Adoptive transfer of donor-B lymphocytes is safe and improves immunity in patients after allogeneic stem cell transplantation – a phase I/IIa first-in-human study

Immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is slow and patients carry a high and prolonged risk for opportunistic infections. We hypothesized that the adoptive transfer of donor B cells can foster post-HSCT immuno-reconstitution. Here we report on the results of a first-in-human phase I/IIa study aimed to evaluate the feasibility and safety of adoptively transferred donor B cells and to test their activity upon recall vaccination.

GMP-grade B cell products were generated from the original stem cell donor donor by leukapheresis. 15 allo-HSCT patients were enrolled and treated after taper of immunosuppression (median day +148, range 130 to 160). Patients with an EBV reactivation > 10.000 copies/ml and an acute GVHD grade III/IV in their history were excluded. Patients received four different doses of B cells (0.5x106 - 4.0x106 B-cells per kg body weight (BW)). To test the activity of infused donor memory B cells in vivo patients were vaccinated with a pentavalent vaccine 7 days after B cell transfer. The primary endpoint was safety and tolerability. The secondary endpoints were frequency of antibody-producing cells between dose groups 7 days after vaccination.

After two step separation (CD3 depletion and CD19 enrichment) the median proportion of B cells was 96.1% (range 84.9-99.1%) and of CD3-positive T cells 0.08% (range 0.01%-0.82%). We observed a significant increase of plasmablasts after vaccination and an increase of serum titers against vaccine antigens with a stronger response in patients receiving higher B cell numbers. The analysis of immunoglobulin VH-sequences by next-generation-sequencing revealed that plasmablasts responding to the vaccination originated from memory B cell clones from the donor. Donor B cell transfer was safe as no EBV reactivation was observed, and only low-grade GvHD occurred in 4 out of 15 patients.

This phase I/IIa first-in-human study on adoptively transferred donor B cells was designed to evaluate safety (EBV reactivation, GVHD) and efficacy in improving humoral immunity after allo-HSCT. Our data show that transfer of donor B cells into allo-HSCT recipients is feasible and safe and resulted in enhanced memory B-cell responses. This pilot trial may pave the way for further studies exploring the adoptive transfer of memory B cells to reduce the frequency of infections after allo-HSCT.

There are no conflict of interests.