Oncology and Neurooncology
Proteome-based personalized anti-cancer cell therapy
Our team initiated a long-term research to study the use of the stem cells (SCs) in neurooncology and to develop the proteome-based personalized anti-cancer cell product (PBPACP) and the cell systems with specified properties for the complex therapy of glial tumors of the brain and brain metastases of breast and lung cancer.
We have studied the cellular and molecular mechanisms of migration, homing, cell adhesion and pathotropism of adult SCs to the cancer cells (CCs) in vitro and in vivo for seven years. We performed the comparative proteomic mapping of the proteins and whole transcriptome profiling of the gene expression of neural SCs (CD34+) and cancer SCs (CD133+) that have been isolated from the glial tumors of the human brain (U87 and U251 lines of glioblastoma multiforme) and of the rodent brain (C6 line of rat glioma). The obtained data have been bioinformatically processed and the results mathematically modeled.
We demonstrated the global structural proteomic and transcriptomic differences of adult SCs, established fundamental scientific evidence that permitted development of the novel platform of the individually tailored regulatory effect on the reproductive and proliferative functions of cancer SCs achieved with specified secretomes of autologous hematopoietic SCs with modified profile of gene expression.
- We demonstrated that the SCs always arrive to the tumor in the brain, find the cancer cells and cancer SCs, adhere to them and perform weak regulatory influence through to the by-stander effect.
- Low effectiveness of the anti-cancer regulatory and controlling influence of SCs on cancer cells and cancer SCs is conditioned by the systemic mechanisms of speciation in the carcinogenesis that can be overcome by the specific modification of the effector properties of the SCs based on the data of proteomic mapping of the proteins and whole transcriptome profiling of the gene expression.
- In the cancer SCs proteome we can map from 30 to 60% of the specific proteins and the bioinformational analysis of them detects the intracellular pathways of signal transduction that have not been modified by carcinogenesis and remain accessible for the targeted regulatory effect.
- Control and management of the proliferative and reproductive functions of the cancer SCs can be achieved by affecting the known target membrane proteins of these intracellular pathways of signal transduction in the cancer SCs.
- Available databases of protein-protein interactions permit detection of the main protein ligand that can interact with the target membrane proteins of the intracellular pathways of signal transduction, activate them in the cancer SCs and manage effector functions of the cancer SCs.
- The methods of chemical induction modify the transcriptomic profiles of the SCs for the specific purposes avoiding genetic engineering and thus develop the cell product of the autologous SCs that express the necessary regulatory ligands.
- The special software have been developed to search the Affymetrix transcriptome databases for the agents that are able to modify the gene expression of the SCs for specific goals and to detect the time and conditions that are necessary for modification.
The experiments on the rat brain tumor models demonstrated the effectiveness of the proposed cytoregulatory therapy by the cell systems with modified profile of gene expression in the suppression of the reproductive and proliferative properties of the cancer cells and cancer SCs of the brain tumor. The role and place of the proposed cytoregulatory method of anti-tumor treatment in the complex conventional (cytoreductive, cytotoxic and cytostatic) therapy and immune therapy of the brain tumors have been shown. We proposed a new paradigm of the proteome-based anti-tumor therapy aimed at the transfer of the acute and lethal malignant process into chronic and non-lethal disease controlling the amount of the cancer cells and regulating the cancer SCs.
Currently, the application to patent the technology in the Russian Federation has been filed, the approvals of the Scientific Boards and Ethical Committees of the Russian Cancer Research Centre of the Russian Academy of Sciences and Federal Medical-Biological Agency for clinical trials. The trials are also registered at the webpage www.clinicaltrail.gov:
- NCT01782287 for Proteome-based Immunotherapy of Lung Cancer Brain Metastases
- NCT01782274 for Proteome–based Immunotherapy of Brain Metastases from Breast Cancer
- NCT01759810 for Proteome-based Personalized Immunotherapy of Glioblastoma
The preliminary results of the proteome-based therapy of different types of cancer is presented in the following tables:
Table 1.Distribution of the patients with different tumors grade III or IV into control and trial groups that received the proteome-based immunotherapy.
№ п/п | Type of cancer | Number of case records | Number of cases in the trial group | Control group |
---|---|---|---|---|
1. | Lung cancer | 81 | 10 | 21 |
2. | Breast cancer | 63 | 10 | 13 |
3. | Glioblastoma multiforme. | 72 | 11 | 12 |
4. | Kidney cancer | 20 | 5 | 10 |
5. | Uterine and ovarian cancer | 35 | 7 | 10 |
6. | Soft tissue sarcoma | 38 | 5 | 10 |
7. | Stomach cancer | 29 | 5 | 10 |
8. | Colorectal cancer | 39 | 6 | 10 |
9. | Head and neck tumors | 16 | 3 | 7 |
10. | Melanoma | 45 | 8 | 10 |
11. | Total: | 438 | 70 | 113 |
Table 2.
