Tag: MCL

Novel Therapeutic Strategies for Targeting the Lymphoma Microenvironment

Ruan Face By Jia Ruan, MD, PhD

Although conventional chemotherapy is primarily aimed at tumor cells, we now know of the importance of neighborhood cells, included within the tumor mass. These include endothelial cells and pericytes that form blood vessels, macrophages that mediate inflammation, and fibroblasts and extracellular matrix proteins that build matrix and scar tissues. The interaction between the tumor cells and their neighborhood is collectively known as the tumor microenvironment. Given the importance of the tumor microenvironment in maintaining tumor growth and developing resistance to conventional chemotherapy, novel strategies that target the microenvironment are under active investigation. Clinical researchers led by, Dr. Jia Ruan, have recently published 2 important studies on developing novel therapeutic strategies that target lymphoma angiogenesis (blood vessel formation) and lymphangiogenesis (lymphatic vessel formation) within the tumor microenvironment.

The first study was published in the leading hematology journal Blood in collaboration with Dr. Leandro Cerchietti, a lymphoma biologist, and Dr. Katherine Hajjar, a vascular biology expert, both at Weill Cornell Medical College. The study found that pericytes, the vascular accessory cells surrounding the endothelial cells, are important players in lymphoma tumor angiogenesis, and represent potentially novel therapeutic targets for anti-lymphoma therapy. Specifically, the Weill Cornell lymphoma researchers treated human diffuse large B-cell lymphoma (DLBCL) growing in mouse models with an oral drug called imatinib. This incapacitated a critical cell surface receptor within the pericytes, namely platelet-derived growth factor receptor β (PDGFRβ), which is important for the survival of the pericytes and its communication with the endothelial cells. As a result, lymphoma-associated microvascular blood vessel formation was reduced due to programmed-cell death of both pericytes and endothelial cells. This ultimately translated into therapeutic effect of lymphoma growth impairment. This study provided proof of principal that targeting non-tumor vascular cells within the lymphoma microenvironment can result in significant inhibition of lymphoma growth, providing the basis for more refined consideration of anti-angiogenesis as a treatment strategy for lymphoma patients.

The second study published in Cancer Research, in collaboration with Dr. Lijun Xia, a glycoprotein and vascular biology expert at the Oklahoma Research Foundation. The researchers found that 1) lymphatic vessels, which form the vascular network known as lymphangiogenesis, contributed to the growth and spreading of lymphomas in an experimental model of mantle cell lymphoma (MCL), and 2) treatment with the immunomodulatory drug lenalidomide potently inhibited the growth and spreading of MCL by disabling tumor lymphangiogenesis. Mechanistically the researchers demonstrated that treatment with lenalidomide reduced the number of MCL-associated macrophages and their production of a growth factor important for the formation of lymphatic vessels, namely vascular endothelial growth factor-C (VEGF-C). This is the first study to address the potential importance of lymphangiogenesis in lymphoma growth, and provided a novel perspective of the mechanisms of action of lenalidomide in lymphoma therapy. This pre-clinical study synergizes with our recent clinical data displaying high response rates and durable remissions with the biologic combination of lenalidomide + rituximab in patients with previously untreated MCL.

Both studies open potentially new novel paths to treating lymphoma, exemplifying the Lymphoma Program’s commitment to the bench-to-bedside translational research that brings cutting-edge science to patient care.

References

1. Blood. 2013 Jun 27:121(26):5192-202. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.

2. Cancer Res. 2013 Dec 15:73(24):7254-64. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma.

Ibrutinib Receives FDA Approval for MCL Therapy

Yesterday, the FDA announced approval for ibrutinib, or Imbruvica in the treatment of patients with mantle cell lymphoma (MCL), who have previously received at least one other therapy. According to the FDA press release:

“Imbruvica is intended for patients with MCL who have received at least one prior therapy. It works by inhibiting the enzyme needed by the cancer to multiply and spread. Imbruvica is the third drug approved to treat MCL. Velcade (2006) and Revlimid (2013) are also approved to treat the disease.”

“Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The agency worked cooperatively with the companies to expedite the drug’s development, review and approval, reflecting the promise of the Breakthrough Therapy Designation program.”

“Imbruvica is the second drug with breakthrough therapy designation to receive FDA approval. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave the FDA the ability to designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.”

“The FDA is approving Imbruvica under the agency’s accelerated approval program, which allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. The FDA also granted Imbruvica priority review and orphan-product designation because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease, respectively.”

The physicians in the Lymphoma Program at Weill Cornell Medical College are happy to have had the opportunity to be part of this important study, and would like to thank all the patients who participated in the trials. Further information on  trials involving MCL and/or ibrutinib can be found on our listings of non-Hodgkin lymphoma clinical trials.

ICML Update: Preliminary Results From a Phase I Trial of Palbociclib (PD 0332991) plus Bortezomib in Patients with Previously Treated Mantle Cell Lymphoma

Recently, at the 12th International Conference on Malignant Lymphoma, Dr. Peter Martin, presented preliminary results from a phase I study evaluating palbociclib (also known as PD 0332991) combined with bortezomib in patients with previously treated mantle cell lymphoma. Mantle cell lymphoma is characterized by genetic changes that result in loss of cell cycle control, resulting in unrestrained cell proliferation. Palbociclib is an oral drug that specifically inhibits CDK4, enzyme that is central to the proliferation of mantle cell lymphoma cells. Data from WCMC demonstrated that palbociclib could arrest the growth of mantle cell lymphoma cells and that prolonged growth arrest could sensitize the cells to killing by low doses of bortezomib, thereby potentially improving its efficacy and tolerability. In our recent oral presentation at the ICML, we reported that palbociclib could be safely combined with low-dose bortezomib and that the combination appeared to have promising efficacy. Our results suggest that strategies to control the cell cycle should be explored.

For a full listing of all current clinical trials underway in the Lymphoma Program, please click here.