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Building IP: BMY/Providence Health&Services Patent Grant re "CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy"
CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy Provided herein are methods for selecting a cancer patient for anti-CTLA-4 immunotherapy, or predicting whether a cancer patient will respond to anti-CTLA4 immunotherapy, based on measured levels of CXCL1 1 and/or sMICA. Such methods are useful for determining whether an anti-CTLA-4 immunotherapy is likely to improve overall survival of a cancer patient. Also provided herein are methods of treating a cancer patient with an anti-CTLA-4 immunotherapy, wherein the patient is first tested for levels of CXCL1 1 and/or sMICA. Also provided are methods for treating a cancer patient with a CXCL1 1 antagonist or sMICA ant agonist alone, or in combination with each other and/or with additional anti-cancer agents, such as a CTLA-4 antagonist.
Primary Examiner: Rawlings; Stephen L Attorney, Agent or Firm: REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2016/016769, filed Feb. 5, 2016, which claims priority to U.S. Provisional Application No. 62/112,359, entitled "Soluble Immunoregulatory Proteins as Predictors of Overall Survival of Advanced Melanoma Patient", filed on Feb. 5, 2015, and U.S. Provisional Application No. 62/220,726, entitled "CXCL11 and SMICA as Predictive Biomarkers for Efficacy of Anti-CTLA4 Immunotherapy", filed Sep. 18, 2015. The contents of the aforementioned applications are hereby incorporated by reference. We claim: 1. A method of treating cancer in a patient with anti-CTLA-4 immunotherapy comprising: (a) determining the levels of CXCL11 in serum from the patient; and (b) if the levels of CXCL11 are below 35 pg/mL, then administering a therapeutically effective amount of an anti-CTLA4 immunotherapy, and if the levels of CXCL11 are at or above 35 pg/mL, then not treating the patient with an anti-CTLA4 immunotherapy, wherein the anti-CTLA4 immunotherapy comprises an antibody comprising the heavy and light chain variable region sequences set forth in SEQ ID NOs: 1 and 2, respectively, and wherein CXCL11 has the amino acid sequence set forth in SEQ ID NO: 3. 2. The method of claim 1, wherein the cancer is melanoma. 3. The method of claim 1, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer. 4. The method of claim 1, wherein the antibody is administered to the patient at between 1 mg/kg to 10 mg/kg. 5. The method of claim 1, wherein, if the patient is administered the antibody, then further administering to the patient one or more additional therapeutics. 6. The method of claim 1, wherein the patient has previously failed IL-2 therapy. 7. The method of claim 1, wherein the patient has previously failed dacarbazine therapy. 8. The method of claim 1, wherein the patient has previously failed temozolomide therapy. 9. A method of treating cancer comprising administering a therapeutically effective amount of an antibody comprising the heavy and light chain variable region sequences set forth in SEQ ID NOs: 1 and 2, respectively, to a patient identified as having serum levels of CXCL11 at or above 35 pg/mL, wherein CXCL11 has the amino acid sequence set forth in SEQ ID NO: 3. 10. The method of claim 9, wherein the cancer is melanoma. 11. The method of claim 9, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer. 12. The method of claim 9, wherein the antibody is administered to the patient at between 1 mg/kg to 10 mg/kg. 13. The method of claim 9, wherein the patient is further administered one or more additional therapeutics. 14. The method of claim 9, wherein the patient has previously failed IL-2 therapy. 15. The method of claim 9, wherein the patient has previously failed dacarbazine therapy. 16. The method of claim 9, wherein the patient has previously failed temozolomide therapy. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 29, 2019, is named MXI_542US_Substitute_Sequence_Listing.txt and is 3,537 bytes in size. BACKGROUND Ipilimumab is a human monoclonal antibody that specifically binds to cytotoxic T lymphocyte antigen-4 (CTLA-4). CTLA-4 is expressed on activated T cells, has structural similarities to the costimulatory molecule CD28, and binds to the same ligands as CD28, albeit with higher affinity. Binding of CTLA-4 to CD80/CD86 inhibits T cell activation by limiting interleukin-2 (IL-2) production and expression of the IL-2 receptor (CD25) (Wolchok et al., Annals of the New York Academy of Sciences 2013; 1291:1-13). Ipilimumab prevents CTLA-4 from binding its ligands, thereby promoting activation of effector T cells via prolonged CD28 signaling (Rudd et al., Immunol Rev 2009; 229:12-26). In addition, anti-CTLA-4 antibodies can deplete intratumoral regulatory T cells, subverting yet another mechanism of immunosuppression (Simpson et al., J Exp Med 2013; 210:1695-1710). Ipilimumab was approved in the United States for the treatment of metastatic melanoma in 2011. While a significant breakthrough in the treatment of metastatic melanoma, there is a need to increase the percentage of patients who achieve a response to treatment, such as prolonged overall survival. Unlike traditional cancer therapies, immunotherapeutics act