MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT (PSCT19)

Radboud University Medical Center

Status and phase

Completed

Phase 2

Phase 1

Conditions

Hematological Malignancies

Treatments

Biological: MiHA-loaded PD-L-silenced DC Vaccination

Study type

Interventional

Funder types

Other

Identifiers

NCT02528682

PSCT19

Details and patient eligibility

About

Allogeneic stem cell transplantation (allo-SCT) is a potent treatment, and sometimes the only curative treatment for aggressive hematological malignancies. The therapeutic efficacy is attributed to the graft-versus-tumor (GVT) response, during which donor-derived CD8+ T cells become activated by recipient minor histocompatibility antigens (MiHA) presented on dendritic cells (DC). Consequently, these alloreactive donor T cells clonally expand, acquire effector functions and kill MiHA-positive malignant cells. However, in a substantial number of patients persistence and recurrence of malignant disease is observed, indicating that insufficient GVT immunity is induced. This is reflected by our observation that not all patients develop a productive CD8+ T cell response towards MiHA mismatched between the recipient and donor. We found that the PD-1/PD-L1 co-inhibitory pathway is involved in dampening MiHA-specific CD8+ T cell expansion and function post-transplantation. Therefore, a promising strategy to induce or boost GVT immune responses is pre-emptive or therapeutic vaccination with ex vivo-generated donor DCs loaded with MiHA that are exclusively expressed by recipient hematopoietic cells and their malignant counterparts. In contrast to pre-emptive donor lymphocyte infusion (DLI) with polyclonal donor T cells, this MiHA-DC vaccination approach has less risk of inducing graft-versus-host disease (GVHD) and the potency to induce more efficient GVT-associated T cell immunity. In addition, the potency of this DC vaccine will be further enhanced by interference with the PD-1/PD-L1 co-inhibitory pathway, using siRNA mediated PD-L1/PD-L2 silencing.

Enrollment

10 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients with AML, myelodysplasia (MDS), ALL, CML (accelerated or blast phase), CLL, MM, malignant NHL or HL, who underwent HLA-matched allo-SCT
Patients positive for HLA-A2 and/or HLA-B7
Patients positive for HA-1, LRH-1 and/or ARHGDIB transplanted with corresponding MiHA-negative donor
Patients ≥18 years of age
WHO performance 0-2
Witnessed written informed consent

Exclusion criteria

Life expectancy < 3 months
Severe neurological or psychiatric disease
Progressive disease needing cytoreductive therapy
HIV positivity
Patients with acute GVHD grade 3 or 4
Patients with severe chronic GVHD
Patients with active infections (viral, bacterial or fungal) that require specific therapy. Acute anti-infectious therapy must have been completed within 14 days prior to study treatment
Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease)
Severe pulmonary dysfunction
Severe renal dysfunction (serum creatinine > 3 times normal level)
Severe hepatic dysfunction (serum bilirubin or transaminases > 3 times normal level)
Patients with known allergy to shell fish