Investigational therapy for B-cell malignancies offers three targets in one CAR T cell
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B-cell activating factor is a ligand protein, which makes it uniquely suited as a therapeutic option for the newly emerging class of multitargeted chimeric antigen receptor T-cell therapies.
That’s according to Reshmi Parameswaran, MS, PhD, assistant professor in the department of medicine at Case Western Reserve University School of Medicine and member of the immune oncology program at Case Comprehensive Cancer Center, who has spent most of her career investigating potential uses of the protein as an effective cancer therapy target.
Parameswaran — who is also a scientist in the division of hematology and oncology at UH Seidman Cancer Center — started her research on the B-cell activating-factor (BAFF) ligand during her postdoctoral fellowship, and she identified the existence of a BAFF receptor on the surface of B-cell acute lymphoblastic leukemia cells.
“After coming to understand the role of BAFF signaling in ALL cells, I came to believe that exploiting this surface receptor expression could be an interesting therapeutic approach,” she told Healio.
This led to collaboration with Novartis on the subsequent development of an anti-BAFF receptor monoclonal antibody for the treatment of precursor B-cell ALL.
Now Parameswaran's lab has developed a new BAFF ligand-based CAR T-cell therapy that binds to multiple receptors on mature B cells with the aim of providing a safer and more durable therapeutic option for patients with B-cell malignancies.
Results from a preclinical study of the investigational BAFF CAR-T, published in Nature Communications, demonstrated encouraging antitumor capabilities.
Parameswaran spoke with Healio about the novel cell therapy her lab developed, what makes it unique compared with other CAR T-cell therapies and the research planned to assess its efficacy among humans.
Healio: Can you explain your rationale for developing a CAR-T that targets BAFF?
Parameswaran: Given my previous experience with BAFF receptor antibodies as a therapeutic, my thoughts moved toward the ability to use the ligand BAFF as part of a CAR-T for hematologic malignancies. I thought this could be especially useful for B-cell cancers because nearly all of them express BAFF receptors.
Conventional CARs are constructed to include the variable antibody chain — or single-chain variable fragment (scFv). Our lab considered the use of a natural ligand, such as BAFF, within the CAR construct instead of an antibody sequence. It can bind to three receptors: BAFF-R, B-cell maturation antigen (BCMA), and transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI).
Healio: What is the perceived advantage of using a natural ligand approach instead of a scFv?
Parameswaran: Using an antibody scFv against BAFF-R means those CAR-Ts only would be able to bind to BAFF receptors. Similarly, if you created a BCMA-directed CAR with a BCMA antibody chain, it could only bind to BCMA on the surface of cancer cells. However, a natural ligand can bind to multiple receptors. In the case of the CAR-T we created, it binds to three receptors, making it equivalent to the use of three different CARs in one T cell.
Healio: What did your preclinical research show about the potential of BAFF-targeted CAR-T to treat B-cell malignancies?
Parameswaran: My lab conducted a preclinical study in mice using three disease models that included B-cell ALL, non-Hodgkin lymphoma and multiple myeloma. Results showed the BAFF ligand-based CAR-T was active in killing cancer cells. This therapy also should be equally as effective against most B-cell malignancies, such as chronic lymphocytic leukemia and other B-cell lymphomas.
Healio: Would this CAR construct allow for the treatment of multiple malignancies using a single product and manufacturing method?
Parameswaran: Yes. Preclinical research showed cancer cell-killing capabilities in multiple B-cell malignancies. Designed to be given as single dose, BAFF CAR-T is an autologous therapy that — with the same manufacturing process — can be used to treat any one of multiple diseases, including ALL, CLL, NHL or multiple myeloma.
Healio: What has your preclinical research shown about potential treatment-related toxicities?
Parameswaran: CD19-directed CAR T cells target and kill both early and mature B cells. However, BAFF CAR-T spares early B cells because BAFF receptors are expressed only on mature B cells. This allows early B cells to replenish mature ones and helps avoid B-cell aplasia frequently observed among patients who receive CD19-directed CAR-T.
Additionally, whereas most CAR-Ts use viral transduction for gene delivery, this therapy uses transposon as a nonviral gene delivery approach. This method is safer and more cost-effective than the viral vector method used to create current-generation CAR T-cell therapies.
Our lab's own limited analysis of serum markers and the function of several organs showed no treatment-related toxicities. Our commercial partner, Luminary Therapeutics, contracted a third-party company to conduct a larger study for the toxicity assessment used in our IND submission. A detailed analysis that included evaluation of organ function, histologic studies and blood serum values showed no observable treatment-related toxicities.
Healio: How optimistic are you that this therapy will produce benefits for humans?
Parameswaran: I am very hopeful. My institution has optioned the rights for this therapy to Luminary Therapeutics, which has submitted an IND application to the FDA. Once the application is approved, we will be able to start treating patients with this therapy as part of our planned clinical trial. If this therapy is successful for patients with non-Hodgkin lymphoma, then I hope we will expand the trial to include patients with other B-cell malignancies.
References:
Parameswaran R, et al. Cancer Res. 2010;doi:10.1158/0008-5472.CAN-10-0300.
Parameswaran R, et al. Mol Cancer Ther. 2014;doi:10.1158/1535-7163.MCT-13-1023.
For more information:
Reshmi Parameswaran, MS, PhD, can be reached at rxp278@case.edu.
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