Harnessing Hypoimmune Allogeneic BCMA CAR T Cells for Enhanced Anti-Tumor Efficacy and Immune Evasion in Pre-Clinical Models

The study explores the use of engineered CAR T cells designed to evade both adaptive and innate immune rejection, which could be beneficial for treating patients with refractory multiple myeloma. The engineered cells are derived from healthy donors and modified to prevent recognition as "non-self" by disrupting the T cell receptor and major histocompatibility complexes. They also overexpress CD47 to avoid "missing-self" recognition and thus suppress NK and macrophage cell killing. These modifications are achieved through a lentiviral construct that includes BCMA CAR expression.

The research methodology involved transducing T cells from healthy donors with a second-generation BCMA CAR lentivirus. The transduction efficiency and efficacy of these CAR T cells were evaluated both in vitro using cytotoxicity assays against multiple myeloma tumor lines and in vivo using systemic tumor models in NSG mice.

The results showed that the engineered BCMA CAR T cells significantly reduced tumor growth and prolonged survival in the in vivo tumor models, demonstrating efficacy comparable to other clinically validated BCMA CARs. Furthermore, the overexpression of CD47 in these CAR T cells led to superior in vitro efficacy against BCMA+ tumor cells at low effector-to-target ratios.

The ongoing studies aim to further characterize the immune evasion properties and in vivo efficacy of these hypoimmune-edited CAR T cells. The team has previously shown that similar hypoimmune-edited CD19 CAR T cells can evade immune cell recognition, suggesting that the hypoimmune CD47-BCMA CAR T cells may offer an enhanced alternative to current autologous CAR T cell therapies.