Cervical Cancer – Bench to Bedside

AbstractCervical cancer is the second most common cancer in Indian women and 4th most common cancer in women world-wide. Over nearly two decades, we have carried out epidemiological and molecular studies in cervical cancer, with an intent to identify potential early diagnostic biomarkers, predictive and prognostic markers, develop newer therapies against cervical cancer and identify potential new targets for therapy.Our studies had identified 14 high risk and 10 low risk human papilloma virus (HPV) in our cervical cancer patients for the first time; had identified life style related cofactors in the development of cervical cancer (paan chewing, parity, early age at first sexual intercourse and first childbirth, husband with two or more sexual partners). We have developed a p16 ELISA kit for cervical cancer screening for use at point of care like PHC's; identified a 7 gene signature which help identify patients who can be treated with radiotherapy alone; identified potential prognostic markers for use in the clinic; developed the country's first Dendritic cell vaccine therapy for cervical cancer and completed the phase 1 study; have identified newer potential therapeutic targets for treatment of cervical cancer.

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A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer

Oncotarget ◽

10.18632/oncotarget.24118 ◽

2018 ◽

Vol 9 (11) ◽

pp. 10110-10117 ◽

Cited By ~ 15

Author(s):

Hatem Soliman ◽

Fatema Khambati ◽

Hyo S. Han ◽

Roohi Ismail-Khan ◽

Marilyn M. Bui ◽

...

Keyword(s):

Breast Cancer ◽

Dendritic Cell ◽

Solid Tumors ◽

Invasive Breast Cancer ◽

Phase 1 ◽

Dendritic Cell Vaccine ◽

Cell Vaccine

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Dynamics of the immune status in patients with cervical cancer receiving complex treatment with dendritic cell vaccine.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17005 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17005-e17005

Author(s):

Anna P. Menshenina ◽

Oleg I. Kit ◽

Elena Yu. Zlatnik ◽

Elena S. Bondarenko ◽

Inna A. Novikova ◽

...

Keyword(s):

Cervical Cancer ◽

Dendritic Cell ◽

Nk Cells ◽

Immune Status ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Control Group ◽

Dendritic Cell Vaccination ◽

Maximal Effect ◽

Complex Treatment

e17005 Background: The purpose of the study was to determine the influence of complex treatment with dendritic cell vaccine on the dynamics of the immune status of patients with cervical cancer. Methods: 17 patients with cervical cancer (CC) T2b-4аN0-1M0-1 received chemotherapy with combined radiotherapy to the pelvic area. Between courses of cytostatic treatment, patients underwent dendritic cell vaccination (DCV) planned individually depending on the treatment effect, which was evaluated by the results of examination, US, CT and MRI. A control group included 19 patients with locally advanced CC receiving standard polychemotherapy (PCT) and radiotherapy. Immune status of patients was evaluated by flow cytometry (FACSCantoII BD) including T, B, NK cells, Tregs (CD4+CD25+CD127dim), memory T cells (Тm) and naïve T lymphocytes (Th0) was determined in the dynamics of the treatment. Results were calculated as a percentage from the total number of lymphocytes, for Tregs – in % from CD3+CD4+ cells, for Тm and Th0 – in % from CD3+CD4+ and CD3+CD8+ cells. Results: 1 to 4 cycles of PCT with DCV caused a transient increase in Tregs after the 1st cycle, with further regression to the initial levels; other studied lymphocyte subsets remained unchanged. Only after 8 or more DCV cycles, a favorable immunological dynamics developed; however, it was not observed in controls. DCV increased levels of lymphocytes with potential cytotoxicity: CD3+CD8+ (from 19.0±2.0 to 28.8±1.5%), NK cells (from 12.0±2.0 to 21.2±1.9%). During DCV courses helper-inducer Tm amount rose from 51.7±6.3 to 69.7±4.3%, while in remission – CD8+Tm grew from 28.5±2.1 to 40.4±5.3% (p < 0.05 for all cases). Repeated DCV was satisfactorily tolerated by CC patients and, when used in complex treatment, caused a pronounced clinical effect. DCV did not lead to serious adverse events. Patients in remission are still observed. Conclusions: Treatment for CC with DCV causes a positive dynamics of the immune status, with the maximal effect after 8 and more DCV cycles. Remission is apparently maintained due to an increase in the level of TmCD8+ cells.

