Posted December 16, 2022

Larry Kwak, M.D., Ph.D., City of Hope

Non-Hodgkin’s lymphoma (NHL) is a cancer which affects lymphocytes, an important component of the immune system, including B cells. T‑cells, another type of lymphocyte, recognize specific proteins (antigens) and assist in clearing pathogens. Recently, immunotherapies called chimeric antigen receptor (CAR) T‑cells have been developed to treat NHL. CAR T‑cells utilize healthy T‑cells engineered to recognize tumor cell antigens, thereby targeting the cancer cells for destruction. In current CAR‑T cell therapy for NHL, engineered T‑cells recognize a B‑Cell marker called CD19. While this therapy has been successful, approximately 20%-30% of treated NHL patients experience reoccurrence, possibly due to a new B‑Cell population no longer expressing CD19.²

Dr. Larry Kwak generated an antibody that recognizes the B‑Cell activating factor receptor (BAFF-R) that is essential for cell survival and expressed on malignant B cells.² This antibody was used to produce a prototype CAR‑T therapy targeting BAFF-R (BAFF-R-CAR‑T) for use in CD19-negative lymphoma models. With a Fiscal Year 2017 Peer Reviewed Cancer Research Program Idea Award with Special Focus, Dr. Kwak and his team sought to optimize their BAFF-R-CAR‑T.

Dr. Kwak’s research team first evaluated different protein structures for their CAR. Three variations of the BAFF-R-CAR‑T, each expressing a slightly different version of the CAR, were tested in various lymphoma cell lines to select the version with the highest efficacy. Using the selected CAR, the team assessed the anti-tumor activity of various types of T‑cells. These optimization experiments led to the successful development a BAFF-R-CAR‑T with cytotoxicity (toxicity to cells) in lymphoma cell lines and demonstrated the ability to reduce tumor size in a lymphoma mouse model and achieved 100% survival.

Next, the team sought to compare their BAFF-R-CAR‑T to the currently approved CD19-CAR‑T cells in both CD19-negative and CD19-positive B‑Cell tumor cell lines. Their findings indicated that, while both treatments were cytotoxic in CD19-positive tumor cells, only BAFF-R-CAR‑Ts were cytotoxic to CD19-negative cells. These results were confirmed in a CD19-negative mouse model, where only the BAFF-R-CAR‑T cells led to reduction of the established CD19-negative tumor. To demonstrate translatability to humans, the team assessed the BAFF-R-CAR‑T in CD19-negative B cell tumor samples derived from patients who experienced reoccurrence after treatment with CD19-CAR‑T therapy. The team found that BAFF-R-CAR‑T cells were more active than the CD19-CAR‑T cells in patient samples, indicating the potential of the BAFF-R-CAR‑Ts to elicit a more robust immune response to the targeted tumor cells.

Dr. Kwak and his team began the process of manufacturing and testing the CAR‑T cells for clinical use. They generated a clinical version of BAFF-R-CAR‑T that incorporated features to make the therapy safer. To assess the efficacy of the clinical variant, the prototype and clinical BAFF-R-CAR‑T cells were compared to two controls in a lymphoma mouse model. Tumor regression and increased survival were observed in both the prototype and clinical CAR‑Ts, but not in the controls, indicating that the clinical variant was as effective as the prototype previously developed. With the ultimate goal of translation to a clinical setting, the team conducted several experiments to obtain Investigational New Drug status and eventual U.S. Food and Drug Administration (FDA) approval. The clinical BAFF-R-CAR‑T successfully met or exceeded all requirements needed for FDA approval and supported the start of a phase 1 clinical trial to assess the safety and optimal dose for BAFF-R-CAR‑T cell therapy.

With the beginning of clinical translation, Dr. Kwak and his team continued to develop their BAFF-R-CAR‑T therapy. The team hypothesized that a CAR‑T targeting both CD19 and BAFF-R would therapeutically outperform sequential use of both CAR‑T therapies. Therefore, they developed dual CD19/BAFF-R CAR‑T cells and evaluated the construct in vitro and in vivo. Results indicated that the dual CAR‑T therapy successfully eradicated all types of tumor cells in mixed models of lymphoma when compared to CD19-CAR‑T or BAFF-R-CAR‑T alone and, as a result, may be therapeutically advantageous compared to a CAR‑Ts targeting a single antigen.

The team has successfully generated, optimized, tested, and begun translation of a novel CAR‑T therapy that has the potential to impact Service Members at risk for NHL due to exposure to environmental risk factors. Their BAFF-R-CAR‑T is currently in clinical trials, and the recently developed dual CD19/BAFF-R-CAR‑Ts indicate a potential benefit to NHL patients who have relapsed due to the persistence of a CD19-negative tumor cell population. In addition, these therapies could be applied to other B‑Cell malignancies and potentially improve CAR‑T therapy by preventing therapy resistance.

Link:
Public and Technical Abstracts: Novel CAR‑T Therapy Targeting BAFF-R Against B‑Cell Lymphomas

Publications:
¹1 Dong Z, Cheng WA, Smith DL, et al. 2020. Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions. Cancer Immunology, Immunotherapy. 69:2139-2145. doi:10.1007/s00262-020-02614-8.

²Qin H, Dong Z, Wang X, et al. 2019. CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Sci Transl Med. 11(511). doi:10.1126/scitranslmed.aaw9414.

³Wang X, Dong Z, Awuah D, et al. 2022. CD19/BAFF-R dual targeted CAR T cells for treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. Leukemia. 36(4):1015–1024. doi:10.1038/s41375-021-01477-x.

Clinical Trial:
BAFFR Targeting CAR‑T Cells for the Treatment of Relapsed or Refractory B‑Cell ALL - Full Text View - ClinicalTrials.gov

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Last updated Thursday, December 15, 2022