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Clinical Development of PD-1 Blockade in Hematologic Malignancies.

ABSTRACT: Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway.

SUBMITTER: Pianko MJ

PROVIDER: S-EPMC5785103 | biostudies-literature | 2018 Jan/Feb

REPOSITORIES: biostudies-literature

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Publications

Clinical Development of PD-1 Blockade in Hematologic Malignancies.

Pianko Matthew J MJ Goldberg Aaron D AD Lesokhin Alexander M AM

Cancer journal (Sudbury, Mass.) 20180101 1

Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinatio ...[more]

PMID: 29360725

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Project description:Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action-direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.

Dataset Information

Clinical Development of PD-1 Blockade in Hematologic Malignancies.

Publications

Clinical Development of PD-1 Blockade in Hematologic Malignancies.

Similar Datasets

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