The objective of the study is to improve the T cell killing by treating the patient with in the laboratory cultured professional antigen presenting cells (DCs) which are loaded with specific antigens that are only present on blood and cancer cells…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints are the evaluation of safety and efficacy, the occurance of
GvHD and the induction of a positive response to the combined DLI and DC
treatment
Secondary outcome
The immune effects of the combined modality including the induction of specific
mHag responses
Background summary
For many patients with a hematological malignancy donor stem cell
transplantation is the only chance on a cure. The therapeutic effect of this
therapy is due to so called killer cells (T lymphocytes) present in the donor
transplant. These cells may recognize the cancer cells based on the presence of
specific structures on the membrane (minor histocompatibility antigens: mHags)
en subsequently kill them. Donor T cells (DLI) are frequently infused in
patients that have not responded optimal to the donor stem cell transplant.
However this procedure may be complicated with severe and sometimes fatal
complications :Graft versus Host Disease. This is caused by the attack of the T
cells on normal organs of the patient. Additionally in many patients the
anti-tumor effect of the killer cells is too weak due to the lack of so called
antigen presenting cells (Dendritic cells: DC). These DCs must stimulate the T
cells and activate them against the cancer cells. It is likely that the
therapeutic effect of the infusion of donor T cells (DLI) is improved by
co-infusion of donor DC*s that are loaded with suitable hematopoietic
restricted mHags
Study objective
The objective of the study is to improve the T cell killing by treating the
patient with in the laboratory cultured professional antigen presenting cells
(DCs) which are loaded with specific antigens that are only present on blood
and cancer cells of the patient (hematopoietic restricted) and absent on the
healthy organ cells of the patient.
Study design
This is a phase I/II study with the primary goal to evaluate the safety and
efficacy of a combined DLI and DC vaccination for relapsed or residual disease
after donor stem cell transplantation and a previous DLI. Study endpoints are
grade 4 CTC toxicity, late onset acute GvHD grade 3 and 4 en for efficacy
response criteria related to the different hematological malignancies
Intervention
Suitable patients will be treated with a combined infusion of donor DC*s and
DLI which are loaded with relevant mHags. Patients with minimal 1 relevant
mismatch in the Graft versus Tumor direction are eligible (HA-1, HA-2, ACC1,
ACC2, PANE1, LRH-1, CD19L, UTA2-1 or HB-1). The infusion of the DC*s will be
repeated twice. Patients will be monitored for side effects, anti-tumor
response , immune effcts and the development of specific anti-mHag responses.
Positive outcome of the study may implicate that Donor DC vaccination will
become standard for patients with relapsed and residual disease after donor
stem cell transplant with the aim to improve the cure rate.
Study burden and risks
Burden associated with participation: The usual procedure for patients not
responding to a first DLI is a second DLI containing a higher T cell dose.
Patients included in the vaccination trial will receive the same T cell dose
combined with the DC vaccination. For both categories of patients routine
investigations at the out patient clinic weekly or two weekly are performed to
monitor the general physical status status and tumor load of the patients. This
may include bone marrow investigations, immune phenotyping and cytogenetics and
imaging techniques like CT scans, MRI and/or PET scans.
Extra study procedures include: DC vaccinations 3 times repeated with an
interval of 2 weeks. Blood sampling for evaluation of the immune effects: 40
ml of blood will be obtained at week -2 and at weeks 0, 1, 2, 4 , 6, 10, 14 and
20 after the first vaccination and DTH skin tests at 2 weeks after the third DC
vaccination
Risks associated with the investigational product. Potential risk is the
induction of GvHD. To minimize this side effect we will infuse the same T cell
dose as given with the first DLI and maintain an interval of at least 10 weeks
between the first and second DLI. In addition to avoid overlapping toxicities
we will keep an interval of 4 weeks between recruiting in the first 3 patients
and starting the DLI + vaccination. This will allow interrupting the
vaccination scheme in the following patients in case unacceptable toxicity is
observed in the preceding patient.
In a previous phase I/II trial of DLI combined with unloaded host DC*s no
toxicity (GvHD) was recorded. (manuscript submitted). As in the current trial
we will use only haematopoietic restricted mHags we expect but cannot exclude
excessive toxicity. For this reason toxicity is one of the major endpoints of
the study.
Benefit: A second dose escalated DLI is the standard next treatment step for
patients not responding to a first DLI. This procedure is associated with a
substantial risk of severe sometimes fatal GvHD. If proven feasible and
effective, (sustained) complete remissions may be achieved in patients with an
otherwise fatal outcome of their disease.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
1.Patient with a measurable persistent disease after preceding DLI given for persistent or relapsed malignancy after allo-SCT. Reinduction chemotherapy in case of rapidly progressive disease (e.g. in AML) is allowed.
2. Recipient and donor with at least one relevant mismatch in mHags HA-1, HA-2, ACC1, ACC2, PANE1, LRH-1, CD19L or HB-1 in the Graft versus Tumor (GvT) direction (recipient mHag positive, donor mHag negative).
3. Recipient and donor positive for the relevant HLA, presenting the mismatched mHag(s).
4. Expression of the mismatched mHag in the lineage from which the malignancy has arisen.
5. Age 18-70 years
6. Absence of acute GvHD > grade 1 or extensive chronic GvHD
7. No prior or concomitant treatment for 8 weeks with immunosuppressive drugs such as prednisone, cyclosporine A and MMF.
8. WHO performance 0-2 (see appendix 1)
9. Absence of severe cardiac hepatic, renal, or metabolic disease
10. Written informed consent
Exclusion criteria
1. WHO performance 3-4
2. Presence of severe cardiac hepatic, renal, metabolic disease
3. Rapidly progressive disease, despite reinduction therapy
4. Life expectancy < 3 months
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 12402 NTR |
| EudraCT | EUCTR2012-002435-28-NL |
| CCMO | NL39604.000.12 |