Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults
Conditions
Keywords
Individualized peptide vaccination, Immunotherapy, Tumor-specific mutations, Neoantigens
Brief summary
The aim of this clinical study is to evaluate the feasibility and safety of an individualized peptide vaccination approach in patients with acute lymphoblastic leukemia (ALL). For this purpose, tumor-specific mutations are analyzed by comparative exome sequencing of tumor and healthy reference tissue. Expression of variants is further validated by RNA sequencing. In a second step, HLA-binding (human leukocyte antigen-binding) peptides derived from mutated protein sequences are selected for vaccination. The peptides are administered as a vaccination cocktail with adjuvant GM-CSF and Imiquimod over a course of 9 months and a total of 16 vaccinations. Primary objective is the de novo induction of a specific T cell response without unacceptable toxicity and acute GvHD (graft versus host disease).
Interventions
BIOLOGICALIndividual peptide vaccination with adjuvant GM-CSF and Imiquimod
Intradermal injection of a cocktail of 3-5 individual HLA-binding peptides. Subcutaneous injection of adjuvant GM-CSF at vaccination site. Topical administration of Imiquimod at vaccination site.
Sponsors
German Cancer Research Center
Universität Tübingen
University Hospital Tuebingen
University Children's Hospital Tuebingen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric patients and young adults with ALL (T, B, pro-B, pre-B or c-ALL) ≥CR3 or with ≥1st relapse after stem cell transplantation (SCT); or patients in ≤CR2 who have received SCT without having reached a sufficient molecular remission prior to, or after SCT (defined as MRD ≥10\^-4); or patients with initially refractory disease to standard treatment who could proceed to stem cell transplantation with alternative treatment options. * Hematological remission has to be reached (\<5% blasts in bone marrow or detectable minimal residual disease (MRD) ≤5x10\^-2) after salvage chemotherapy and/or subsequent SCT.
Exclusion criteria
* Frank relapse (\>5% leukemic blasts). * Ejection fraction \<25%; Creatinine-clearance \<40ml/min; Bilirubin \>4mg/dl, Transaminases \>400 units/ml; severe infection (HIV, Hepatitis), acute GvHD III-IV or chronic GvHD. * Significant psychiatric disabilities, uncontrolled seizure disorders or severe peripheral neuropathy/ leukoencephalopathy. * Signs of autoimmune disease (i.e. idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia). * Need for immunosuppressive drugs. * No tumor material available for exome sequencing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary endpoint is success of treatment defined as a patient showing a vaccination-induced T-cell response without unacceptable toxicity and acute GvHD of Grade III or higher or extensive chronic GvHD until day 120 (after 10 vaccinations). | 120 days | Side effects wil be assessed according to NCI common toxicity criteria V4.0. GvHD will be graded according to Glucksberg criteria. A vaccine-specific response will be defined by an at least 2-fold elevated cytokine expression of CD4+ and/or CD8+ T cells over background in response to stimulation with the vaccine peptides. A vaccine-induced response will be defined by an at least 2-fold elevated response at a certain timepoint compared to pre-vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period. | 246 days | T-cell responses will be measured after completion of the study at day 246 and will be analyzed with regard to the T-cell responses at day 120. |
| To evaluate changes in minimal residual disease (MRD) during and after treatment. | 246 days | Possible reduction of MRD levels on days 36, 120 and 246 (after 7, 10 and 16 vaccinations) measured as reduction of 1 log compared to baseline yes/no. |
| To evaluate the relapse rate during and after treatment. | 246 days | Relapse rates will be assessed on days 120 and 246. |
| To evaluate the event-free survival (EFS) during and after treatment. | 246 days | EFS will be assessed on days 120 and 246. |
Countries
Germany
Outcome results
None listed