Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers
Inventors
Yarchoan, Robert • Zeldis, Jerome B. • POLIZZOTTO, Mark N. • Davis, David A. • SERETI, Irini • ULDRICK, Thomas S. • WHITBY, Denise • Khetani, Vikram
Assignees
Celgene Corp • US Department of Health and Human Services
Publication Number
US-10001483-B2
Publication Date
2018-06-19
Expiration Date
2036-06-24
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Abstract
Provided herein are uses of gene and protein biomarkers as a predictor of clinical sensitivity of Kaposi's sarcoma (KS) or Kaposi's sarcoma-associated herpesvirus (KSHV) induced lymphoma and patient response to treatment with an immunomodulatory compound. Further provided herein are methods for the treatment or management of Kaposi's sarcoma or KSHV-induced lymphoma with an immunomodulatory compound, alone or in combination with doxorubicin.
Core Innovation
The invention provides methods for treating or managing Kaposi's sarcoma-associated herpesvirus (KSHV) induced lymphoma and Kaposi's sarcoma (KS) by administering immunomodulatory compounds such as pomalidomide, lenalidomide, or thalidomide. The methods include identifying patients who are sensitive to treatment with these compounds, dosing regimens, and the use of biomarkers like major histocompatibility complex class I (MHC-1) to predict and monitor patient response.
The invention addresses the problem of Kaposi's sarcoma and KSHV-associated lymphomas, including primary effusion lymphoma (PEL), which lack effective oral therapies and have high morbidity, particularly in immunodeficient patients such as those with HIV/AIDS. Existing treatments, including cytotoxic chemotherapy and antiretroviral therapy, have limitations such as poor tolerability, cumulative toxicity, and restricted access in resource-limited settings. There is an unmet need for oral agents that are effective long-term and accessible widely.
Claims Coverage
The patent contains one main independent claim related to the treatment method of KSHV-induced lymphoma with immunomodulatory compounds. The inventive features focus on identification of patients sensitive to treatment, administration of specific compounds, and combination therapies.
Method of treating KSHV-induced lymphoma with pomalidomide or related compounds
A method comprising identifying patients with KSHV-induced lymphoma sensitive to treatment with a compound of the formula corresponding to pomalidomide or its pharmaceutically acceptable salt, solvate, or stereoisomer and administering a therapeutically effective amount of the compound to the patient.
Selection of patient sensitive to treatment based on MHC-1 levels
Identifying patients having decreased levels of major histocompatibility complex class I (MHC-1) in biological samples relative to non-infected controls as an indicator of likelihood of effective response to the treatment with immunomodulatory compounds such as pomalidomide, lenalidomide, or thalidomide.
Administration methods and dosing regimens of immunomodulatory compounds
Administering the compound in amounts of about 1 to 5 mg per day orally, including cycles of administration with periods of drug followed by rest, for treating KSHV-induced lymphoma or Kaposi's sarcoma, optionally in combination with additional active agents.
Combination therapy with additional active agents
The treatment method further comprising administration of an additional therapeutically effective active agent selected from doxorubicin, PD-1 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors to enhance therapeutic efficacy.
The claims focus on methods for treating KSHV-induced lymphoma and Kaposi's sarcoma by identifying sensitive patients using biomarkers and administering immunomodulatory compounds such as pomalidomide, alone or in combination with other therapeutic agents, with specific dosing regimens.
Stated Advantages
Pomalidomide and related immunomodulatory compounds provide effective oral therapy options for KS and KSHV-induced lymphomas.
Treatment with pomalidomide is well tolerated with mild and manageable adverse effects.
The compounds augment immune responsiveness including increasing numbers and activation of peripheral T-cells.
Use of biomarkers such as MHC-1 levels allows prediction and monitoring of patient response and compliance.
The combination with other agents (e.g., doxorubicin, PD-1/PD-L1 inhibitors) provides potential synergistic therapeutic effects.
Documented Applications
Treatment or management of Kaposi's sarcoma-associated herpesvirus (KSHV) induced lymphoma, including primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD).
Treatment or management of Kaposi's sarcoma (KS), including advanced, relapsed, refractory cases, and in patients with or without HIV infection.
Predicting, monitoring response to treatment, and assessing patient compliance by measuring biomarkers such as MHC-1 in biological samples.
Combination therapy for KS using immunomodulatory compounds together with agents such as doxorubicin or immune checkpoint inhibitors (PD-1, PD-L1, CTLA-4 inhibitors).
Use of immunomodulatory compounds to augment immune responsiveness in immunodeficient patients.
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