Clinical Trials Logo

Clinical Trial 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 brain metastases of breast cancer (BMBC) involves allogeneic haploidentical hematopoietic stem cells (HSCs), dendritic vaccine (DV) and cytotoxic lymphocytes (CTLs).

TCs and TSCs are isolated from BMBC 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-based HSCs.

Autologous HSCs, DV and CTLs are administered as in the first line therapy.


Clinical Trial Description

The trial will include 60 cases of refractor brain metastases from breast cancer (BMBC) of different malignancy after no less than one line of standard chemotherapy and complete course of radiotherapy.

The first line therapy of BMBC involves allogeneic hematopoietic stem cells (HSCs), dendritic vaccine (DV) and cytotoxic lymphocytes (CTLs).

HSCs are used to stimulate individualized adoptive immune response, to affect tumor cells toxically and to regulate tumor stem cells (TSCs) targetedly in order to suppress their reproductive and proliferative potential. To obtain HSC the donor receives 8 subcutaneous administrations of granulocyte colony-stimulating factor (G-CSF) with 8-10 hours interval for 4 days. The first three days a single dose is 2.5 mcg per 1 kg weight, the last day the dose is doubled. The stem cells are harvested at day 5. Red blood cells are withdrawn by centrifuging. The content of cell markers is evaluated by flow cytometry. The result is assessed after cytoconcentrate enrichment and removal of mature cells and plasma from it. The preparation is stored in tubes per 4 ml with cryoprotector and 10% polyglucin solution. Stem cell proportion is no less than 0.5x106 CD34+, and lymphocytes proportion is no less than 0.5x109 per one administration.

The sample of brain tumor is obtained through stereotaxic/endoscopic/open biopsy from all patients included into the trial. The tumor cells (TCs) and TSCs are immunochemically isolated from BMBC biopsy sample. One part of tumor sample is used for standard histological, cytological and immunochemical testing, while tumor cells (TCs) and tumor stem cells (TSCs) (CD44+, CD24-/LowLin-) are isolated from the other part.

Dendritic cells are isolated from peripheral blood mononuclear cells and cultured. Tumor sample provides tumor specific antigens to prepare the dendritic vaccine (DV).

Preparation of CTLs aims to enhance cytotoxic effect on tumor due to great number of circulating CTLs. Cytotoxic lymphocytes (CTLs) are isolated from about 100 ml of peripheral blood after 3 DV administrations, and of them dendritic cells (DCs) are grown. Then, peripheral blood is repeatedly taken, and lymphocytes are isolated. The CTLs are co-cultured with DCs loaded with tumor antigens (first line therapy) or recombinant proteins analogous to key oncospecific proteins (second line therapy) for several times to expand their number (108-109). Their immunophenotype is detected and CTLs are cryopreserved. The first stimulation of CTLs with DCs lasts 6-8 days, the second lasts 2-4 days, next 2 days the lymphocytes are stimulated for the third and fourth time. And then the received lymphocytes are stimulated by IL-2 for 2 days.

Six months after the first line therapy completion the efficiency is evaluated and the cohort demonstrating efficiency continues the therapy, while cohort demonstrating no efficiency will continue the trial with the second line therapy.

The second line therapy arm uses DV with recombinant proteins analogous to key oncospecific proteins, autologous CTLs and autologous HSCs with modified proteome.

Autologous HSCs are received from the trial participant as described previously. Cell preparation of HSC for active comparator arm is obtained of the cytoconcentrate of autologous mononuclear cells of peripheral blood after mobilization as specified for experimental arm. Tumor specific antigens for active comparator group are provided by tumor tissue of the patient.

TCs and TSCs as well as HSCs of the patient undergo complete transcriptome mapping and gene expression profiling (CTMGEP) and proteome mapping and protein profiling (PMPP). Key (3 or 4 proteins with maximal normalized intensity) oncospecific proteins (OSP) are determined according to proteome testing of TCs, while proteome profiling of TSCs and use of databases of protein-protein relations permit detection of intracellular signal transduction pathways (ISTP) unaffected by carcinogenesis and capable of regulation. Also, receptor membrane targets to affect these signal pathways (acceptor membrane proteins) are detected, as well as proteins that are able to activate them (protein ligands). CTMGEP of TSCs confirms diagnosed functional ISTP. Mathematical modeling of CTMGEP and comparison with Affymetrix GeneChip Human genome U133A Array data reveals perturbagens able to chemically induce HSCs and to modify their proteome profile in order to provide secretion of requisite protein ligands. The database analysis permits understanding of how changes in gene expression induced by a low-molecular agent or micro RNA corresponds with the changes observed in the examined profile. If correspondence is significant, it is supposed, that the agent or similar agents can initiate the effect. If anticorrelation is significant, the agent is supposed to initiate an opposite effect in gene expression modification. The transcriptome of HSCs is modified by co-culturing mononuclear cells with perturbagens. Their biological efficiency is evaluated in vitro in Homunculus bioreactor. Then preparation is stored as described previously.