primarily upon cells of the immune system. The requirement for the immune system as a third-party mediator of the drug's activity suggests the balance of positive and negative regulators of the immune response at the time of therapy may be a critical determinant of efficacy for any immunotherapy. Cytokines, chemokines, and soluble receptors regulate the survival, activity, and location of immune effector cells and thus represent potential players in determining drug efficacy. Of particular interest are soluble factors involved in the recruitment and regulation of effector T cells representing the most readily measurable clinical biomarkers. With an increasing number of treatment options available and increased use of targeted therapies, predictive biomarkers that identify those patients most likely to benefit from a specific treatment would be highly beneficial. SUMMARY Provided herein are methods for optimizing treatment of a cancer patient (e.g., a patient diagnosed with metastatic melanoma) with an anti-CTLA-4 immunotherapy. These methods include a) selecting a cancer patient for treatment with an anti-CTLA-4 immunotherapy, or b) predicting the responsiveness of a cancer patient for treatment with an anti-CTLA-4 immunotherapy, or c) treating a cancer patient with anti-CTLA-4 immunotherapy, by determining whether the patient is likely to benefit from treatment with an anti-CTLA-4 immunotherapy (e.g., a CTLA-4 antagonist). In one embodiment, the determination is based on measuring the level of CXCL11 and/or sMICA in a biological sample from the patient, and comparing the level with a threshold level, wherein levels of CXCL11 and/or sMICA below the threshold level is indicative that the patient is likely to respond to anti-CTLA-4 immunotherapy, and levels above the threshold level is indicative that the patient is unlikely to respond to anti-CTLA-4 immunotherapy. If the levels of CXCL11 and/or sMICA are below the threshold level, then the patient a) is selected for treatment with an anti-CTLA-4 immunotherapy, or b) predicted to be responsive to anti-CTLA-4 immunotherapy. In another embodiment, the determination is based on measuring the level of CXCL11 and/or sMICA in a biological sample from the patient, and if the levels of CXCL11 and/or sMICA are below the threshold level, then the patient is administered a therapeutically effective amount of an anti-CTLA-4 immunotherapy. Alternatively, the determination is based on obtaining the levels of CXCL11 and/or sMICA in a biological sample from the patient, and if the levels of CXCL11 and/or sMICA are below a threshold level, then the patient is administered a therapeutically effective amount of an anti-CTLA4 immunotherapy, or administration of a therapeutically effective amount of an anti-CTLA4 immunotherapy is ordered. In another embodiment, the patient is further administered a therapeutically effective amount of a CXCL11 antagonist and/or sMICA antagonist. Alternatively, administration of a therapeutically effective amount of a CXCL11 antagonist and/or sMICA antagonist is ordered. Administration of the CXCL11 antagonist and/or sMICA antagonist, or the order to administer the CXCL11 antagonist and/or sMICA antagonist, can be concurrent with, or sequential to, administration of the anti-CTLA-4 immunotherapy. In another embodiment, the CXCL11 antagonist and/or sMICA antagonist is a protein (e.g., an antibody or antigen-binding portion thereof), small molecule, or nucleic acid. In another embodiment, the step of determining the level of CXCL11 and/or sMICA in a biological sample from the patient involves determining the level of CXCL11 and/or sMICA protein or gene expression. For example, the level of CXCL11 or sMICA is determined by contacting the biological sample from the patient with an agent that binds to CXCL11 or sMICA, respectively (e.g., an anti-CXCL11 antibody or anti-sMICA antibody or antigen-binding portion thereof), and detecting the binding of the agent to CXCL11 or sMICA in the biological sample (e.g., serum). In another embodiment, the threshold level for CXCL11 is about 35 pg/mL, as measured by bead assay, and/or the threshold level for sMICA is about 247 pg/mL, as measured by a bead-based immunoassay. The methods of the present invention can be applied to patients diagnosed with various types of cancer, e.g., melanoma, and/or wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer. In another embodiment, the method includes administering one or more additional therapeutics and/or includes cancer patients that have previously failed at least one non-CTLA-4-based therapy, e.g., administration of IL-2, dacarbazine, or temozolomide. In another embodiment, the anti-CTLA-4 immunotherapy is an anti-CTLA-4 antibody, such as, ipilimumab or tremelimumab, which is administered to the patient at various dosages (e.g., at between 1 mg/kg to 10 mg/kg, at 3 mg/kg, or at 10 mg/kg) and intervals (e.g., every 1 to 4 weeks, every 3 weeks, 4 times, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times or more). Other features and advantages of the instant disclosure will be apparent from the following detailed description and examples, which should not be construed as limiting. |
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