL)
Assignee:	H. Lee Moffitt Cancer and Research Institute, Inc. (Tampa, FL)
Application Number:	14/399,669
Patent Claims:	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.

Details for Patent 9,863,935

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Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011	⤷ Try a Trial	2032-05-08
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

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