i. Adoptive immunotherapy after CBT

A. Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Serrano LM, Pfeiffer T, Olivares S, Numbenjapon T, Bennitt J, Kim D, Smith D, McNamara G, Al-Kadhimi Z, Rosenthal J, Forman SJ, Jensen MC, Cooper LJ. Blood. 2006;107:2643-52.

One of the criticisms of UCBT, compared with other unrelated sources of hematopoietic stem cells, has been that donor anonymity precludes augmenting the GVL effect by infusions of donor-derived lymphocytes. The ability to generate B-ALL–specific T cells from UCB by enforcing expression of a chimeric immunoreceptor provides a potential solution to this limitation. Furthermore, the setting of UCBT may be particularly well suited to adoptive immunotherapy, since the slow pace of hematopoietic recovery provides a period of relative lymphopenia in which adoptively transferred T cells might expand using homeostatic mechanisms inherent to recovering the lymphocyte pool, and the relatively low incidence of severe GVHD means that recipients will be less likely to be taking immunosuppressive medications that might impair the function and persistence of the adoptively transferred T cells.

While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, the authors developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, was developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19⁺ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19⁺ tumor cells specifically and repetitively.

The authors concluded that their data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19⁺ B-ALL relapse.

(Comment: The above work was presented and discussed by Dr. Laurence Cooper at the Fourth Annual International Umbilical Cord Blood Transplantation Symposium in Los Angeles, May 19-20, 2006.)