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Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer.

ABSTRACT: Ovarian cancer is a leading cause of death among gynecological malignancies, and novel therapies are urgently needed. Here we report preliminary findings on the potential safety and efficacy of 6B11-OCIK, an adoptive cell therapy of autologous T cells induced by the humanized anti-idiotypic antibody 6B11 minibody plus dendritic cells and cytokines, against platinum-resistant recurrent or refractory ovarian cancer in three patients. We found that 6B11-OCIK treatment was safe and well tolerated after five cycles of intravenous infusion with an initial dose of 1-2×10⁹ cells and a dose-climbing strategy. Hemoglobin, platelets, white cell count, creatinine or liver enzyme values, coagulation function, kidney and heart function were not significantly affected over the duration of therapy. Two of the three enrolled patients showed potentially drug-related grade 1 and 2 weakness, and no other adverse events were observed. Of the three enrolled patients, one had stable disease and two showed disease progression. The patient with favorable clinical efficacy had better immune response as measured by 6B11-OCIK proliferation capacity, activation ability of CD3+CD8+ tumor-specific cytotoxic T lymphocytes and CD3+CD56+ cytokine-induced killer cells, and tumor cell killing efficiency. Changes in circulating tumor cells after treatment were consistent with serum level CA125 in the patient with stable disease (both decreased), while differences were observed in the two patients with disease progression (increased CA125 in both and decreased CTC in the patient with better immune response), suggesting that variation of circulating tumor cells was more consistent with immune response and reflected efficacy directly. This preliminary study suggested that autologous 6B11-OCIK treatment was safe and had potential clinical efficacy against ovarian cancer. Patients with better immune response had more favorable efficacy. In addition to imaging, CA125 and immunophenotypes, CTC monitoring may represent a potential indicator of immunotherapy response.

SUBMITTER: Cheng H

PROVIDER: S-EPMC8366315 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeEtirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma.Patients and methodsA total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS).ResultsThe overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days.ConclusionBoth schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

Project description:Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies to avoid platinum inefficacy and to exploit platinum sensitivity. TOV-21G devoid of FANCF expression, OV-90 and SKOV-3 were employed as examples of platinum-sensitive, platinum-intermediate and platinum-resistant cell lines, respectively. Antineoplastic agents examined included mitomycin C, doxorubicin, etoposide, gemcitabine, chlorambucil, paclitaxel, triapine and X-rays. Their effectiveness against cell lines was analyzed by clonogenic assays. Cytotoxic profiles of mitomycin C and carboplatin were similar, with mitomycin C exhibiting greater potency and selectivity against TOV-21G than carboplatin. Cytotoxic profiles of doxorubicin, etoposide and X-rays overlapped with that of carboplatin, while OV-90 overexpressing Rad51 was more resistant to chlorambucil than SKOV-3. The efficacy of paclitaxel and triapine was independent of platinum sensitivity or resistance. Consistent with these cytotoxic profiles, cisplatin/mitomycin C, triapine, and paclitaxel differed in the capacity to induce phosphorylation of H2AX, and produced unique inhibitory patterns of DNA/RNA syntheses in HL-60 human leukemia cells. Paclitaxel and triapine in combination produced additive antitumor effects in M109 murine lung carcinoma. In conclusion, mitomycin C is potentially more effective against Fanconi anemia pathway-deficient EOCs than carboplatin. Doxorubicin and etoposide, because of their overlapping cytotoxic properties with carboplatin, are unlikely to be efficacious against platinum-refractory EOCs. Paclitaxel and triapine are effective regardless of platinum sensitivity status, and promising in combination for both platinum-sensitive and platinum-refractory EOCs.

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Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer.

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