Blinatumomab is a bispecific antibody construct that can transiently connect a patient’s cytotoxic T cells with B-cell lymphoma or leukemia cells. Clinical studies have shown response rates greater than 80%, both in patients with relapsed B-cell non-Hodgkin’s lymphoma (NHL) and in patients with residual B-precursor acute lymphoblastic leukemia (ALL). While these high response rates need confirmation in larger trials, they provide clinical proof-of-concept for the novel therapeutic principle of BiTE antibodies, and suggest an effective circumvention of immune evasion mechanisms frequently limiting other T cell-based therapies.
Chimeric, humanized or human monoclonal antibodies have become an important addition to the arsenal of modern cancer therapies.1 While regular antibodies can block oncogenic receptors on the cell surface, engage immune cells bearing antibody-binding Fc receptors, or neutralize angiogenic factors, none of them can recruit T cells, the most effective cancer-fighting cells in the body. Retrospective studies have shown that the mere presence of T cells inside human tumors strongly correlates with longer survival.2 In numerous mouse studies, T cells were shown to eradicate even large tumors3, and stunning responses have occasionally been observed in end-stage melanoma patients after adoptive transfer of ex-vivo expanded, tumor-derived T cells4 or treatment with anti-CTLA-4 antibody, a booster of T cell responses.5
|Dose Level||Drug Patients (Total of N = 43)||Overall Responses||Complete Responses||Partial Responses||Response Rate (%)|
|0.0005, 0.0015, 0.005 mg/m2 per day||12||0||0||0||0|
|0.015 and 0.030 mg/m2 per day||19||4||2||2||21|
|0.060 mg/m2 per day||12||11||4||7||91|
|Table 1. Evidence for dose-dependent activity of blinatumomab in Phase 1 study with relapsed NHL patients. Results from six different dose levels ranging from 0.0005 to 0.06 mg/m2 body surface per day are shown. Responses were centrally assessed by computer tomography scans using Cheson criteria. (Source: Micromet)|
Recombinant and hybridoma technologies have enabled the construction of bispecific antibodies with two different binding arms that can directly attach T cells to cancer cells, overcoming the limitation of natural antibodies. Such “T cell-engaging antibodies” have only recently shown positive results in the clinic. One is catumaxomab, which just received market approval in Europe for treatment of ascites in ovarian cancer patients.6 Catumaxomab is in fact trispecific with one arm binding tumor cells, one binding T cells, and one binding antigen-presenting cells.
Another promising T cell-engaging antibody is blinatumomab,7 which belongs to the class of “bispecific T-cell engager”.8 It has two arms, one binding to CD19 on malignant and normal B cells and one binding to CD3 on T cells. CD19 is expressed on a wide variety of human lymphoma and leukemia descending from B-cells, and, in fact, is routinely used in the clinic as a marker protein to decide whether a blood-borne tumor is derived from B cells. Numerous non-clinical studies have studied blinatumomab’s efficacy in animal models and its mode of action, which involves redirected lysis of tumor cells and concomitant activation of T cells.9 Blinatumomab is currently being investigated in two clinical studies. One is a Phase 1 study in NHL patients, and the other, a Phase 2 study in ALL patients with residual tumor cells in bone marrow, both of which were presented in June 2009 at the annual meeting of the European Hematology Association (EHA) in Berlin, Germany.
The NHL study is recruiting patients who relapsed after treatment with several standard therapies, including anti-CD20 monoclonal antibody rituximab and fludarabine, and were therefore in need of a novel kind of therapy. The majority of patients had either follicular or mantle cell lymphoma. The dose-escalating Phase 1 study started with just 0.0005 mg blinatumomab per square meter body surface per day, whereby the BiTE antibody was continuously infused for 4 to 8 weeks via a belt-worn mini pump.10 For comparison, 375 mg of rituximab are given per week to NHL patients per square meter body surface. At 0.005 mg blinatumomab and higher doses, all patients showed a swift and sustained removal of target cells from their blood stream. At 0.015 mg per square meter per day and higher, objective partial and complete tumor responses were observed. The effect of blinatumomab on organ infiltration by lymphoma cells was shown by histological analysis of bone marrow biopsies and, in one case, liver biopsy. The percentage of responding patients increased with the dose. At 0.06 mg per square meter per day, 11 out of 12 patients receiving the BiTE antibody for at least one week showed objective partial or complete responses, translating into a response rate of >90% (Table 1).11 Without any further treatment, some patients have now had full and partial remissions lasting for more than one year. The majority of clinical side effects were reversible on treatment and culminated during the first days of infusion. These include flu-like symptoms including chills, fever, fatigue, and headache. The most prominent laboratory adverse events were lymphopenia and increase of C-reactive protein. Treatment in a number of patients had to be discontinued early due to neurological adverse events, which were fully reversed when treatment ceased.10 The nature of these events is currently under investigation and mitigation strategies are being explored in the ongoing Phase 1 trial.
