Milestones of Hematopoietic Stem Cell Transplantation – From First Human Studies to Current Developments

Abstract

Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA) system allowed improved donor selection, including HLA-identical related and unrelated donors. Besides bone marrow, other stem cell sources like granulocyte-colony stimulating-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from GvL or antitumor effects. Whereas in the early years, malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal; nowadays, allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity. This chapter will summarize the key milestones of HSCT and introduce current developments.

Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

“…Existing tumor‐reactive CTLs in non–T‐cell‐depleted grafts are responsible for the induction of GVT effects . We showed that the initial frequencies of MART1‐reactive CTLs were similar in both T‐cell sources, but the CB CTLs were primarily naïve (CCR7+CD45RA+) while the PB CTLs had a mixed phenotype consisting of naïve (59%) and memory CD45RA– (34%) T cells.…”

Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients

“…HSCT improves disease‐free survival for hematologic childhood malignancies and is either a last resort when other treatments have failed or as initial therapy for particularly aggressive diagnoses . Myeloablative conditioning regimens that include TBI and chemotherapy accomplish the dual goals of eradicating underlying malignant cells and providing immunosuppression to maximize rates of engraftment …”

“…The use of fractionated TBI has become standard and involves delivering multiple (six to eight) relatively small doses over 3–4 days for a total dose of 12–14 Gy . This approach maximizes the effect on malignant cells by allowing a higher total irradiation dose while simultaneously reducing the rate of tissue morbidity …”

“…17 Myeloablative conditioning regimens that include TBI and chemotherapy accomplish the dual goals of eradicating underlying malignant cells and providing immunosuppression to maximize rates of engraftment. 4,5,17,18 The use of fractionated TBI has become standard and involves delivering multiple (six to eight) relatively small doses over 3-4 days for a total dose of 12-14 Gy. [18][19][20][21] This approach maximizes the effect on malignant cells by allowing a higher total irradiation dose while simultaneously reducing the rate of tissue morbidity.…”

Advances in Hematopoietic Stem Cell Transplantation

“…About 200 trials were made between 1959 and 1962; however none of the recipient became long time survivors [15]. It seems that the unsuccessful allogeneic bone marrow transplantations were due to poor histocompatibility typing available, lack of effective supportive care such as antibiotics, lack of transfusional support with platelets and to the TBI protocol that was not so effective to achieve the immunosuppression necessary [1,[16][17][18].…”