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Dendritic cell vaccine as an alternative to opioid analgesia in patients with advanced cervical cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18022 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18022-e18022

Author(s):

Anna P. Menshenina ◽

Oleg I. Kit ◽

Elena M. Frantsiyants ◽

Tatiana I. Moiseenko ◽

Ekaterina V. Verenikina ◽

...

Keyword(s):

Cervical Cancer ◽

Pain Relief ◽

Severe Pain ◽

Pain Syndrome ◽

Opioid Analgesics ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Advanced Cervical Cancer ◽

Moderate Pain ◽

Intense Pain

e18022 Background: Locally advanced and progressive cervical cancer is always accompanied by the pain syndrome. The common analgesics include non-steroidal anti-inflammatory drugs and opioids. The purpose of the study was to assess allogeneic dendritic cell vaccine (DCV) as an alternative analgesic in patients with advanced cervical cancer. Methods: The pain syndrome dynamics was assessed in 20 patients with advanced T3-4N1M0-1 cervical cancer receiving subcutaneous paravertebral injections of allogeneic DCV in a total alternating dose of 5-10 million cells every 2 weeks. Patients received DCV for one year, with a total of 24 vaccine therapy sessions and a total dosage of 180 million dendritic cells. The pain intensity was assessed on a verbal rating scale: 0 – no pain; 1 – mild pain; 2 – moderate pain; 3 – severe pain; 4 – extremely intense pain. Results: Prior to the therapy, 15 patients (75%) had severe pain; 2 (10%) - moderate pain; 3 (15%) - extremely intense pain. After 4-6 DCV injections, the pain intensity decreased, patients refused opioid analgesics. After 10-12 DCV sessions, 19 (95%) (p < 0.05) women had no pain at all, patients denied additional pain relief with non-opioid analgesics. Unrelieved pain was registered only in one cervical cancer patient. Conclusions: DCV injections in patients with advanced cervical cancer provide pain relief thereby improving their quality of life.

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Dynamics of oxidative blood status and activity of antioxidant system of erythrocytes in patients with cervical cancer receiving combination therapy with dendritic cell vaccine.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e17516 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17516-e17516

Author(s):

Irina A. Goroshinskaya ◽

Anna P. Menshenina ◽

Elena M. Frantsiyants ◽

Tatiana I. Moiseenko ◽

Ekaterina V. Verenikina ◽

...

Keyword(s):

