T and NK cell mediated immunotherapy in osteosarcoma; a preclinical feasibility study

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood
and adolescence. In the last decades, the introduction of (neo-)adjuvant
chemotherapy combined with radical resection of the tumor has resulted in an
improved overall survival from less than 20% to 60-70%. However, further
intensification of chemotherapeutic interventions has not resulted in an
additional improvement in survival, indicating that a significant subgroup of
OS patients is resistant to currently used cytostatic agents. Therefore, novel
therapeutic modalities are required to improve outcome in high risk and
relapsed patients. The therapeutic potential of T and/or NK cell-mediated
immunotherapy in the treatment of various types of malignancies has been
demonstrated in preclinical and clinical studies. However, at present
experimental evidence on the susceptibility of OS to autologous and/or
allogeneic T/NK cell-mediated effector mechanisms is limited. In addition, the
occurrence and functional relevance of immune evasion mechanisms in the various
clinical stages of OS is undefined.

We hypothesize that NK and/or T cell-mediated immunotherapy may represent a
novel therapeutic option for patients with refractory and/or metastatic OS.
Therefore, we will study molecular mechanisms that determine the susceptibility
of osteosarcomas to T and NK cell mediated immunotherapy in both an autologous
and allogeneic setting. The final aim is to provide evidence for the
implementation of NK and/or T cell-mediated immunotherapy strategies in future
clinical studies.

On a large cohort of both historical and prospectively obtained primary OS and
OS cell lines representing various stages of disease the following studies will
be performed we will:
1. Characterize in primary OS and OS cell lines the expression of gene
products/proteins that are known to be involved in T/NK cell-mediated
recognition, directional migration and immune-mediated cytolysis, study the
expression of candidate T cell target antigens, and identify potential immune
evasion strategies in OS.
2. Evaluate the correlation between immunological phenotype and clinical
behavior/outcome.
3. Characterize the NK and T cell effector potential towards OS cell lines and
the correlation with (immunological) phenotype, and provide evidence whether
allogeneic effector cells act favorably in comparison with autologous
effectors.

The burden for the participants is very limited. The extra tumor biopsy is
performed during the regular session The marrow aspirate is performed under
routine anesthesia when the central venous access is being implanted. The extra
blood samples will be obtained via the central venous access together with a
routine blood examination. Based on our experience with these procedures, the
additional risk associated with participation in this study is negligible.