Patient-individualized Peptide Vaccination Based on Tumor-specific Mutations in Children and Young Adults With Primary/Relapsed ALL

Study Overview
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Brief Summary
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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).

Official Title
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Prospective Phase I/II Study: Patient-individualized Peptide Vaccination Based on Whole Exome Sequencing With Adjuvant GM-CSF (Granulocyte Macrophage Colony-stimulating Factor) in Children and Young Adults With Primary/Relapsed Acute Lymphoblastic Leukemia

Conditions
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Primary/Relapsed Acute Lymphoblastic Leukemia (ALL) of Childhood, Adolescents and Young Adults

Intervention / Treatment
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* Biological: Individual peptide vaccination with adjuvant GM-CSF and Imiquimod


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br> | Biological: Individual peptide vaccination with adjuvant GM-CSF and Imiquimod<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 120 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate CD4+ and/or CD8+ T-cell responses over the vaccination period. | 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. | 246 days | 
| To evaluate changes in minimal residual disease (MRD) during and after treatment. | 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. | 246 days | 
| To evaluate the relapse rate during and after treatment. | Relapse rates will be assessed on days 120 and 246. | 246 days | 
| To evaluate the event-free survival (EFS) during and after treatment. | EFS will be assessed on days 120 and 246. | 246 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Individualized peptide vaccination, Immunotherapy, Tumor-specific mutations, Neoantigens