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Proteome-based Immunotherapy of Brain Metastases From Breast Cancer

Primary Purpose

Neoplasm Metastasis

Status
Unknown status
Phase
Phase 2
Locations
Russian Federation
Study Type
Interventional
Intervention
Dendritic vaccine, allogeneic hematopoietic stem cells, cytotoxic lymphocytes
Dendritic vaccine, autologous hematopoietic stem cells, cytotoxic lymphocytes
Sponsored by
NeuroVita Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neoplasm Metastasis focused on measuring Neoplasm Metastasis, Brain metastasis, Breast cancer

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Morphologically confirmed breast cancer metastases to brain (in case of relapse and impossibility of biopsy, diagnosis based on radiological and other diagnostic methods)
  • Brain metastases of breast cancer refractor to the 1-st and following conventional chemotherapies and radiotherapy, in case their removal is not possible
  • Brain metastases of breast cancer relapses after no less than one course of conventional chemotherapy and radiotherapy in case their removal is not possible.
  • Availability of HLA partially compatible related donor
  • Life expectancy of no less than 3 months
  • Absence of severe decompensated organ dysfunction
  • Informed consent of the patient
  • Informed consent of the donor

Exclusion Criteria:

  • Failure to meet one of the inclusion criteria

Sites / Locations

  • ZAO "NeuroVita Clinic of Interventional and Restorative Neurology and Therapy"

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

allogeneic stem cells

autologous stem cells

Arm Description

3 ml suspension of allogeneic hematopoietic cells in 0.9%NaCl solution is administered in L3-L4 vertebrae interspace with 16-18G needle. The preparation is administered every 2 weeks for the first 2 months (at day 1, 14, 28, 42, 56). 2 ml of individual dendritic vaccine are administered subcutaneously in 4 points (shoulders and abdomen) 3 times every 14 days from the therapy beginning (at day 14, 28 and 42). Meloxicam, 7.5mcg once a day is started from day 7 till day 42. Preparation of cytotoxic lymphocytes is administered intrathecally once in 2 weeks during the first 3 months, and then once in a month for three months.

3 ml suspension of proteome-modified autologous hematopoietic cells in 0.9%NaCl solution is administered in L3-L4 vertebrae interspace with 16-18G needle. The preparation is administered every 2 weeks for the first 2 months (at day 1, 14, 28, 42, 56). 2 ml of individual dendritic vaccine are administered subcutaneously in 4 points (shoulders and abdomen) 3 times every 14 days from the therapy beginning (at day 14, 28 and 42). Meloxicam, 7.5mcg once a day is started from day 7 till day 42. Preparation of cytotoxic lymphocytes is administered intrathecally once in 2 weeks during the first 3 months, and then once in a month for three months.

Outcomes

Primary Outcome Measures

All cause mortality

Secondary Outcome Measures

Complete disappearance of all tumor foci

Full Information

First Posted
January 30, 2013
Last Updated
October 11, 2017
Sponsor
NeuroVita Clinic
Collaborators
Blokhin's Russian Cancer Research Center, Russian Foundation of Technological Development, The Serbsky State Scientific Center for Social and Forensic Psychiatry, National Institute of Regenerative Medicine, SRC Bioclinicum
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1. Study Identification

Unique Protocol Identification Number
NCT01782274
Brief Title
Proteome-based Immunotherapy of Brain Metastases From Breast Cancer
Official Title
Proteome-based Personalized Immunotherapy of Brain Metastases From Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Unknown status
Study Start Date
December 2012 (undefined)
Primary Completion Date
December 2018 (Anticipated)
Study Completion Date
December 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NeuroVita Clinic
Collaborators
Blokhin's Russian Cancer Research Center, Russian Foundation of Technological Development, The Serbsky State Scientific Center for Social and Forensic Psychiatry, National Institute of Regenerative Medicine, SRC Bioclinicum

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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: Complete effect - full disappearance of all tumor foci Partial effect - reduction of tumor size and/or metastatic foci by no less than 50% and no signs of new neoplasms Stabilization - reduction of tumor foci size by less than 50% and no signs of new neoplasms 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"

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplasm Metastasis
Keywords
Neoplasm Metastasis, Brain metastasis, Breast cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
allogeneic stem cells
Arm Type
Experimental
Arm Description
3 ml suspension of allogeneic hematopoietic cells in 0.9%NaCl solution is administered in L3-L4 vertebrae interspace with 16-18G needle. The preparation is administered every 2 weeks for the first 2 months (at day 1, 14, 28, 42, 56). 2 ml of individual dendritic vaccine are administered subcutaneously in 4 points (shoulders and abdomen) 3 times every 14 days from the therapy beginning (at day 14, 28 and 42). Meloxicam, 7.5mcg once a day is started from day 7 till day 42. Preparation of cytotoxic lymphocytes is administered intrathecally once in 2 weeks during the first 3 months, and then once in a month for three months.
Arm Title
autologous stem cells
Arm Type
Active Comparator
Arm Description
3 ml suspension of proteome-modified autologous hematopoietic cells in 0.9%NaCl solution is administered in L3-L4 vertebrae interspace with 16-18G needle. The preparation is administered every 2 weeks for the first 2 months (at day 1, 14, 28, 42, 56). 2 ml of individual dendritic vaccine are administered subcutaneously in 4 points (shoulders and abdomen) 3 times every 14 days from the therapy beginning (at day 14, 28 and 42). Meloxicam, 7.5mcg once a day is started from day 7 till day 42. Preparation of cytotoxic lymphocytes is administered intrathecally once in 2 weeks during the first 3 months, and then once in a month for three months.
Intervention Type
Biological
Intervention Name(s)
Dendritic vaccine, allogeneic hematopoietic stem cells, cytotoxic lymphocytes
Intervention Type
Biological
Intervention Name(s)
Dendritic vaccine, autologous hematopoietic stem cells, cytotoxic lymphocytes
Primary Outcome Measure Information:
Title
All cause mortality
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Complete disappearance of all tumor foci
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
reduction of tumor size by no less than 50% and absence of new foci
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Morphologically confirmed breast cancer metastases to brain (in case of relapse and impossibility of biopsy, diagnosis based on radiological and other diagnostic methods) Brain metastases of breast cancer refractor to the 1-st and following conventional chemotherapies and radiotherapy, in case their removal is not possible Brain metastases of breast cancer relapses after no less than one course of conventional chemotherapy and radiotherapy in case their removal is not possible. Availability of HLA partially compatible related donor Life expectancy of no less than 3 months Absence of severe decompensated organ dysfunction Informed consent of the patient Informed consent of the donor Exclusion Criteria: Failure to meet one of the inclusion criteria
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrey S. Bryukhovetskiy, MD
Organizational Affiliation
ZAO "NeuroVita Clinic of Interventional and Restorative Neurology and Therapy"
Official's Role
Principal Investigator
Facility Information:
Facility Name
ZAO "NeuroVita Clinic of Interventional and Restorative Neurology and Therapy"
City
Moscow
ZIP/Postal Code
115478
Country
Russian Federation

12. IPD Sharing Statement

Citations:
PubMed Identifier
25789053
Citation
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 Reference
result
PubMed Identifier
25303679
Citation
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.
Results Reference
result

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Proteome-based Immunotherapy of Brain Metastases From Breast Cancer

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