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A Human Peripheral Blood Mononuclear Cell PBMC Engrafted Humanized Xenograft Model for Translational Immuno-oncology I-O Research
Published on: August 15, 2019
First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic
Nehal J Lakhani1, Drew Rasco2, Hengbang Wang3
1START Midwest, Grand Rapids, Michigan.
Purpose:
B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA).
Patients And Methods:
Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint.
Results:
Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule.
Conclusions:
Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.
Insights
Pelcitoclax, a dual BCL-2 and BCL-xL inhibitor, shows antitumor activity and is well tolerated in solid tumors. Its efficacy is enhanced when combined with agents targeting MCL-1, supporting further clinical development.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- B-cell lymphoma-extra-large (BCL-xL) is a key regulator of apoptosis and a target for cancer therapy.
- Inhibition of BCL-xL can lead to platelet toxicity, limiting its clinical application.
- Pelcitoclax (APG-1252) is a novel prodrug designed as a potent, dual inhibitor of BCL-2 and BCL-xL.
Purpose of the Study:
- To evaluate the antitumor activity and safety profile of pelcitoclax.
- To elucidate the mechanism of action (MOA) of pelcitoclax in preclinical models.
- To explore the potential of pelcitoclax in combination therapies for solid tumors.
Main Methods:
- Antitumor activity and MOA were assessed using cell line-derived and patient-derived xenograft (PDX) models.
- A Phase I clinical trial involved 50 patients with metastatic small-cell lung cancer and other solid tumors receiving intravenous pelcitoclax.
- Safety, tolerability, and preliminary efficacy (RECIST v1.1) were the primary and secondary endpoints, respectively.
Main Results:
- Pelcitoclax demonstrated potent BAX/BAK-dependent, caspase-mediated antiproliferative and apoptogenic activity in cancer cells.
- In PDX models, pelcitoclax disrupted BCL-xL complexes, correlating with tumor growth inhibition.
- The drug was well tolerated, with preliminary overall response and disease control rates of 6.5% and 30.4%. A once-weekly schedule reduced adverse events like thrombocytopenia.
- Combination with taxanes enhanced antitumor effects by downregulating myeloid cell leukemia-1 (MCL-1).
Conclusions:
- Pelcitoclax exhibits significant antitumor activity and a favorable safety profile in solid tumors.
- The drug's mechanism involves disruption of antiapoptotic protein complexes, leading to cancer cell apoptosis.
- Pelcitoclax warrants further clinical investigation, especially in combination with agents that downregulate MCL-1.