Distribution of cancer cases of grade III and IV by age and sex in the control groups.
№ п/п | Type of cancer | Number of patients | Males | Females | Age of males | Age of females |
---|---|---|---|---|---|---|
1. | Lung cancer | 21 | 14 | 7 | 56,5 | 64,6 |
2. | Breast cancer | 13 | - | 13 | - | 54,7 |
3. | Glioblastoma multiforme | 12 | 8 | 4 | 64,7 | 63,5 |
4. | Kidney cancer | 10 | 5 | 5 | 62,6 | 63,5 |
5. | Uterine and ovarian cancer | 10 | - | 10 | - | 48,5 |
6. | Soft tissue sarcoma | 10 | 7 | 3 | 48,6 | 54,8 |
7. | Stomach cancer | 10 | 10 | - | 66,2 | - |
8. | Colorectal cancer | 10 | 8 | 2 | 56,2 | 51,2 |
9. | Head and neck tumors | 7 | 2 | 5 | 49,1 | 60,2 |
10 | Melanoma | 10 | 8 | 2 | 56,4 | 60,1 |
11. | Total: | 113 | 62 | 51 | 57,3 | 57,9 |
Table 3.
Distribution of cancer cases of grade III and IV by age and sex in the trial groups.
№ п/п | Type of cancer | Number of patients | Male / Female | Age Male / Female |
---|---|---|---|---|
1. | Lung cancer | 10 | 8 / 2 | 64,1 / 63,3 |
2. | Breast cancer | 10 | - / 10 | - / 52,7 |
3. | Glioblastoma multiforme | 11 | 7 / 4 | 36,1 / 58,5 |
4. | Kidney cancer | 5 | 5 / - | 55,6 / - |
5. | Uterine and ovarian cancer | 7 | - / 7 | - / 52,1 |
6. | Soft tissue sarcoma | 5 | 4 / 1 | 56,2 / 44 |
7. | Stomach cancer | 5 | 4 / 1 | 56,2 / 61 |
8. | Colorectal cancer | 6 | 3 / 3 | 54,3 / 51,8 |
9. | Head and neck tumors | 3 | 3 / - | 44,3 / - |
10 |
Melanoma |
8 |
6 / 2 |
46,2 / 48,5 |
11. | Total: | 70 | 40 / 30 | 51,6 / 53,9 |
Table 4
Distribution of cancer cases with metastases to brain depending on the degree of compensation according to Karnofsky/ECOG score
Karnofskу/ ECOG (%/points) | Breast cancer cases with brain metastases number/% | Lung cancer cases with brain metastases number/% | Glioblastoma multiforme cases number/% |
---|---|---|---|
90 / 1 | 1 / 7,7 | 1 / 4,8 | - / - |
80/ 1 | 1 / 7.7 | 4 / 19 | 2 / 16.6 |
70 / 2 | 2 / 15.4 | 4 / 19 | 2 / 16.6 |
60 / 2 | 4 / 30.8 | 5 / 23.8 | 3 / 25 |
50 / 3 | 3 / 23.1 | 1 / 4.8 | 2 / 16.6 |
40 / 3 | - / - | 2 / 9.6 | 1 / 8.3 |
20-30/4 | 2 / 15.4 | 4 / 19 | 2 / 16.6 |
Table 5
Distribution of the trial groups cases depending on the degree of compensation according to Karnofsky/ECOG score
Karnofskу/ ECOG (%/points) | Breast cancer cases with brain metastases number/% | Lung cancer cases with brain metastases number/% | Glioblastoma multiforme cases number/% |
---|---|---|---|
90 / 1 | - / - | 1 / 10 | 1 / 9.1 |
80 / 1 | 1 / 10 | 1 / 10 | 2 / 18.1 |
70 / 2 | 2 / 20 | 2 / 20 | 2 / 18.1 |
60 / 2 | 4 / 40 | 3 / 30 | 1 / 9.1 |
50 / 3 | 2 / 20 | 1 / 10 | 1 / 9.1 |
40 / 3 | 1 / 10 | 1 / 10 | 2 / 18.1 |
20-30 / 4 | - / - | 1 / 10 | 2 / 18.1 |
Table 6
Distribution of cancer cases of grade III and IV depending of the immunotherapy strategies
№ | Type of cancer | Proteome-based adoptive immunotherapy (dendritic vaccine and cytoregulatory therapy) number/% | Proteome-based targeted biomedical cell product number/% | Combined cell/pharmaceutical remodeling of the anti-cancer function (precision immunotherapy) number/% |
