Proteome-based Personalized Immunotherapy of Glioblastoma

Summary

Trial Hypothesis: Acute, progressing lethal neurooncological process can be transferred into chronic and non-lethal, the survival rates and life quality can be improved by of control of tumor cells (TCs) quantity and targeted regulation of effector functions of tumor stem cells (TSCs). Brief Description: The first line therapy of glioblastoma multiforme (GBM) involves allogeneic haploidentical hematopoietic stem cells (HSCs), dendritic vaccine (DV) and cytotoxic lymphocytes (CTLs). TCs and TSCs are isolated from GBM sample. Dendritic cells are isolated from peripheral blood mononuclear cells and cultured. Tumor sample provides tumor specific antigens to prepare DV. CTLs are obtained from peripheral blood after DV administrations. HSCs are harvested from closely related donor after granulocyte-colony-stimulating factor (G-CSF) administration. Allogeneic HSCs are administered intrathecally 5 times every 2 weeks, at day 1, 14, 28, 42, 56. DV is given 3 times every 2 weeks (day 14, 28, 42) subcutaneously in four points. CTLs are administered every 2 weeks for 3 months, then 3 times every 1 month intrathecally. Six months after the therapy completion, the efficiency is evaluated and the cohort demonstrating efficiency continues the therapy, while cohort demonstrating no efficiency is transferred to active comparator arm. Second line therapy involves DV with recombinant proteins, CTLs and autologous HSC with modified proteome. Autologous HSCs are mobilized by G-CSF. Carcinogenesis-free intracellular pathways of signal transduction able to respond to targeted regulation of therapeutic cell systems with specific properties, are detected in TSCs using complete transcriptome profiling of gene expression, proteome mapping and profiling of proteins, bioinformation and mathematical analysis and mathematical modeling of protein profiles. To find key oncospecific proteins in TSCs and TCs, the targets for TSCs regulation are detected, as well as protein ligands able to regulate reproductive and proliferative properties of TSCs. Using these data of TCs and TSCs proteins, the cell preparations to initiate adoptive immune response are prepared: DV loaded with recombinant proteins analogous to key tumor antigens, CTLs and autologous proteome-modified HSCs. Autologous proteome-modified HSCs, DV and CTLs are administered as in the first line therapy.

Timeline

Start

2012-12

Primary completion

2018-12

Completion

2020-12

Publications

• Results Bryukhovetskiy IS, Mischenko PV, Tolok EV, Zaitcev SV, Khotimchenko YS, Bryukhovetskiy AS. Directional migration of adult hematopoeitic progenitors to C6 glioma in vitro. Oncol Lett. 2015 Apr;9(4):1839-1844. doi: 10.3892/ol.2015.2952. Epub 2015 Feb 10.
• Results Bryukhovetskiy A, Shevchenko V, Kovalev S, Chekhonin V, Baklaushev V, Bryukhovetskiy I, Zhukova M. To the novel paradigm of proteome-based cell therapy of tumors: through comparative proteome mapping of tumor stem cells and tissue-specific stem cells of humans. Cell Transplant. 2014;23 Suppl 1:S151-70. doi: 10.3727/096368914X684907. Epub 2014 Oct 9.

Drugs

Indications