Mariele Goebeler

Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkins lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.

Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival

PURPOSE Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. RESULTS Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab

T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.

Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking

The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19- relapses remain a major challenge in about 10% to 20% of patients. Here, we analyzed 4 CD19- ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager (BiTE) blinatumomab. Three were on-drug relapses, with the CD19- escape variant first detected after only 2 treatment courses. In 1 patient, the CD19- clone appeared as a late relapse 19 months after completion of blinatumomab treatment. All 4 cases showed a cellular phenotype identical to the primary diagnosis except for CD19 negativity. This argued strongly in favor of an isolated molecular event and against a common lymphoid CD19- progenitor cell or myeloid lineage shift driving resistance. A thorough molecular workup of 1 of the cases with early relapse confirmed this hypothesis by revealing a disrupted CD19 membrane export in the post-endoplasmic reticulum compartment as molecular basis for blinatumomab resistance.

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

PURPOSE To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m(2), 5-fluorouracil 2000 mg/m(2), folinic acid 500 mg/m(2) weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m(2) applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS). RESULTS A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio=1.14; 95% confidence interval (CI) 0.94-1.37; P=0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio=1.08, P=0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P=0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P=0.006) CONCLUSION mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.

Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange.

EXtend and eXjange were prospective, 1‐yr, non‐interventional, observational, multicentre studies that investigated deferasirox, a once‐daily oral iron chelator, in iron‐overloaded chelation‐naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily‐routine setting of office‐based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two‐monthly intervals. Data from 123 chelation‐naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation‐naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug‐related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion‐dependent patients with MDS.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6–47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3–78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9–6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1–0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21–0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.