The Phase 2 study with blinatumomab is treating B-precursor ALL patients in complete hematological remission but, after consolidation of a front-line therapy, are left with tumor cells in their bone marrow (called “minimal residual disease”, or MRD). The cells can only be found during bone marrow biopsies using sensitive polymerase chain reaction (PCR)-based methods that detect tumor-specific chromosomal changes. Persistence of such tumor cells is associated with poor outcome and a high rate of hematological relapse. Patients with more than one leukemic blast cell per 10,000 normal bone marrow cells after consolidation therapy have a median time to hematological relapse of only 4.1 months.12 Allogeneic hematopoietic stem cell transplantation (HSCT), which can be associated with high morbidity and mortality, is currently the only curative approach for adult patients with MRD.
|Number of Patients||MRD Negativity Achieved|
|Bcr/abl Negative (Individual Rearrangements)||11||9|
|Bcr/abl Negative; t(4;11)||2||1|
|Patients Evaluable for Response MRD Response Rate||16||13 (81%)|
|Table 2. High response rate of blinatumomab in phase 2 study with patients having residual ALL. Three patients with Bcr/Abl-positive disease responding to blinatumomab were refractory to tyrosine kinase inhibitors dasatinib or imantinib. One patient thereof had a T315I mutation. Of three patients not responding to the BiTE antibody, two had stable disease and one a hematological relapse during the third treatment cycle. One patient was not evaluable due discontinuation of treatment after a neurological adverse event. (Source: Micromet)|
In the Phase 2 study, one six-week treatment cycle consisted of a four-week continuous intravenous infusion of 0.015 mg blinatumomab per square meter body surface per day followed by a two-week treatment-free interval. This could be followed by three more cycles, or an allogeneic HSCT. In 13 out of 16 evaluable patients (81%), no residual tumor cells were any longer detectable after the first treatment cycle, as assessed by PCR-based analysis (Table 2). 13 The other three patients showed a stabilization of their disease. Overall, the safety profile of blinatumomab was very favorable with only one permanent treatment discontinuation due to a fully reversible neurological adverse event.
Blinatumomab is a promising novel agent for the treatment of multiple B-cell malignancies that either present as bulky or minimal residual disease. The very high response rates observed in the first two trials now need confirmation in larger trials. They may indicate that T cells can be very effectively engaged in patients by a BiTE antibody and no longer face the multitude of immune escape mechanisms typically limiting specific T-cell responses with most other T-cell therapies. A pivotal trial with blinatumomab is in the planning stage for treating adult ALL patients.
1. Baeuerle PA. Drug Discovery and Development, www.drugdiscoverytrends.com. May 1, 2008.
2. Zhang L, et al. New Engl J Med. 348: 203 (2003).
3. Carpenito C, et al. Proc. Natl. Acad. Sci. USA 106: 3360 (2009).
4. Rosenberg SA, et al., Nat. Rev. Canc. 8: 299 (2008).
5. Sarnaik AA, Weber JS. Cancer J. 15: 169 (2009).
6. Shen J, Zhu Z. Curr. Opin. Mol. Ther. 10: 273 (2008).
7. Nagorsen D, et al. Leukemia Lymphoma 50: 1 (2009).
8. Baeuerle PA, Reinhardt C. Canc. Res. 69: 4941 (2009).
9. Baeuerle PA, et al. Curr. Opin. Mol. Ther. 11: 22 (2009).
10. Bargou R, et al. Science 321: 974 (2008).
11. Klinger M, et al. poster at 14th congress of EHA, abstract no. 430 (2009).
12. Raff T, et al. Blood 109 : 910 (2007).
13. Topp MS, et al. presentation at 14th congress of EHA, abstract no. 482 (2009).
About the Authors
Gerhard Zugmaier holds a MD from Tuebingen University. After a post-doctoral fellowship at the National Cancer Institute, Bethesda, and at Lombardi Cancer Center, Georgetown University Medical Center, Washington D.C., he obtained his board certification in internal medicine and in hematology and medical oncology at Marburg University Medical Center, where he is a faculty member. He joined Micromet in 2006 from Roche.
Patrick Baeuerle holds a PhD in biology from the Munich University, and did post-doctoral research at MIT. In 1998, he joined Micromet from Tularik Inc., where he headed drug discovery. He was Germany’s most frequently cited biomedical scientist of the past decade, and 38th worldwide.
Filed Under: Drug Discovery