Haploidentical Hematopoietic Cell Transplantation

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment for various hematologic and immunologic disorders. Historically, selection of a suitable allo-HCT donor relied exclusively on degree of human leukocyte antigen (HLA) matching between the donor and the recipient to avoid the intense bidirectional immunologic reactions causing graft rejection and graft-versus-host disease (GHVD). However, a fully HLA matched related or unrelated donor cannot be identified in a significant proportion of allo-HCT candidates. Unfortunately, less than 30% of the patients referred for transplantation have a matched sibling donor (MSD) available, while the chance of finding a matched unrelated donor (MUD) varies widely based on ethnicity and race. Furthermore, a longer time to obtain the stem cells from an unrelated donor (average of 3–4 months) makes it difficult to proceed to transplant for patients who urgently need this procedure. Umbilical cord blood (UCB) transplantation has been used for patients without an HLA matched donor; however, limitation in obtaining an adequate number of the stem cells, especially for adult recipients, and immaturity of the immune system transplanted are associated with higher treatment-related mortality (TRM).

Haploidentical hematopoietic cell transplantation (Haplo-HCT) is now increasingly utilized over the past several decades, during which several strategies have been developed to better control the intense alloreactivity from the donor-recipient HLA mismatch, and is now the fastest growing type of allogeneic transplant worldwide. Moreover, with continuous improvement in transplant outcomes now similar to HLA-matched donor transplants, Haplo-HCT has the potential to become the alternative donor of choice for patients who do not have an MSD and are in urgent need of this procedure. Box 7.1 summarizes potential benefits of using haploidentical donors for transplantation.

Box 7.1

Benefits of Using Haploidentical Donors for Transplantation

Increase donor availability for almost all patients
Rapid availability of stem cells for patients who need an urgent transplant
Low cost of graft acquisition without the need of stem cell banking or use donor registry
Increase ability to procure adequate doses of stem cells (which correlate with outcomes)
Donor availability to collect additional cells for future cellular therapy or stem cell boost
Potential for a stronger graft-versus-tumor (GVT) effect because of higher degree of human leukocyte antigen (HLA) mismatch between the donor and recipient as compared with HLA matched transplants

Evolution of Haploidentical Hematopoietic Cell Transplantation

HLA system is a prominent part in antigen presentation and immunologic reactions, which is controlled by genes located on chromosome 6. It encodes cell surface molecules specialized to present antigenic peptides to the T-cell receptor (TCR) or recognizes polymorphic fragments of foreign HLA molecules, generating intense immune responses. The degree of donor-recipient HLA incompatibility correlates directly with the risk of GVHD, which is primarily mediated by donor T cells against recipient’s mismatched HLA antigens. Historically, conventional GVHD prophylaxis has been inadequate in controlling strong GVHD reactions in T-cell replete Haplo-HCT. Before 1990s, transplantation of a full HLA haplotype mismatched graft triggered a high incidence of severe GVHD, engraftment failure and organ toxicity, resulting in an unacceptable treatment-related morbidity and mortality.

To mitigate the alloimmune reactions responsible for the development of severe acute GVHD (aGVHD), several methods of T-cell depletion were developed. Multiple studies showed that T-celldepleted grafts could achieve engraftment and reconstitution of hematopoiesis yet a higher incidence of graft rejection and infections complications have been noted. Rejection of T-cell–depleted bone marrow cells could be overcome by increasing the stem cell dose. Using this approach, Aversa and colleagues showed a low incidence of aGVHD in patients receiving a highly myeloablative conditioning (MAC) regimen and megadose of CD34+ selected graft. Unfortunately, myeloablative chemotherapy and the complete lack of donor T cells in the graft resulted in a high TRM related to infectious complications, especially viral infections.

Subsequent graft manipulation strategies focused on immunomagnetic depletion of donor T and B cells while preserving different lymphocyte subsets and graft-facilitating cells, thereby enhancing engraftment without the need of intense myelosuppression or high doses of stem cells. In adult patients with hematologic malignancies, Bethge et al. showed that using a reduced-intensity conditioning (RIC) regimen and a CD3+ /CD19+ depleted graft could induce more rapid engraftment and immune reconstitution compared to their historical experience of CD34+ selected grafts. In this study, 28 of 29 patients successfully engrafted with median time to neutrophil engraftment of 12 days. However, almost half of the patients succumbed to grade 2 to 4 aGVHD and only 35% survived beyond 1 year post transplant. Similar results were reported in a phase II prospective multicenter study. Nevertheless, this method appeared more feasible in pediatric patients. In a prospective phase II trial in children with acute leukemia and myelodysplastic syndrome (MDS) using the same approach, primary engraftment occurred in 87% of the patients with low incidence of aGVHD (20% grade 2–4) and TRM (8% at 1 year).

Modern Methods of Haploidentical Transplantation

Initially, different investigators focused on diminishing the risk of GVHD using either CD34+ selection or depletion of T and B cells from the graft. These approaches resulted in extensive depletion of donor T cells and were associated with a higher risk of engraftment failure and delayed immunologic recovery, leading to an unacceptable morbidity and mortality. Evidence has shown that T-cell components in the graft are a prerequisite of successful engraftment and long-term immunity against pathogens, as well as effective graft-versus-tumor (GVT) effect. It has become clear over time that either a full haploidentical graft without effective control of alloreactivity or extensive T-cell depletion cannot provide adequate transplant outcomes, hence research evolved towards partial depletion of donor T cells or more intense pharmacologic modulation applied early posttransplant. These more advanced technologies have provided a major step forward in successfully overcoming the HLA barrier, hasten immunologic reconstitution without increasing the risk of GVHD or TRM, and improved survival comparable with HLA matched grafts, making haploidentical donors a valued alternative source of stem cells for transplantation.