Cervical Cancer ◽

Dendritic Cell ◽

Combination Therapy ◽

Catalase Activity ◽

Locally Advanced ◽

Dendritic Cell Vaccine ◽

Vaccine Therapy ◽

Cell Vaccine ◽

Sod Activity ◽

Radical Processes

e17516 Background: The combination treatment with plasmapheresis and non-specific immunotherapy for locally advanced cervical cancer (CC) is shown to be effective. We studied the effect of immunotherapy with dendritic cell vaccine (DCV) as a part of combination therapy on the intensity of the lipid peroxidation (LPO) and activity of antioxidant enzymes. Methods: Plasma and erythrocyte content of malondialdehyde (MDA), the activity of superoxide dismutase (SOD), catalase, glutathione dependent enzymes and the content of reduced glutathione (GSH) in erythrocytes were determined in 24 patients with CC of T2a-2bN0-1M0 stages and in 25 women without cancer. The patients underwent neoadjuvant chemotherapy (CT) with cisplatin and bleomycin, followed by 2 cycles of DCV, for a total of 6 courses of CT and 12 cycles of DCV. Results: Initially, patients demonstrated intensification of free radical processes enhancing after PCT and the first two DCV: MDA in erythrocytes elevated by 52.2-111.7%, in the blood plasma by 2.2-3.5 times. Subsequent DCV cycles normalized the LPO. MDA levels after 4 DCV cycles were lower than the initial values in erythrocytes by 30.4% (p = 0.04), in plasma by 55.6% (p = 0.007), i.e. were similar to the levels in healthy women. The SOD activity was decreased by 16.7-27.3% (p < 0.005) after 4-6 DCV cycles and normalized after the 7th cycle. The catalase activity in erythrocytes was decreased before treatment and after PCT by 42.4% (p = 0.000000), during vaccine therapy by 20.5-37.7% (p < 0.0005). In reduced catalase activity, inactivation of hydrogen peroxide was realized, apparently, by glutathione peroxidase (GPO), and its increased activity (by 37-102.3%, p≤0.00005) was supported by a high GSH content - by 11.6-52.4% (p < 0.02) above the norm at all stages after the 2nd DCV cycle. And only with the complete normalization of the erythrocyte MDA content, the GPO activity after the 7th DCV cycle decreased by 46.7% (p = 0.000000) relative to the levels before the treatment and did not differ significantly from the values in donors. Conclusions: Vaccine therapy helped to enhance the activity of the glutathione system becoming the most important component of antioxidant protection in the blood of CC patients. Already 3-4 DCV cycles normalized the LPO sharply increased in CC patients during CT. Multi-course vaccine therapy allowed maintaining the optimal oxidative status of the blood.

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Durable Responses and Survival in High Risk AML and MDS Patients Treated with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Blood ◽

10.1182/blood-2019-127881 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1381-1381 ◽

Cited By ~ 1

Author(s):

Luca L.G. Janssen ◽

Theresia M. Westers ◽

Jeroen Rovers ◽

Peter Valk ◽

Jacqueline Cloos ◽

...

Keyword(s):

Clinical Trial ◽

Dendritic Cell ◽

High Risk ◽

Complete Remission ◽

Research Funding ◽

Medical Center ◽

Phase 1 ◽

Dendritic Cell Vaccine ◽

Cell Vaccine

Background. Maintenance of induced responses remains a significant unmet medical need in patients with acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In this study we show additional data on long-term follow up and patient-related risk factors from the phase 1 study. Methods. AML- or MDS-patients (n=12), ineligible for HSCT, were included in a post-hoc clinical analysis of the DCP-001 phase I trial, receiving DCP-001 vaccination at the Amsterdam University Medical Center, VU University Medical Center, Amsterdam, the Netherlands (NCT01373515). All clinical data, including baseline characteristics as cytogenetics, pre-and post-vaccination treatment and morphologic blast counts in follow up, were retrospectively collected from corresponding patient files. Targeted next generation sequencing (NGS) gene panel data and cytogenetics were utilized to determine (cyto-)genetic risks following the European Leukemia Net (ELN) 2017 criteria. We defined 'response' as decreased or stable morphologic blast counts in bone marrow at day 126 (last day of official study evaluation) compared to study entry. Results. Seven out of twelve patients responded to treatment, the other patients showed progressive disease (data are summarized in table 1). The median relapse free survival (RFS) for the responding patients was 420 days (range 90-1849) and overall survival (OS) was 1090 days (90-2160); two patients died early in complete remission (CR) due to infection (respectively at 90 and 184 days). Notably, three of these patients were intermediate risk and four were poor risk patients based on the ELN risk classification for AML or Revised International Prognostic Scoring System (IPSS-R) for MDS. The median OS for the non-responders was 144 days (range 59-209). These five patients had relapsed or refractory disease at start of vaccination with detectable circulating peripheral blasts; four of them received additional azacitidine (AZA) therapy prior to vaccination. Moreover, they were vaccinated after induction and consolidation therapy with a median time between diagnosis and first vaccination of 611 days (219-2310) compared to 240 days (105-1398) for the seven responding patients. Of the latter, all were in complete remission (CR) (n=5) or had morphologic marrow blast counts <10% (n=2) at the start of vaccination. Two responders that progressed and two that relapsed after vaccination were treated with AZA, resulting in one complete remission and two partial responses (one non-evaluable due to sample failure), see figure 1. Conclusion/discussion. Clinical data of the phase 1 trial show that DCP-001 may prolong duration of remission or smoldering disease in intermediate and high risk AML or MDS patients. Response was associated with treatment by vaccination shortly after achieving CR. This should be taken into account in selection criteria of future vaccination studies. Hence, an international multi-center phase 2 study (ADVANCE II; NCT03697707) is currently being conducted to determine the effect of DCP-001 on measurable residual disease (MRD) in AML patients, aiming to convert them to a MRD negative state. Furthermore, we demonstrated that AZA can be applied as rescue therapy upon progression after vaccination. Disclosures Rovers: DCprime: Employment. Cloos:Daiicchi Sankyo: Speakers Bureau; Glycomimetics: Research Funding; Takeda: Research Funding; Novartis: Other: MRD assessments of clinical trials, Research Funding; Merus: Other: MRD assessment of a clinical trial , Research Funding; Genentech: Consultancy, Research Funding; Helsinn: Other: MRD assessment of a clinical trial; DCPrime: Other: MRD assessment of a clinical trial. de Gruijl:DCprime: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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EFFECT OF ANTHRACYCLINE ANTITUMOR ANTIBIOTICS UPON TRANSCRIPTION ACTIVITY OF CANCER-TESTIS ANTIGENS IN MODEL EXPERIMENTS WITH HeLa CELLS