Individual DV is prepared from the leukoconcentrate of peripheral blood of the patient. The lymphocytes are isolated, cultured with G-CSF and interleukin-2, conditioned by tumor-specific antigens, TNF-α and PGE2 for 48 hours and loaded with recombinant proteins identical to key tumor-specific antigens detected at proteomic testing of TCs. Basic mechanism of individual DV immune effect is elaboration of tumor toxic lymphocytes by the organism of the patient.

CTLs are obtained as described previously. The intervention is described in the appropriate section.

Toxicity will be evaluated according to CTC-NCI criteria. Efficiency is assessed according to the following criteria:

1. Complete effect - full disappearance of all tumor foci

2. Partial effect - reduction of tumor size and/or metastatic foci by no less than 50% and no signs of new neoplasms

3. Stabilization - reduction of tumor foci size by less than 50% and no signs of new neoplasms

4. Progress - growth of tumor foci during the therapy. In case of mosaic effect, when part of foci progresses and part is stable or reducing, the therapy is continued but the cases are analyzed outside the context "Response to the therapy" ;


Study Design


Related Conditions & MeSH terms


NCT number NCT01782274
Study type Interventional
Source NeuroVita Clinic
Contact
Status Enrolling by invitation
Phase Phase 2/Phase 3
Start date December 2012
Completion date December 2020

See also
  Status Clinical Trial Phase
Withdrawn NCT06057636 - Hypnosis for Pain in Black Women With Advanced Breast Cancer: A Feasibility Study N/A
Terminated NCT03166631 - A Trial to Find the Safe Dose for BI 891065 Alone and in Combination With BI 754091 in Patients With Incurable Tumours or Tumours That Have Spread Phase 1
Terminated NCT01441115 - ECI301 and Radiation for Advanced or Metastatic Cancer Phase 1
Active, not recruiting NCT03775980 - CIRSE Emprint Microwave Ablation Registry
Completed NCT01114958 - Pilot Study of Intra-Arterial Cisplatin With IV Thiosulfate in Patients With Lung Cancer or Lung Metastases Phase 1
Terminated NCT03986593 - Cryoablation of Bone Metastases From Endocrine Tumors N/A
Active, not recruiting NCT04458259 - Study of PF-07265807 in Participants With Metastatic Solid Tumors. Phase 1
Completed NCT01218542 - Whole Brain Radiation Therapy With Boost to Metastatic Tumor Volume Using RapidArc N/A
Not yet recruiting NCT03175146 - A Study to See Whether Stereotactic Body RadioTherapy (SBRT) Can Shrink Tumours Within the Liver Safely N/A
Active, not recruiting NCT02395224 - A Longitudinal Study of Colorectal Cancer Patients With Metastatic Disease in Middle-Norway
Completed NCT02374411 - Knowledge, Attitudes, and Practice of Surgeons Toward Nutrition Support in HIPEC Patients N/A
Recruiting NCT01960829 - Everolimus in Selected Patients With Metastatic Melanoma: Efficacy and Safety Study Phase 2
Completed NCT01933789 - Improving Communication About Serious Illness N/A
Terminated NCT01846429 - Oral Bicarbonate as Adjuvant for Pain Reduction in Patients With Tumor Related Pain Phase 1
Recruiting NCT01564810 - Cetuximab in Combination With Chemotherapy for the Treatment of Metastatic Colorectal Cancer Phase 4
Completed NCT00375245 - Rapamycin With Grapefruit Juice for Advanced Malignancies Phase 1
Completed NCT00207116 - An Exploratory Pharmacogenomic Study of Monotherapy Erbitux in Subjects With Metastatic Non Small Cell Lung Carcinoma Phase 1
Completed NCT00232726 - Clinical Study of Previously Untreated Patients With Malignant Melanoma Phase 2
Completed NCT00207103 - MAD in Cancer Patients: Safety of BMS-582664 in Patients With Advanced or Metastatic Solid Tumors Phase 1
Completed NCT00172003 - Effect of Zoledronic Acid in Patients With Renal Cell Cancer and Bone Metastasis Phase 4