MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT

NCT02528682 | Completed Phase 1

• 1 other identifier: PSCT19
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hematological Malignancies

Keywords

dendritic cells; PD-L1/L2 silencing; vaccination; stem cell transplantation; minor histocompatibility antigens

Outcome Measures

Primary Outcomes (3)

• Evaluation of toxicity

  Toxicity will be measured using the NCI CTCAE criteria (http://ctep.cancer.gov/reporting/ctc.html). Possible toxicities include constitutional symptoms such as fever, chills, myalgias, malaise and allergic reactions.

  From day 0 until day 84

• Development of GVHD

  DC vaccination may result in GVHD, which will be scored and treated if indicated according to standard guidelines.

  From day 0 until day 84

• The generation and magnitude of an immunological response

  When after DC vaccination \>1.0% of all CD8+ lymphocytes at any time point are specific CD8+ T cells to the used MiHA vaccine target, a complete response will be considered to be present. When the percentage is between 0.02% and 1%, but has been doubled during two weeks, a partial immune response will be considered to be present.

  From day 0 until day 84

Secondary Outcomes (2)

• Changes in chimerism

  day 0, day 14, day 28, day 64, day 84

• Disappearance of residual disease

  day 0, day 14, day 28, day 64, day 84

Study Arms (1)

Single arm

EXPERIMENTAL

MiHA-loaded PD-L-silenced DC Vaccination

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

Interventions

MiHA-loaded PD-L-silenced DC Vaccination BIOLOGICAL

Eligible patients will receive one cycle of donor DC vaccination consisting of maximal 3 immunizations, given at 2 week intervals. PD-L1/L2-silenced, MiHA mRNA-electroporated donor DC will be infused intravenously (2.5x105/kg body weight).

Single arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Dutch Cancer Society: collaborator

Study Sites (1)

Trialoffice Haematology-Oncology

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

MeSH Terms

Conditions

Hematologic Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Nicolaas Schaap, MD/PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2015
• First Posted: August 19, 2015
• Study Start: January 1, 2016
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: April 1, 2021

Record last verified: 2021-01

Locations

NL (1)