Haploidentical Hematopoietic Cell Transplantation

Published on 04/03/2015 by admin

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Chapter 48 Haploidentical Hematopoietic Cell Transplantation

Bimalangshu R. Dey, Thomas R. Spitzer

Haploidentical Hematopoietic Cell Transplantation: Why Bother?

Haploidentical hematopoietic cell transplantation (HCT) involves related donor-recipient combinations sharing one haplotype who are mismatched for one to three human leukocyte antigens (HLA) on the other haplotype

• Only 30% of patients have an HLA genotypically or phenotypically matched related donor

• Successful haploidentical HCT would mean that most patients would have an immediately available donor

• A more potent graft-versus-tumor (GVT) effect may occur following histoincompatible HCT

Myeloablative Haploidentical HCT: Survival Outcomes—Conclusions in 1985

• Equivalent following HLA-matched and single HLA antigen–mismatched related HCT

• Inferior following two to three HLA antigen–mismatched HCT

Myeloablative Haploidentical HCT: Conclusions in 1997

• For favorable-risk hematologic malignancies

Haploidentical HCT is associated with inferior survival outcomes

• For intermediate- to high-risk hematologic malignancies

Single HLA antigen–mismatched related transplant equals matched unrelated-donor transplant

• For intermediate- to high-risk hematologic malignancies

Two HLA antigen–mismatched related transplant equals single HLA antigen–mismatched unrelated donor transplant

Haploidentical HCT: Conclusions in 2011

Haploidentical HCT is feasible in selected circumstances in which matched donors are unavailable. However, the following problems remain:

• It is unclear whether a stronger graft-versus-leukemia effect occurs

• Graft-versus-host disease (GVHD) and graft rejection are problematic, although becoming more manageable with vigorous T-cell depletion (TCD) and high stem cell dose

• Immune reconstitution, particularly following TCD, is poor

Nonmyeloablative Haploidentical HCT: Rationale

• Reduced early transplant-related mortality

• More candidates for HCT by virtue of age or comorbidity

• Mixed chimeric platform to prevent GVHD and optimize a GVT effect via donor lymphocyte infusion

Nonmyeloablative Haploidentical HCT: Conclusions

• Engraftment occurs in the majority of cases

• GVHD, prolonged immunodeficiency, and disease relapse remain challenging

• Mixed chimerism is achievable and may serve as a platform for adoptive cellular therapy

• Sustained remissions following donor graft rejection are seen and suggest an alternative antitumor mechanism

• Mixed chimerism can be used as a platform for achieving donor-specific solid organ tolerance

Haploidentical Hematopoietic Cell Transplantation: Ongoing Novel Efforts to Improve Transplant Outcomes

Selective Allodepletion

• Unmanipulated donor lymphocyte infusions (T-cell add-backs) cause significant graft-versus-host disease (GVHD).

• Selective depletion of specific host-reactive donor T cells (instead of global T-cell depletion) may mediate graft-versus-tumor (GVT) and antimicrobial immune responses without causing significant GVHD.

Cells and Cytokines of Special Appeal (Importance)

Natural Killer Cells

• Natural killer (NK)-cell alloreactivity in GVH direction following T cell–depleted transplant can dramatically reduce leukemic relapse.

• NK-cell alloreactivity in GVH direction can lead to lower rates of graft rejection due to donor NK–mediated lysis of host residual T cells.

• NK-cell alloreactivity in GVH direction can reduce GVHD via donor NK–mediated depletion of host antigen-presenting cells (and sparing of epithelial target tissues).

Immunoregulatory T Cells

• Ex vivo expanded regulatory T cells may inhibit GVHD while enhancing immune reconstitution and facilitating GVT effects.

Mesenchymal Stem Cells

• Ex vivo expanded mesenchymal stem cells have the potential to diminish GVHD while facilitating immune reconstitution.

Cytokines and Chemokines

• A number of cytokines and chemokines and their associated monoclonal antibodies can influence effector cell development, activation, trafficking, and thereby transplant outcomes, including engraftment, GVHD, immune reconstitution, and antitumor effects.

Haploidentical Hematopoietic Cell Transplantation: Future Directions

Approaches involving T-cell depletion or modulation are likely required to prevent severe graft-versus-host disease. Therefore we will need the following:

• Improved immune reconstitution, such as pathogen-specific cytotoxic T lymphocytes (CTLs) and better infectious disease monitoring

• Strategies to prevent disease relapse, such as adoptive natural killer cells, regulatory T cells, and tumor-specific CTLs

• Prospective, multicenter trials to define optimal regimens and post–hematopoietic cell transplantation care

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Figure 48-1 SCHEMA OF A STRATEGY TO OPTIMIZE THE OUTCOMES OF HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION.

Manipulation of the graft: A high CD34+ cell dose will likely improve donor engraftment by overcoming host-mediated resistance; selective ex vivo depletion of donor alloreactive T cells may reduce the incidence of severe acute graft-versus-host disease (GVHD) while preserving a graft-versus-tumor (GVT) effect and improving immune recovery. Enrichment and modulation of cellular and cytokine environment: Killer immunoglobulin-like receptor ligand (KIR-L) mismatching in the GVH direction will prompt donor natural killer (NK) cells to promote engraftment by attacking host T cells (T), diminish acute GVHD by depleting host antigen-presenting cells (APC) while eliminating host-derived malignant cells (M). Ex vivo expanded NK cells, mesenchymal stem cells (MSC), regulatory T cells (Tregs), NK Tregs, and soluble factor (SF; IL-7) will further augment donor engraftment, innate and adaptive immune responses, and reduce GVHD while not impairing GVT effects. MSC and NK Tregs, via IL-4 production, will skew donor T cells toward an antiinflammatory Th2 phenotype that is associated with reduced GVHD. Optimizing GVT effect and immune recovery without GVHD by unmodified donor leukocyte infusion (DLI): Ex vivo engineered tumor antigen and pathogen (virus)-specific donor-derived T cells (both cytotoxic T lymphocytes and CD4 cells) can be used to prevent and/or treat relapse of an underlying malignancy and opportunistic infections, respectively. In some circumstances, unmodified DLI may be used to convert mixed chimerism to full donor chimerism (FDC), probably enhancing a GVT effect without augmenting GVHD.

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