---|---|---|---|---|
1. | Lung cancer | 10 / 14.3 | 10 / 33.3 | 8 / 16 |
2. | Breast cancer | 10 / 14.3 | 7 / 23.3 | 7 / 14 |
3. | Glioblastoma multiforme | 11 / 15.8 | 10 / 33.3 | 8 / 16 |
4. | Kidney cancer | 5 / 7.2 | - / - | 2 / 4 |
5. | Uterine and ovarian cancer | 7 / 10 | - / - | 3 / 6 |
6. | Soft tissue sarcoma | 5 / 7.1 | - / - | 3 / 6 |
7. | Stomach cancer | 5 / 7.1 | - / - | 4 / 8 |
8. | Colorectal cancer | 6 / 8.5 | 2 / 6.7 | 5 / 10 |
9. | Head and neck tumors | 3 / 4.2 | 1 / 3.4 | 2 / 4 |
10 | Melanoma | 8 / 11.4 | - / - | 8 / 16 |
11. | Total: | 70 / 100 | 30 / 100 | 50 / 100 |
Table 7
Effectiveness of the anti-cancer immunotherapy in different cancers of III and IV grade
№ | Type of cancer | Deterioration number/% | No effect number/% | Effective number/% | Highly effective number/% |
---|---|---|---|---|---|
1. | Lung cancer | 1 / 25 | 2 / 10.5 | 5 / 18.5 | 1 / 25 |
2. | Breast cancer | 1 / 25 | 1 / 5.3 | 3 / 11.1 | 3 / 75 |
3. | Glioblastoma multiforme | 2 / 50 | 3 / 15.7 | 5 / 18.5 | - / - |
4. | Kidney cancer | - / - | 1 / 5.3 | 1 / 3.7 | - / - |
5. | Uterine and ovarian cancer | - / - | 1 / 5.3 | 2 / 7.4 | - / - |
6. | Soft tissue sarcoma | - / - | 1 / 5.3 | 2 / 7.4 | - / - |
7. | Stomach cancer | - / - | 2 / 10.5 | 2 / 7.4 | - / - |
8. | Colorectal cancer | - / - | 2 / 10.5 | 3 / 11.1 | - / - |
9. | Head and neck tumors | - / - | 2 / 10.5 | - / - | - / - |
10. | Melanoma | - / - | 4 / 21 | 4 / 14.8 | - / - |
11. | Total: | - / 100 | 19 / 100 | 27 / 100 | 4 / 100 |
Table 8
Time of life of the glioblastoma cases and breast cancer and lung cancer cases with metastases to the brain in the examined groups.
№ | Type of cancer | Time from diagnosis to death (control group) Months | Time to the detection of tumor focus in the brain (control group) Months | Time from diagnosis to death (trial groups) Months | Time to the detection of tumor focus in the brain (trial groups) Months |
---|---|---|---|---|---|
1. | Lung cancer | 10.6 | 6,1 | 11.2 | 12,6 |
2. | Breast cancer | 45.7 | 2.25 | 59,6 | 8,7 |
3. | Glioblastoma multiforme | 12,3 | 5,2 | 36 | 12,6 |
4. | Total: | 22.8 | 4,51 | 35,6 | 11,3 |
Table 9
The safety of the immunotherapy of cancer and other malignant diseases.
№ | Type of cancer | No complications number/% | Minimal complications number/% | Moderately severe complications | Severe (vital) complications number/% |
---|---|---|---|---|---|
1. | Lung cancer | 6 / 15.3 | 2 / 22.2 | 1 / 33,3 | - / - |
2. | Breast cancer | 7 / 17.9 | - / - | 1 / 33,3 | - / - |
3. | Glioblastoma multiforme | 5 / 12.9 | 3 / 33.3 | - / - | 2 / 100 |
4. | Kidney cancer | 2 / 5.1 | - / - | - / - | - / - |
5. | Uterine and ovarian cancer | 3 / 7.6 | - / - | - / - | - / - |
6. | Soft tissue sarcoma | 3 / 7.6 | - / - | - / - | - / - |
7. | Stomach cancer | 4 / 10.2 | - / - | - / - | - / - |
8. | Colorectal cancer | 2 / 5.1 | 1 / 11.1 | 1 / 33,3 | - / - |
9. | Head and neck tumors | 2 / 5.1 | - / - | - / - | - / - |
10. | Melanoma | 5 / 12.9 | 3 / 33.3 | - / - | - / - |
11. | Total: | 39 / 100 | 9 / 100 | 3 / 100 | 2 /100 |