APRIL/BCMA Targeted Agent May Block Tumor Growth, Drug Resistance in Myeloma

Kenneth C. Anderson, MD

BION-1301, a novel monoclonal antibody that targets B-cell maturation antigen (BCMA) and its ligand A PRoliferation-Inducing Ligand (APRIL), may block multiple myeloma cell proliferation and reduce drug resistance and immunosuppression in the tumor microenvironment, according to a preclinical study recently published in Blood.

The study, led by Kenneth Anderson, MD, PhD, and Yu-Tzu Tai, PhD, of Dana-Farber Cancer Institute, demonstrated through in vivo and in vitro preclinical studies that the APRIL/BCMA ligand/receptor pair drives multiple myeloma tumor growth and survival, and activates immunosuppressive mechanisms that allow the tumor to thrive.

APRIL is overproduced in patients with multiple myeloma and binds to BCMA to stimulate a wide variety of responses that promote multiple myeloma growth.

In preclinical models, the anti-APRIL agent BION-1301, developed by Aduro Biotech, was shown to halt tumor growth and overcome drug resistance to chemotherapeutic agents lenalidomide (Revlimid) and bortezomib (Velcade).

“Current therapies for patients with multiple myeloma have significantly improved patient survival; however, a need for new treatments exists as drug resistance develops in the majority of the cases,” said Andrea van Elsas, PhD, chief scientific officer of Aduro Biotech Europe in a statement.

“With the recent elucidation of the important role of the tumor microenvironment, we believe that blocking APRIL using our proprietary monoclonal anti-APRIL antibody BION-1301 could allow for a highly targeted immunotherapy approach to treat multiple myeloma, particularly when added to standard of care chemotherapy. Based on these promising preclinical data, we intend to initiate a clinical trial of BION-1301 next year.”

In addition to multiple myeloma, APRIL’s role in other cancers and in B-cell dependent autoimmune and inflammatory diseases indicates that BION-1301 may also be useful in treating chronic lymphocytic leukemia, colorectal cancer, and Berger’s disease.

OncLive: What is the role of APRIL/BCMA ligand/receptor pair in multiple myeloma?

To better understand the role of APRIL/BCMA and the potential of this novel agent, OncLive spoke with Anderson, who is program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute and Kraft Family Professor of Medicine at Harvard Medical School.Anderson: APRIL is elevated in the bone marrow microenvironment in myeloma and it binds to BCMA and activates signaling cascades, mediating myeloma cell growth and survival. Therefore, targeting APRIL will block activation, growth, and survival of myeloma.

By blocking VEGF, we can significantly impact BCMA-related microvessel density increases and other related impacts. This includes activation of osteoclast adhesion of the tumor cell, stroma, and ontogenesis. Probably the best target in myeloma is BCMA because it is so selective it is only expressed on myeloma and normal plasma cells. The other modalities that are being used to target BCMA include BCMA antibodies, BCMA BiTEs (bispecific T-cell engagers), BCMA CAR T cells, and there is BCMA auristatin immunotoxin.

What have you learned so far about the role that BION-1301 could potentially play?

Could this type of agent be used to treat patients who have become resistant to other therapies?

Could an agent like BION-1301 be potentially used in combination with other agents?

Targeting APRIL is the novel agent BION-1301. It is the only treatment that targets the ligand and has a positive effect on the tumor cell and in the bone marrow microenvironment, as well.We have just completed the preclinical models in animal models and it is my understanding that it will enter clinical trials next. Time will tell what kind of impact it will have. It is novel; there are no other therapies that target APRIL in the bone marrow microenvironment and effects on the tumor, the tumor-host interaction, and the microenvironment. We are excited to see what clinical impact this will have, both direct and indirect, in myeloma.We studied this in myeloma cells, both in vitro and in vivo, which had the p53 mutation. Those patients are high risk. We also studied it in patient cell lines and cells that were resistant to lenalidomide and bortezomib; we think that our preclinical data suggest that it may be able to overcome drug resistance to these agents.In preclinical studies, we did combine it with lenalidomide as well as with bortezomib. There is at least additive activity.

What are the next steps in this research?

There is also some rationale for combining it with immunotherapies, although it is very early. The tumors that are BCMA overexpressed also express PD-L1. APRIL induces checkpoint inhibitors and IL-10. Therefore, by blocking APRIL and blocking the BCMA activation, you may very well be downregulating checkpoint inhibitors and regulating IL-10, as well.Our next ongoing work is to look at delineating the immune effects of targeting APRIL in more detail.

Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth, chemoresistance, and immunosuppression in the bone marrow microenvironment [published online ahead of print April 28, 2016]. Blood. pii: blood-2016-01-691162.