First bone marrow transplant between unrelated patients. First xenotransplantation of bone marrow. Bone marrow and a kidney from a baboon are transplanted into a patient. The patient dies 26 days later from infection. Jeff Getty continued to struggle with HIV for many years and died in Add to collection. But the idea of using radiation to kill off the bone marrow caught the attention of doctors specializing in the treatment of bone marrow failure disorders. By the s, E. Donnall Thomas of Cooperstown, N.
But even in a controlled setting, he found that total body exposure to radiation led to lung problems in patients. At Johns Hopkins, meanwhile, George Santos began studying another way to kill off diseased bone marrow: administration of a chemotherapeutic drug cocktail that included busulfan and cyclophosphamide. Santos soon found that cyclophosphamide not only killed off bone marrow without the toxic effects observed in total body radiation but also had strong anti-cancer properties.
His research into this drug, in particular, paved the way for modern-day bone marrow transplant efforts. In , Thomas performed the first successful bone marrow transplant on a patient with aplastic anemia using Santos' chemotherapy approach. Santos was a man well ahead of his time, says Jones, director of the Johns Hopkins Bone Marrow Transplantation Program—a program that Santos himself founded in and headed until his retirement in Santos was among the first to recognize and study the positive effects of a postoperative condition known as graft-versus-host disease, or GVHD.
Thus, mild GVHD works in tandem with chemotherapy by killing cancerous cells the chemotherapy may have missed. In addition to discovering of the benefits of the drug cyclophosphamide, Santos also found benefits to another chemotherapeutic drug, 4-CH. When Thomas conducted the first successful bone marrow transplant in the early s, doctors only knew how to conduct allogeneic transplants—those requiring two individuals, a donor and patient.
But Santos soon realized that 4-CH helped purge cancerous cells in a damaged marrow, thus paving the way for self, or autologous, transplants. In this type of transplant, blood stem cells are collected from a patient, frozen while the patient undergoes chemotherapy, and then re-injected several months later. Bone marrow is a spongy tissue found in the centre of bones. It contains cells called haematopoietic or blood-making stem cells. These stem cells produce millions of blood cells, such as red cells, white cells and platelets, every day.
These blood cells are relatively transient; they are produced as required, and when no longer needed, they die. Haematological blood cell cancers, such as leukaemia, usually arise in the bone marrow.
A single blood cell that has been mutated damaged begins to divide uncontrollably, producing copies of itself that eventually fill the bone marrow and spread through the blood system. Chemotherapy and sometimes radiotherapy is used to kill these cancer cells. Before the advent of bone marrow transplantation, high doses of chemotherapy, sufficient to kill all the cancer cells, could not be used, as they also killed the normal cells in the bone marrow.
With the demonstration of successful bone marrow transplantation however, doctors were able to use higher, more effective doses of chemotherapy and radiation. These higher doses also kill normal bone marrow cells, but now these cells can be replaced with donor cells. The first bone marrow transplants were performed in identical twins, and then in siblings, because cells from unrelated donors were rejected by patients. Where possible, it is preferable for matched siblings or other close relatives to act as bone marrow donors.
When a matched relative is unavailable, international Bone Marrow Donor Registries exist to match unrelated donors with patients. Priming and expanding donor T cells ex vivo against patient TAA will resolve the issue of vaccinating the patient himself; however, this will require very high costs.
Monoclonal antibodies mAb are in routine use in the treatment of hematologic malignancies. Rituximab, an anti-CD20 antibody, is the standard treatment protocol for B cell lymphomas. Gemtuzumab ozogamicin, a humanized anti-CD33 mAb conjugated to calicheamicin-derivate toxin, has been used in AML and been shown when incorporated in low dose with chemotherapy to result in improved overall survival.
These antibodies bind target tumor cells and at the same time bind and harness polyclonal cytotoxic T cells to cause highly efficient lysis of targeted tumor cells. Chimeric antigen receptors CARs are recombinant receptors that provide both antigen-binding and T cell-activating functions Figure 2. The engineering of CARs into T cells requires that T cells be cultured to allow for gene transduction and stable clonal expansion. Any cell surface molecule can be targeted through a CAR.
Current CARs are limited to recognizing only cell surface antigens T cell receptors recognize both cell surface and intra-cellular proteins. Furthermore, CARs can target tumor cells that down-regulate HLA expression or use proteasomal antigen processing, two mechanisms that contribute to tumor escape from TCR-mediated immunity.
