Dual-Targeting CAR-T Therapies Show Promise in Overcoming B-Cell Cancer Treatment Resistance
核心洞察
Researchers at University Hospitals Seidman Cancer Center (搜索) developed a novel BAFF CAR-T therapy that targets three receptors (BAFF-R (搜索), BCMA (搜索), TACI (搜索)) instead of one, potentially reducing antigen escape seen in CD19 (搜索)-only therapies.
A separate bispecific CAR-T therapy (LV20.19) targeting both CD20 (搜索) and CD19 (搜索) achieved a 90% overall response rate in a phase 1/2 trial for relapsed/refractory B-cell non-Hodgkin lymphoma (搜索).
The BAFF CAR-T approach may cause less severe B-cell aplasia compared to CD19 (搜索) therapies since BAFF receptors are not expressed by early-stage B-cells.
Two groundbreaking CAR-T cell therapies are showing significant promise in addressing treatment resistance challenges that have limited the effectiveness of current B-cell cancer (搜索) treatments, according to recent research developments.
Novel Triple-Target BAFF CAR-T Therapy Addresses Antigen Escape
Researchers at University Hospitals Seidman Cancer Center (搜索) and Case Western Reserve University have developed a novel B-cell activating factor (BAFF) CAR-T therapy that targets three receptors simultaneously—BAFF-R (搜索), BCMA (搜索), and TACI (搜索)—instead of the single CD19 (搜索) target used in current therapies. This multi-target approach addresses a critical limitation of existing treatments: antigen escape.
"Cancer cells are tricky," explained Dr. Reshmi Parameswaran, senior author of the study published in Nature Communications. "The cancer cells will shed the CD19 (搜索) antigen and suddenly become CD19-negative and therefore not respond to the CD19 CAR T-cell therapy. Thus, there is a great need to identify alternative targeting strategies and CAR designs."
The BAFF CAR-T therapy demonstrated robust cytotoxicity against multiple B-cell cancers in both laboratory and animal studies, including mantle cell lymphoma (搜索), multiple myeloma (搜索), and acute lymphoblastic leukemia (搜索) xenograft mouse models. At least two of the three targeted receptors are found in almost all B-cell cancers, with some cancers expressing all three.
Reduced Side Effects Profile
Unlike CD19 (搜索) CAR-T therapies that kill both early and mature B cells, the BAFF CAR-T approach spares early B cells because these cells do not express BAFF receptors. This selectivity could significantly reduce treatment-related complications.
"CD19 (搜索) CAR T-cell therapy adverse effects include severe B-cell aplasia, due to pan-B-cell expression of the CD19 marker," Parameswaran noted. "Unlike CD19 CAR T cells, BAFF CAR T cells designed to target BAFF receptors may produce less severe B-cell aplasia, as the BAFF receptors are not expressed by early-stage B-cells."
The research team plans to file an Investigational New Drug (IND) application with the FDA in the coming weeks and aims to launch a clinical trial in patients with non-Hodgkin lymphoma (搜索) within several months.
Bispecific CAR-T Shows 90% Response Rate
Meanwhile, a separate bispecific CAR-T therapy (LV20.19) targeting both CD20 (搜索) and CD19 (搜索) has demonstrated impressive clinical results in a phase 1/2 trial. The therapy achieved a 90% overall response rate among 29 patients with relapsed or refractory B-cell non-Hodgkin lymphoma (搜索).
Dr. Nirav N. Shah from the Medical College of Wisconsin reported that patients in the 8-day manufacturing group showed a 90% response rate with 70% achieving complete responses, while the 12-day manufacturing group had a 78% response rate with 22% complete responses.
The study enrolled patients with a median age of 64 years who had received a median of four previous lines of therapy. Disease types included diffuse large B-cell lymphoma (搜索) (16 patients), mantle cell lymphoma (搜索) (10 patients), and follicular lymphoma (搜索) (3 patients).
Manufacturing Innovation and Safety Profile
The LV20.19 therapy utilizes a rapid manufacturing process using interleukin-7 and IL-15 for cell expansion, which can be completed in 8-12 days compared to longer timeframes for commercially available CAR-T therapies. Onsite manufacturing using the CliniMACS Prodigy production system allowed for infusion of fresh, noncryopreserved cell products in 26 of 29 patients.
"There are preclinical and clinical data that show that using [interleukin]-7 and IL-15 for cell expansion can improve the CAR T-cell product by increasing the number of T cells with central memory and stem cell memory phenotypes, which is important for CAR T-cell persistence and could help mitigate disease relapse," Shah explained.
Safety data showed that cytokine release syndrome occurred in 90% of patients, but only one patient experienced high-grade (grade 3) CRS. Twenty-eight percent of patients developed immune effector cell-associated neurotoxicity syndrome (ICANS), with 10% experiencing grade 3 ICANS.
Clinical Development Progress
Both therapies represent significant advances in CAR-T cell technology. The LV20.19 therapy is currently being evaluated in a multicenter phase 2 trial as third-line therapy for patients with diffuse large B-cell lymphoma (搜索), with the goal of FDA approval for commercial use.
"This dual-targeted CAR is one of the furthest along in terms of clinical development," Shah noted. "We have shown that dual targeting is effective and potentially the next step for CAR T-cell therapy."
The development of these multi-target approaches addresses fundamental challenges in CAR-T therapy, including treatment resistance and severe side effects, potentially expanding treatment options for patients with B-cell malignancies who have limited therapeutic alternatives.