With significant improvements in NRM, disease relapse remains the major cause of death in patients undergoing haploSCT. Several approaches are under investigation at our institution to prevent and treat disease relapse posttransplant (Table 15-2).
Table 15-2Posttransplant Cellular Therapies Aimed at Decreasing Disease Relapse in HaploSCT ||Download (.pdf) Table 15-2 Posttransplant Cellular Therapies Aimed at Decreasing Disease Relapse in HaploSCT
|Approach ||Rationale ||Pitfalls |
|Unmodified donor lymphocyte infusion (DLI) || || |
Limited experience in haploSCT
Potential for GVHD precipitation
Not targeted to specific antigen(s)
|Engineered donor lymphocytes with a safety suicide switch || || |
|Gamma-delta DLI || || |
|T cells with chimeric antigen receptors (CAR-T) || || |
|Infusion of ex vivo expanded NK cells || || |
Unmodified Donor Lymphocyte Infusion
The readily available haploidentical donors can be sources of posttransplant donor lymphocyte infusion (DLI) administered to prevent or treat early relapse. There is a theoretical higher risk of inducing severe aGVHD with haploidentical DLI; however, the incidence of GVHD was not higher than in matched transplants, possibly due to the tolerizing effect of HDPTCy (30). Among 40 patients with hematological malignancies relapsed after a haploSCT who received unmodified haploidentical DLI (1 × 106/kg CD3+ T cells), aGVHD was noted in 25% (grades III-IV aGVHD in 15%). A third of patients achieved a complete response with a median duration of response of 12 months. Most patients received cytoreductive therapy prior to the DLI infusion. Thus, cellular therapy with haploidentical DLI can be effective posttransplant, and future approaches should improve the safety and efficacy of DLI.
Modified Donor Lymphocyte Infusion Using T Cells With a Safety Switch (Suicide Gene)
One approach to control aGVHD post-DLI would be to insert a suicide gene in the haploidentical donor T cells. If significant aGVHD occurs, a “safety off switch” can “turn off” these T cells and avoid excessive aGVHD. This approach has so far been investigated to boost posttransplant immune recovery after T-cell-depleted haploidentical grafts. Ciceri et al infused DLI engineered T cells to express herpes simplex virus–thymidine kinase suicide gene (can be triggered by ganciclovir to induce apoptosis) (31). The aim was to boost posttransplant immune reconstitution by adding back T cells after a complete or partial T-cell-depleted haploSCT. Grades 1 to 4 aGVHD developed in 20% of patients and was successfully terminated by inducing the suicide gene with ganciclovir. However, ganciclovir may not be the ideal drug in this setting given that it is commonly used posttransplantation to control cytomegalovirus reactivation. Another approach is to use DLI engineered to express an inducible caspase-9 transgene (32). This gene can be induced by a synthetic dimerizing drug, leading to rapid cell death. In a preliminary experience in ten patients, aGVHD developed in five patients and was rapidly reversed with the use of the dimerizing drug.
Chimeric Antigen Receptor T Cells
While the DLI offers nonspecific antitumor activity, the effect is nontargeted. A potential game changer has been the introduction of T cells engineered to express a chimeric receptor, with an extracellular domain that can recognize a specific antigen and an intracellular domain that can activate the cytotoxic T cell. This approach has demonstrated significant activity in tumors expressing CD19, such as acute lymphoblastic leukemia (ALL) or B-cell lymphomas. Maude et al used autologous chimeric antigen receptor (CAR) T cells against CD19 (CTL019) in 30 patients with relapsed-refractory ALL, and complete remission occurred in 90% of patients. They demonstrated that CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who responded (33). We are exploring the use of CAR T cells early after haploidentical transplantation to prevent disease relapse, part of a multiarm clinical trial (34). Our center is the only center so far using CAR T cells after haploidentical transplantation. Four patients (three with ALL and one with diffuse large B-cell lymphoma) received CAR T cells generated using the Sleeping Beauty system. The lymphoma patient achieved remission for the first time after transplant and infusion of CAR T cells. Three of these four patients remained in remission at last follow-up. These results are promising and showed that allogeneic CAR T-cell therapy can be safely given without significant GVHD.
Natural Killer Cells and Killer Immunoglobulin-Like Receptor Mismatch
Natural killer (NK) cells are part of the innate immune system and normally are involved in identifying and killing tumor cells or virally infected cells. The NK cells recognize and target “foreign” cells that lack one or more HLA class I alleles specific to the inhibitory receptors (killer immunoglobulin-like receptors, KIRs) (35). The NK cells do not contribute to GVHD as they target hematopoietic cells sparing other body organs, making them ideal in the transplant setting. This was first observed in the T-cell-depleted setting, where patients with a KIR “mismatch” had a lower incidence of relapse (36). There is great interest in this field to identify haploSCT donors with a KIR mismatch to possibly maximize the graft-versus-tumor effects. Several studies suggested a lower risk of relapse with donors who possess specific activating KIR genes, such as KIR2DS1, KIR2DS2, or the KIR “B” haplotype (37,38,39). We are exploring infusion of ex vivo expanded NK cells using the mb-IL21 method developed at MDACC in haploidentical transplants (protocol 2012-0708) to prevent disease relapse posttransplant in patients with myeloid malignancies (40).