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Hematopoietic stem cell transplantation-50 years of evolution and future perspectives.

Henig I, Zuckerman T - Rambam Maimonides Med J (2014)

Bottom Line: Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients.However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress.Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

ABSTRACT
Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

No MeSH data available.


Related in: MedlinePlus

The Chimeric Antigen Receptor (CAR).A: Construction and function of the CAR. ⓵ Constructed gene contains the tumor-associated antigen binding site (scFv), a co-stimulatory region (e.g. CD28), and an activating signal region (CD3ζ). ⓶ The gene is transfected into the T cell using a viral vector. ⓷ CAR gene incorporates into the cell DNA and translates into CAR protein. ⓸ CAR binds to the tumor-associated antigen (TAA), and the T cell is activated to cause tumor cell lysis, to secrete cytokines, and to proliferate.B: CARs transfected gene encodes to an extra-membrane TAA binding domain (scFv), a transmembrane domain and endomembrane cell activating domain (CD3ζ). First-generation CARs contain one signaling domain, the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs contain the activating domain and a co-stimulatory domain, typically the cytoplasmic signaling domains of the co-stimulatory receptors CD28 and 4-1BB or OX40. Third-generation CARs harness the signaling potential of two co-stimulatory domains: CD28 domain followed by either the 4-1BB or OX40. Fourth-generation CARs may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (e.g. IL-12).
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f2-rmmj-5-4-e0028: The Chimeric Antigen Receptor (CAR).A: Construction and function of the CAR. ⓵ Constructed gene contains the tumor-associated antigen binding site (scFv), a co-stimulatory region (e.g. CD28), and an activating signal region (CD3ζ). ⓶ The gene is transfected into the T cell using a viral vector. ⓷ CAR gene incorporates into the cell DNA and translates into CAR protein. ⓸ CAR binds to the tumor-associated antigen (TAA), and the T cell is activated to cause tumor cell lysis, to secrete cytokines, and to proliferate.B: CARs transfected gene encodes to an extra-membrane TAA binding domain (scFv), a transmembrane domain and endomembrane cell activating domain (CD3ζ). First-generation CARs contain one signaling domain, the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs contain the activating domain and a co-stimulatory domain, typically the cytoplasmic signaling domains of the co-stimulatory receptors CD28 and 4-1BB or OX40. Third-generation CARs harness the signaling potential of two co-stimulatory domains: CD28 domain followed by either the 4-1BB or OX40. Fourth-generation CARs may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (e.g. IL-12).

Mentions: 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). However, CARs do not require antigen processing and presentation by HLA. Therefore CARs recognize antigen on any HLA background, in contrast to T cell receptors (TCR), which need to be matched to the patient’s haplotype. 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.81 The most investigated target to date is CD19 found on B cell lymphocyte and on malignancies arising from it (B cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, B cell acute lymphoblastic leukemia). Several phase I–II studies have been conducted in patients with very refractory disease, with some of the studies showing promising results.82–85 Novel targets are being investigated in preclinical setting like the promising CARs against CD123, which is found on acute myeloid leukemia cells.86,87 Chimeric antigen receptor T cell adoptive therapy seems to have a great potential, and its best effect might be in the allogeneic HSCT setting.


Hematopoietic stem cell transplantation-50 years of evolution and future perspectives.

Henig I, Zuckerman T - Rambam Maimonides Med J (2014)

The Chimeric Antigen Receptor (CAR).A: Construction and function of the CAR. ⓵ Constructed gene contains the tumor-associated antigen binding site (scFv), a co-stimulatory region (e.g. CD28), and an activating signal region (CD3ζ). ⓶ The gene is transfected into the T cell using a viral vector. ⓷ CAR gene incorporates into the cell DNA and translates into CAR protein. ⓸ CAR binds to the tumor-associated antigen (TAA), and the T cell is activated to cause tumor cell lysis, to secrete cytokines, and to proliferate.B: CARs transfected gene encodes to an extra-membrane TAA binding domain (scFv), a transmembrane domain and endomembrane cell activating domain (CD3ζ). First-generation CARs contain one signaling domain, the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs contain the activating domain and a co-stimulatory domain, typically the cytoplasmic signaling domains of the co-stimulatory receptors CD28 and 4-1BB or OX40. Third-generation CARs harness the signaling potential of two co-stimulatory domains: CD28 domain followed by either the 4-1BB or OX40. Fourth-generation CARs may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (e.g. IL-12).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222417&req=5

f2-rmmj-5-4-e0028: The Chimeric Antigen Receptor (CAR).A: Construction and function of the CAR. ⓵ Constructed gene contains the tumor-associated antigen binding site (scFv), a co-stimulatory region (e.g. CD28), and an activating signal region (CD3ζ). ⓶ The gene is transfected into the T cell using a viral vector. ⓷ CAR gene incorporates into the cell DNA and translates into CAR protein. ⓸ CAR binds to the tumor-associated antigen (TAA), and the T cell is activated to cause tumor cell lysis, to secrete cytokines, and to proliferate.B: CARs transfected gene encodes to an extra-membrane TAA binding domain (scFv), a transmembrane domain and endomembrane cell activating domain (CD3ζ). First-generation CARs contain one signaling domain, the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs contain the activating domain and a co-stimulatory domain, typically the cytoplasmic signaling domains of the co-stimulatory receptors CD28 and 4-1BB or OX40. Third-generation CARs harness the signaling potential of two co-stimulatory domains: CD28 domain followed by either the 4-1BB or OX40. Fourth-generation CARs may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (e.g. IL-12).
Mentions: 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). However, CARs do not require antigen processing and presentation by HLA. Therefore CARs recognize antigen on any HLA background, in contrast to T cell receptors (TCR), which need to be matched to the patient’s haplotype. 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.81 The most investigated target to date is CD19 found on B cell lymphocyte and on malignancies arising from it (B cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, B cell acute lymphoblastic leukemia). Several phase I–II studies have been conducted in patients with very refractory disease, with some of the studies showing promising results.82–85 Novel targets are being investigated in preclinical setting like the promising CARs against CD123, which is found on acute myeloid leukemia cells.86,87 Chimeric antigen receptor T cell adoptive therapy seems to have a great potential, and its best effect might be in the allogeneic HSCT setting.

Bottom Line: Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients.However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress.Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

ABSTRACT
Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

No MeSH data available.


Related in: MedlinePlus