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.

Trial registration: ClinicalTrials.gov NCT03542669.

Keywords: adoptive cell therapy; circulating tumor cell; immunotherapy; ovarian cancer; safety and efficiency evaluation.

Figure 1

CT images of patients before and after 6B11-OCIK treatment. (A) Lesion 1 of patient 1 before 6B11-CIK treatment: Plain and contrast-enhanced computed tomography shows a low-density lesion in S6 segment of liver, with slight enhancement. (B) Lesion 1 of patient 1 after 6B11-CIK treatment: CT shows that the lesion in S6 segment of liver became enlarged. (C) Lesion 2 of patient 1 before 6B11-CIK treatment: CT shows local peritoneal thickening. (D) Lesion 2 of patient 1 after 6B11-CIK treatment: Local peritoneum became thicker, and peritoneal effusion was detected. (E) Lesion 3 of patient 1 before 6B11-CIK treatment: Right iliac perivascular lymph node enlargement before treatment. (F) Lesion 3 of patient 1 after 6B11-CIK treatment: The lymph nodes near the right iliac vessels were slightly enlarged; pelvic effusion was detected. (G) Lesions of patient 2 before 6B11-CIK treatment: Low-density nodules were observed in the spleen. (H) PET-CT of patient 2 after 6B11-CIK treatment: Multiple FDG metabolism enhancement lesions were found throughout the body, and tumor recurrence and metastasis were considered. The lesions involved the right adrenal gland, liver capsule, spleen capsule, peritoneum, intestinal surface and multiple lymph nodes at heart diaphragm angle, left costal phrenic angle, mesenteric, abdominal aorta and iliac vascular periphery. (I) Lesions of patient 3 before 6B11-CIK treatment: Enlarged lymph nodes near the left iliac vessels were observed with a size of approximately 3.6×2.2cm. (J) Lesions of patient 3 after 6B11-CIK treatment: Left iliac perivascular enlarged lymph nodes with no change after treatment.

Figure 2

Detection of CTCs and serum CA125 during 6B11-OCIK treatment. (A) Identification of CTCs by iFISH: CTCs of ovarian cancer were pointed by arrows. (a): DAPI+/CD45-/CD31- with aneuploidy of chromosome 8; (b): DAPI+/CD45-/CD31-/HE4+; (c): DAPI+/CD45-/CD31-/CA125+. (B) Variation of the number of CTCs during 6B11-OCIK treatment: During the treatment of 6B11-OCIK, the number of CTCs increased in patient 1 (from 0 to 17 to 10) and decreased in patient 2 (from 46 to 4 to 3) and patient 3 (from 70 to 19 to 17) during the treatment. (C) Variation of serum CA125 during 6B11-OCIK treatment: During the treatment of 6B11-OCIK, CA125 levels in patient 1 and patient 2 increased. The increase was higher in patient 1 (from 324.3 to 2347 U/ml) compared with patient 2 (from 247.6 to 994 U/ml). CA125 levels in patient 3 decreased from 380.4 to 283.5 U/ml.

Figure 3

Amplification and activation characterization of ex vivo–expanded 6B11-OCIK cells. (A) Proliferation of 6B11-OCIK during culture: PBMNCs were amplified in all three patients, with the average cell amplification of 46.92-fold (patient 1), 102.07-fold (patient 2) and 117.95-fold (patient 3). (B-D) Immunophenotypic analysis of expanded 6B11-OCIK and PBMNCs before culture in patients. (B) patient 1; (C) patient 2; (D) patient 3. Results showed activation of DCs (CD86, CD80, CD83, and HLA- DR positive) in 6B11-OCIK. The proportion of CD3+ T lymphocytes, specific CD3+CD8+ killer T cells (CTLs), and CD3+CD56+ NK-like T cells (CIKs) in 6B11-OCIK of all three patients were markedly increased. The T cell proliferation and activation of patient 3 was greater than that of patient 2 and patient 1.

Figure 4

Killing efficiency of 6B11-OCIK against the ovarian cancer cell line HOC1A. The average killing efficiency of 6B11-OCIK from all three patients against the ovarian cancer cell line HOC1A increased with the increase of effect-target ratio. At each effect-target ratio, the killing efficiency was the lowest for patient 1 and highest for patient 3. *P < 0.05; **P < 0.01; ***P < 0.001; ns, no significance, P > 0.05.