Cancer Immune Therapy for the Treatment of Refractory Solid Tumours of Childhood

Monocyte-derived Dendritic Cells Loaded With Tumour Cell Lysates for the Treatment of Refractory Solid Tumours of Childhood

This is an un-blinded Phase 1 study in which 21 patients suffering from solid advanced paediatric malignancies (14 sarcoma and 7 non-sarcoma patients) are treated with AV0113, an anti-tumour immune therapy with autologous Dendritic Cells (DCs) loaded with tumour cell lysates, in order to investigate its safety and feasibility.

For obtaining a clearer picture of AV0113's utility in the treatment of bone and soft tissue sarcoma, a long-term (LT) follow-up investigation of the 14 sarcoma patients, which will be treated using the AV0113 Dendritic Cell Cancer Immune Therapy (DC-CIT) technology is planned, in order to gather first evidence for a potential LT effect of DC-CIT with AV0113.

Furthermore, a comparison of the 14 sarcoma patients treated with AV0113 DC-CIT with a cohort of matched historic control patients that were treated using standard of care will be conducted. It is planned to analyse 42 historic control sarcoma patients that will be matched for disease, recurrences, relapses etc.

In this phase I trial 21 paediatric patients with solid tumours of childhood (14 sarcoma and 7 non-sarcoma patients) that have exhausted all conventional treatment options are recruited for the treatment with AV0113.

Peripheral blood mononuclear cells (MNCs) will be obtained from patients by leukocyte apheresis. Monocytes enriched by density gradient centrifugation from MNCs will be used to generate immature DCs by cultivation in recombinant human interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating-factor (GM-CSF). These immature DCs will be loaded with autologous tumour cell lysates obtained by needle biopsy or surgery prior to tumour vaccination.The antigen loaded immature DCs will then receive a final maturation stimulus transmitted by exposure to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Maturation enables DCs to present antigen with high efficiency to T-lymphocytes. Subsequently, mature loaded DCs will be injected subcutaneously close to tumour free lymph nodes or intra-nodally into tumour free lymph nodes at weekly intervals for at least 6 weeks.

It is anticipated to establish the feasibility and safety of tumour vaccination in the described clinical setting and to find some clinical and/or experimental evidence for the induction of an anti-tumour immune response.

For obtaining a clearer picture of AV0113's utility in the treatment of bone and soft tissue sarcoma, a long-term (LT) follow-up investigation of the 14 Sarcoma patients, which will be treated using the AV0113 DC-CIT technology is planned, in order to gather first evidence for a potential LT effect of DC-CIT with AV0113.

Furthermore, a comparison of the 14 sarcoma patients treated with AV0113 DC-CIT with a cohort of matched historic control patients that were treated using standard of care will be conducted. It is planned to analyse 42 historic control sarcoma patients that will be matched for disease, recurrences, relapses etc.

Inclusion Criteria:

Inclusion criteria for the safety and feasibility testing of AV0113

• Male and female patients with a malignant neoplasia shall be eligible for this protocol provided they have no more "conventional" treatment options and have measurable disease. There is no age limit for participation in this study provided that the tumour is typical for the group of refractory solid neoplasias of childhood.
• Patients must not be HIV-positive.
• Patients must have primary tumour tissue or cells available at sufficient number to allow treatment according to the protocol.
• Patients or legal guardians must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects. Patients or their guardians will be given a copy of the consent form.

Inclusion criteria for patients included in the long-term follow up and comparison with historic controls

• Patients suffering from bone or soft tissue sarcoma that received treatment with AV0113 or are documented in the database of the Medical University Vienna's Department of Orthopaedics.
• At least one disease recurrence after first CR or worse disease condition (e.g.: never reached CR).
• Diagnosis between 1992-2003 and/or "inclusion time point" during the years 2000-2004.
• Availability of date of death or of confirmation that patient is still alive (for the currentness of confirmation that patients are still alive only the time span from 1 April 2014 to 1 April 2015 is accepted).
• Patients not older than 27 years at their ITP.

Exclusion Criteria:

Exclusion criteria for the safety and feasibility testing of AV0113

• Any of the inclusion criteria not met.
• Any condition which, in the investigator's opinion, may pose a risk to the patient or will interfere with the study objectives.

Exclusion criteria for patients included in the long-term follow up and comparison with historic controls

• Date of "inclusion time point" and death or confirmation that patient is still alive at time of evaluation not available.