Haploidentical hematopoietic Cell Transplant With Selective Ex Vivo T-Cell–Depleted Graft

T-Cell–Depleted Haploidentical Transplant With Tregs-Tcons Coinfusion

Regulatory T cells (Tregs) (CD4+ CD25+ Foxp3+ ) comprise 5% to 10% of CD4+ T cells in the blood and have been shown to suppress aberrant immune responses and regulate peripheral T-cell homeostasis. In murine models of transplantation, coinfusion of conventional T cells (Tcons) with Tregs could mitigate lethal GVHD, facilitate immune reconstitution, and preserve GVT effect. Adoptive immunotherapy with donor Tregs (2 × 10 ⁶ /kg) 4 days before transplant followed by infusion of Tcons (1 × 10 ⁶ /kg) and a mega-dose CD34+ selected graft successfully prevented development of GVHD in patients and improved immunologic reconstitution. In the initial study, 26 of 28 patients achieved primary engraftment after a median of 15 days. Acute GVHD grade 2–4 was seen in only two patients, while no chronic GVHD was observed, despite no posttransplant GVHD prophylaxis. T-cell reconstitution was enhanced with early expansion of T-cell repertoires and pathogen-specific responses. Although, none of the patients developed cytomegalovirus (CMV)-associated disease, TRM remained high (13 of 26 patients died of nonrelapse related causes, 8 of whom died of infectious complications). Similar results were reported by the same group in an expanded cohort of 43 patients with high-risk leukemia. At a median follow-up of 46 months, only 2 of 41 evaluable patients relapsed. Result from multivariable analysis showed that Tregs-Tcons adoptive immunotherapy was the only predictive factor significantly associated with a reduced risk of relapse. However, TRM remained high (40%), mainly related to infectious complications, despite laboratory evidence of improved T-cell reconstitution early posttransplant.

Photodepletion of Alloreactive Donor T Lymphocytes

This approach uses photoinactivation of alloreactive T cells, which expand significantly upon exposure to recipient cells. Once activated by recipient-derived antigen presenting cells, alloreactive donor T cells will express surface markers or inhibit function of P-glycoprotein pump, which leads to accumulation of photoactive substances. The alloreactive T cells can then be eliminated from the donor T-cell repertoire following exposure to visible light, whereas resting T lymphocytes capable of providing antiinfection and antitumor reactivity are preserved. A reduced graft alloreactivity can be obtained through the ex vivo administration of TH9402 followed by photodepletion. In a phase I dose finding study of allodepleted T-cell immunotherapy (ATIR101) infusion, 19 adult patients with hematologic malignancies were infused with ATIR101 approximately 1 month after the infusion of CD34+ selected haploidentical graft. Conditioning regimen included fludarabine, thiotepa, antithymocyte globulin (ATG) and myeloablative doses of total body irradiation (TBI) without posttransplant immunosuppression. Mild aGVHD post-ATIR101 infusion was seen in four patients, while extensive chronic GVHD (cGVHD) developed in five patients, with 8-year overall survival (OS) of 37%. These results have shown that ATIR101 can control GVHD reactions and facilitate early immune protection by providing antiinfectious and antileukemic activity without the need for posttransplant immunosuppression. Results of a phase 2 study showed a low TRM (13% vs. 37% at 6 months) and better survival (83% vs. 63% at 6 months) compared with historical controls of patients receiving T-cell–depleted Haplo-HCT.

TCR αβ+/CD19+ Depletion

T-cell receptor (TCR) is composed of two different protein chains. The majority of T cells in peripheral blood express α β TCR (95%), while the rest express γ δ TCR. Preclinical models have shown that α β T cells play a major role in development of GVHD while innate-like γ δ T cells are capable of directly recognizing tumor targets in an major histocompatibility complex (MHC)-independent manner, therefore providing effective antitumor activity. Several studies have demonstrated that a higher number of donor-derived γ δ T cells following HLA partially mismatched allo-HCT correlates with better survival. This provided a strong foundation to use immunomagnetic ex vivo selective depletion of α β T cells from mobilized peripheral blood haploidentical grafts. This method, which results in approximately 4 log reduction of α β T cells, while retaining the majority of CD34+ cells, natural killer (NK) cells, and γ δ T-cells in the graft, was subsequently combined with CD19+ B-cell depletion to prevent posttransplant Epstein Barr virus (EBV)-associated lymphoproliferative disease. In the first reported clinical study, 23 pediatric patients with advanced hematologic malignancies were treated with TCRα β + /CD19+ depleted haploidentical peripheral blood graft. All patients achieved sustained engraftment, rapid immune reconstitution, and had low incidence of GVHD despite no posttransplant pharmacologic GVHD prophylaxis. Lang and colleagues reported in abstract format outcomes of 60 pediatric and adult patients with malignant and nonmalignant diseases who received TCRα β + /CD19+ depleted Haplo-HCT treated in a prospective, multicenter, single-arm, phase I/II clinical trial and documented rapid engraftment with none of the patients developing severe aGVHD. However, high incidence of viral reactivations and diseases were observed (three patients died of adenovirus infections). At 2-year follow-up, OS and disease-free survival (DFS) were 62% and 53%, respectively, while the cumulative incidence of relapse and TRM were 34% and 20%, respectively. Similarly results were noted in other studies both in pediatric and adult patients. Locatelli and colleagues also reported a strong GVT effect in 80 patients receiving a TCRα β + /CD19+ depleted Haplo-HCT. GVHD-free, relapse-free survival (GRFS) was 71% at 5 years, comparable with HLA-matched related and unrelated donor transplants. Moreover, the low risk of GVHD without the need of long-term posttransplant immunosuppression is appealing and can help improve quality of life, especially for pediatric patients.

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