Several phase I—II studies have been conducted in patients with very refractory disease, with some of the studies showing promising results. A: Construction and function of the CAR. Second-generation CARs contain the activating domain and a co-stimulatory domain, typically the cytoplasmic signaling domains of the co-stimulatory receptors CD28 and BB or OX Fourth-generation CARs may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines e.
T cell depletion abrogates GVHD completely with higher rates of non-engraftment, infections, and disease relapse. Host alloreactive donor lymphocytes are responsible for GVHD. Theoretically selective elimination of host alloreactive lymphocytes from the graft will result in significant reduction in GVHD rate without effecting GVL and immune reconstitution.
Selective allodepletion methods rely on the co-culturing of irradiated host peripheral blood mononuclear cells with donor T cells. Alloreactive T cells are activated, identified, and removed either with monoclonal antibodies coupled to magnetic beads or photodepletion procedure Figure 3. Peripheral blood stem cells are collected from the donor with leukopheresis. The graft is then T cell-depleted by positive stem cell selection. The unabsorbed T cells are used for the selective depletion.
On the transplantation day the patient receives the graft and the selective allodepletion T cells. They are expanded in culture with IL-2 and OKT3 , and before use they are inactivated by irradiation.
The cells are co-cultured in a ratio with donor T cells collected by leukopheresis. The cells are then incubated with the photosensitizer TH Alloactivated T cells incorporate the photosensitizer.
Activation of TH by light exposure causes their lysis and allodepletion of the alloreactive lymphocytes. Only non-alloreactive donor T cells remain in the product. Viral infections are a significant cause of morbidity and mortality in transplantation, especially in pediatric patients, and particularly in TCD haploidentical transplantation and in UCB transplantation.
Effective therapies are limited in refractory infections and often associated with significant side effects. Adoptive transfer of virus-reactive T cells offers a means of reconstituting antiviral immunity, and this approach has been successfully used to prevent and treat cytomegalovirus, Epstein—Barr virus, and adenovirus infections.
Adoptive antiviral cytotoxic T cell lines have been used effectively for more than a decade. In December , the one-millionth blood stem cell transplant worldwide was performed. Reduced-intensity conditioning better exploiting the immunotherapeutic GVL effect and improved supportive care have contributed to reduction in TRM rate. Recipient age is rising, and now HSCT is considered optional up to the age of 70 years. Donor availability has dramatically increased thanks to the international collaboration and unrelated volunteer donor registries.
The use of adoptive cellular immunotherapy, tumor vaccinations, and mAbs is expected to change the allogeneic HSCT setting and reduce disease relapse rate. In the coming years allogeneic HSCT is likely to become more complex, more individualized, and more efficient. National Center for Biotechnology Information , U. Rambam Maimonides Med J. Published online Oct Israel Henig , M.
Author information Copyright and License information Disclaimer. Conflict of interest: No potential conflict of interest relevant to this article was reported. E-mail: li. This is an open-access article. This article has been cited by other articles in PMC. Abstract Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Keywords: Adoptive immunotherapy, alternative donor, conditioning, graft-versus-host disease, graft-versus-leukemia, hematopoietic stem cell transplantation.
Table 1. Open in a separate window. Figure 1. Conditioning Regimen Intensity. Extending Donor Availability Apart from possibilities of a matched related sibling donor and a matched unrelated volunteer donor, it has become optional to perform allogeneic HSCT for almost all patients using an alternative donor.
Natural Killer Cell Adoptive Immunotherapy In TCD haploidentical HSCT it was shown that mature fully functioning NK cells derived from differentiation of hematopoietic stem cells emerge in the peripheral blood of the recipient only several weeks after the allograft, while in the early post-transplant period immature poorly functioning NK cells predominate.
Monoclonal Antibodies Monoclonal antibodies mAb are in routine use in the treatment of hematologic malignancies. Chimeric Antigen Receptors Chimeric antigen receptors CARs are recombinant receptors that provide both antigen-binding and T cell-activating functions Figure 2. Figure 2.
Figure 3. Alloreactive T Cell Photodepletion. Antiviral Cytotoxic Cell Lines Viral infections are a significant cause of morbidity and mortality in transplantation, especially in pediatric patients, and particularly in TCD haploidentical transplantation and in UCB transplantation.
Appelbaum FR. Hematopoietic-cell transplantation at N Engl J Med. Allogeneic hematopoietic SCT for patients with autoimmune diseases.
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