BOB1-TCR gene therapy for the treatment of B-Cell Malignancies - A phase I/II clinical trial
Recently, chimeric antigen receptor and bispecific antibody therapy have shown unprecedented early response rates in several B-cell malignancies (BCMs), including Acute Lymphoblastic Leukaemia (ALL), Multiple Myeloma (MM) and Diffuse Large B-Cell Lymphoma (DLBCL). Irrespective of disease entity, however, relapse rates remain high and BCMs continue to be incurable with only few exceptions. We propose T-cell receptor (TCR)-based therapy as a valuable addition to other T-cell redirecting therapies in BCMs as TCR-based therapy allows for targeting of (multiple) intracellular antigens.
We and others proposed B cell Oct-binding protein 1 (BOB1) as a promising target for the treatment of BCMs, since BOB1 is uniformly expressed in BCMs and its expression was shown to be essential for MM and DLBCL cell lines. Previously, we identified a TCR specific for the APAPTAVVL peptide of BOB1 presented in HLA-B*07:02. Specificity of this BOB1-TCR was evaluated in vitro by co-incubation of BOB1-TCR expressing T cells with various HLA-B*07:02+ BOB1+ target cells, including primary patient materials. Potential dangerous cross-reactivities were investigated by co-incubation of BOB1-TCR expressing T cells with various HLA-B*07:02- and HLA-B*07:02+ BOB1- target cells. In vivo efficacy of CD8 T cells transduced with the BOB1-TCR was investigated in an established MM xenograft mouse model with luciferase-expressing U266 cells. Finally, a good manufacturing practice (GMP)-grade manufacturing process for the production of autologous BOB1-TCR engineered CD8 T cells was developed and validated in pre-clinical manufacturing test runs.
HLA-B*07:02+ B-cell tumour cells, including various BCM cell lines and primary ALL, MM and B-cell lymphoma patient materials, were efficiently lysed in vitro by BOB1-TCR engineered CD8 T cells of healthy donors. No cross-reactivities of BOB1-TCR expressing T cells to any HLA-B*07:02- or HLA-B*07:02+ BOB1- target cells were detected. Robust anti-tumour activity of BOB1-TCR transduced CD8 T cells was demonstrated against MM cell line U266 in vivo. The GMP-grade manufacturing process yields BOB1-TCR T-cell drug products of high purity, proliferative capacity and in vitro potency. The GMP-grade manufacturing process is thus considered fit for clinical application.
We hence conclude that BOB1-TCR T cells are efficiently reprogrammed to target malignant B cells without any critical off-target or on-target off-tumour toxicities. A phase phase I/II clinical trial for patients with relapsed or refractory HLA-B*07:02+ ALL, MM, DLBCL and other non-Hodgkin B-cell lymphomas was recently approved by the Dutch Centrale Commissie voor Mensgebonden Onderzoek (CCMO). Patient recruitment is scheduled to start in late 2025.