In the beginning days of blood banking, surgeons would call imperiously for “fresh whole blood” recognizing its superior restorative properties over banked blood. Since then technological advances have made it possible to break down the therapeutic elements of fresh blood into their constituent platelets, red cells, plasma, and clotting factors, and through apheresis, blood bankers can even provide granulocytes, lymphocytes, progenitors, and stem cells. The component therapy concept is so widely accepted that we cease to think it as being unusual. Curiously, and in contrast, transplant physicians have been slower to apply a component therapy approach to their practice. Even today the majority of hematopoietic cell transplantation (HCT), whether from the bone marrow, peripheral blood, or cord blood, is as unmanipulated as the “fresh whole blood” beloved of our surgeons of the past. Nevertheless, the attractions of a component therapy approach to HCT are many including but not limited to (1) T-cell depletion by selection of CD34+ cells, which can reduce GvHD, and (2) infused donor lymphocytes which can improve engraftment and treat leukemic relapse. Careful studies in the 1990s determined the doses of CD34+ cells and lymphocytes in the graft that led to the best outcomes, and donor lymphocyte infusion doses were calibrated to achieve graft-versus-leukemia effects with minimal graft-versus-host disease.
These initial graft manipulations contributed to steady progress to improving HCT outcome, extending the upper age limit of HCT recipients and paving the way for successful transplants from HLA-haploidentical mismatch donors. However, we now see these advances as merely a prelude to the full realization of the component therapy approach through modern cell and gene therapies. Advances in technology in translational research have opened up exciting and powerful new cell-based treatments which promise to dramatically transform the way we perform allogeneic HCT and eliminate the obstacles of GvHD, relapse, and transplant-related mortality (TRM).
In this volume, we review the exciting developments in cell and gene therapy as it relates to HCT. From blood or marrow, a diverse repertoire of cell products are now manufactured including mesenchymal stromal cells (Chap. 12), dendritic cell vaccines (Chap. 11), and NK cells (Chap. 10). Gene-modified T cells can potentially control GvHD through inserted suicide genes. T cells can be targeted to neoplastic cells by transducing them with chimeric antigen receptors (CAR T cells) or artificial receptors (α/β TCRs) (Chaps. 2, 3, 4, 5, 6, and 7). The ultimate goal of cell and gene therapy is to provide remedies for all the major obstacles to successful outcomes of HCT. Regulatory T-cell (Chap. 9) or mesenchymal stromal cell infusions aim to prevent or treat GvHD. Tumor antigen-specific T cells, CAR T cells, α/β TCR T cells, and NK cells can prevent or treat leukemic relapse, and T cells targeting multiple viruses (Chap. 8) can reduce transplant morbidity and mortality. Finally, gene therapy is being used not only in malignant but also in nonmalignant hematologic disorders (Chaps. 13 and 14).
With the rapid advances in treatments of neoplastic disease and the prospect of continuing breakthroughs in treatments, as we have seen with the introduction of tyrosine kinase inhibitors and recently checkpoint inhibitors, we should be wary about predicting where HCT will be by the next decade. However, the rapid advances in cell therapy show a growing ability to render HCT safer and more effective. The progress documented with cell and gene therapy ensures that HCT will continue to remain central to the treatment of neoplastic and nonmalignant disorders for the foreseeable future.