Medical Immunology (Russia) ◽

10.15789/1563-0625-2019-3-539-546 ◽

2019 ◽

Vol 21 (3) ◽

pp. 539-546 ◽

Cited By ~ 1

Author(s):

D. S. Kutilin ◽

Kh. A. Mogushkova

Keyword(s):

Cervical Cancer ◽

Malignant Tumors ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Sterile Culture ◽

Cancer Testis Antigens ◽

Adhesive Surface ◽

Cervical Cancer Cells ◽

Thermal Cycler ◽

Cancer Testis

Cancer-testis antigens (CTA) can be used as a target for immunotherapy of various malignant tumors, including cervical cancer. However, immunotherapy is often used in combination with anthracycline chemotherapy, in particular, doxorubicin (DXR). Their effects upon expression of CTA genes have not been yet studied. Therefore, we studied the effects of doxorubicin at different concentrations and exposure time upon transcriptional profile of 17 cancer-testicular (CT) genes of HeLa CCL-2 cells. A long-term line of human cervical cancer cells (HeLa CCL-2 line) was used in this work. Culturing of HeLa CCL-2 cells was carried out in sterile culture flasks with adhesive surface and ventilated lids at 5% CO2, and 95% humidity at 37 °C, in RPMI-1640 medium with 10% fetal bovine serum, supplied with gentamicin (50 μg/ml), and different concentrations of doxorubicin: 0 μg/ml (control), 2 μg/ml, and 4 μg/ml. Expression levels of 16 RT-genes were determined by quantitative RT-PCR using a Bio-Rad CFX96 thermal cycler. Normalization of results was performed against a reference gene, and expression of tested genes in the control samples. We have found that the time of in vitroexposure, and concentration of doxorubicin exert a significant influence upon expression ofMAGEA1, MAGEA3, MAGEA4, MAGEB1, MAGEB2, GAGE1, GAGE3, BAGE, CTAG1B, XAGE3, NY-ESO1, PRAME1andSYCP1genes, however, without affecting theSSX2, MAGEA2, GAGE4andMAGEC1expression, and DXR concentration as a single factor did not affectMAGEB1andMAGEB2expression. Time of response to DXR effects enabled us to discern early cancer testicular genes with increased expression (MAGEA1, MAGEA3, MAGEA4, NY-ESO1, SYCP1), reduced expression (GAGE1andBAGE), and late inducible testicular genes (GAGE3andXAGE3). These results must be taken into account when carrying out immunotherapy based on the dendritic-cell vaccine technology.

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