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FAP-blocking antibodies offer new therapy
Newsdesk Conventional treatment for non-Hodgkin lymphoma for the CHOP
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[way in which the patients were selected. In particular, this method of classifying patients] was a decisive feature of this trial compared with other studies that have not found any advantage between high-dose and conventional chemotherapy”, argues Schmitz.
This new study also has another limitation—an inadequate description of the type of treatment used for patients who relapsed: “We simply don’t know what happened to patients who relapsed after conventional or high-dose therapy”, concludes Schmitz. Khabir Ahmad
FAP-blocking antibodies offer new therapy Antibodies that block the enzymatic activity of a tumour-promoting protein could offer a new anticancer therapy, US investigators claim. Inhibiting the catalytic activity of a membrane glycoprotein called fibroblast activation protein (FAP), which is selectively expressed in about 90% of all solid tumours, results in fewer tumours and smaller lesions in mice injected with cells containing defective FAP, reported Jonathan Cheng and colleagues (Fox Chase Cancer Center, Philadelphia, PA, USA) at the annual meeting of the American Association for Cancer Research (Orlando, FL, USA; March 27–31, 2004). Previous studies by the investigators have shown that FAP is selectively expressed in epithelial carcinoma cells, stimulating tumour growth. However, until now, the team were unsure how the integral membrane glycoprotein achieved this. “Animal studies have shown that producing lots of FAP in the tumour microenvironment makes the cancer grow faster”, says Cheng. “We are now learning more about how FAP does that.” To investigate whether the integral membrane glycoprotein’s dipeptidyl peptidase (DPP) activity was crucial for tumour growth, the researchers produced HEK293 cells transfected with FAP that lacked catalytic activity. Mice were then given subcutaneous injections of HEK293 cells containing the FAP enzymatic mutant, the wildtype FAP, or vector alone to act as a control. Mice that received the catalysisdeficient mutant produced tumours
half the size of those found in mice given the wildtype FAP. In addition, although all mice injected with wildtype FAP developed tumours, only two-thirds of mice given mutant FAP were found to have tumours—a proportion similar to that seen in the vector-only group.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
© Alfred Pasieka/Science Photo Library
Adults with newly diagnosed, aggressive non-Hodgkin lymphoma who receive intensive chemotherapy plus haemopoietic stem-cell transplantation have a better 5 year event-free survival than do patients who receive CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; N Engl J Med 2004; 350: 1287–95). “Our findings are important because they show that CHOP can no longer be regarded as the standard treatment for such patients”, explains Noel Milpied (University Hospital of Nantes, France). 197 patients (aged 15–60 years) who had aggressive lymphoma and a low, low–intermediate, or high– intermediate risk of death were given either high-dose chemotherapy plus stem-cell transplantation or CHOP chemotherapy. Based on the entire cohort, patients in the high-dose therapy group had a significantly higher event-free survival at 5 years compared with patients in the CHOP group (55% vs 37%). However, the overall survival of the two groups at 5 years was not significantly different. Among patients with a high–intermediate risk, eventfree survival and overall survival were significantly higher for the group given high-dose therapy than for those given CHOP (56% vs 28% and 74% vs 44%, respectively). “This is a well-conducted phase III trial and the results are important”, notes Norbert Schmitz (University of Kiel, Germany). However, he cautions that there are several aspects that need careful consideration: first, the trial included 15 patients with anaplastic lymphoma, which usually has a better prognosis than the more common diffuse large B-cell lymphoma. Second, “there were 23 patients who had diffuse, aggressive unclassifiable lymphoma—a subentity that I do not know how to judge”, Schmitz adds. In addition, Schmitz points out that this is the only study that has excluded high-risk patients in favour of the low, low–intermediate, or high–intermediate risk of death method of classification. “The finding that there was no difference in overall survival in any subgroup except the high–intermediate group may be because of the
Glycoproteins could be new antibody targets.
Cheng’s group also presented data showing that 35 antibodies, selected from the Marasco single-chain Fv phage display library, caused a 30–40% inhibition of FAP enzymatic activity in vitro. “Antibodies have an inherent advantage in that they can specifically target FAP and not other proteins”, notes Cheng. “Although the antibody we have studied so far has had only modest results, we are making some modifications to our existing antibodies to improve the molecule’s ability to block FAP’s action.” The researchers hope that further animal studies involving modified versions of these antibodies will provide additional insights into the potential of this new antibodydirected therapy. Rachel Liddle
THE LANCET Oncology Vol 5 May 2004
For personal use. Only reproduce with permission from The Lancet.
http://oncology.thelancet.com
266
[way in which the patients were selected. In particular, this method of classifying patients] was a decisive feature of this trial compared with other studies that have not found any advantage between high-dose and conventional chemotherapy”, argues Schmitz.
This new study also has another limitation—an inadequate description of the type of treatment used for patients who relapsed: “We simply don’t know what happened to patients who relapsed after conventional or high-dose therapy”, concludes Schmitz. Khabir Ahmad
FAP-blocking antibodies offer new therapy Antibodies that block the enzymatic activity of a tumour-promoting protein could offer a new anticancer therapy, US investigators claim. Inhibiting the catalytic activity of a membrane glycoprotein called fibroblast activation protein (FAP), which is selectively expressed in about 90% of all solid tumours, results in fewer tumours and smaller lesions in mice injected with cells containing defective FAP, reported Jonathan Cheng and colleagues (Fox Chase Cancer Center, Philadelphia, PA, USA) at the annual meeting of the American Association for Cancer Research (Orlando, FL, USA; March 27–31, 2004). Previous studies by the investigators have shown that FAP is selectively expressed in epithelial carcinoma cells, stimulating tumour growth. However, until now, the team were unsure how the integral membrane glycoprotein achieved this. “Animal studies have shown that producing lots of FAP in the tumour microenvironment makes the cancer grow faster”, says Cheng. “We are now learning more about how FAP does that.” To investigate whether the integral membrane glycoprotein’s dipeptidyl peptidase (DPP) activity was crucial for tumour growth, the researchers produced HEK293 cells transfected with FAP that lacked catalytic activity. Mice were then given subcutaneous injections of HEK293 cells containing the FAP enzymatic mutant, the wildtype FAP, or vector alone to act as a control. Mice that received the catalysisdeficient mutant produced tumours
half the size of those found in mice given the wildtype FAP. In addition, although all mice injected with wildtype FAP developed tumours, only two-thirds of mice given mutant FAP were found to have tumours—a proportion similar to that seen in the vector-only group.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
© Alfred Pasieka/Science Photo Library
Adults with newly diagnosed, aggressive non-Hodgkin lymphoma who receive intensive chemotherapy plus haemopoietic stem-cell transplantation have a better 5 year event-free survival than do patients who receive CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; N Engl J Med 2004; 350: 1287–95). “Our findings are important because they show that CHOP can no longer be regarded as the standard treatment for such patients”, explains Noel Milpied (University Hospital of Nantes, France). 197 patients (aged 15–60 years) who had aggressive lymphoma and a low, low–intermediate, or high– intermediate risk of death were given either high-dose chemotherapy plus stem-cell transplantation or CHOP chemotherapy. Based on the entire cohort, patients in the high-dose therapy group had a significantly higher event-free survival at 5 years compared with patients in the CHOP group (55% vs 37%). However, the overall survival of the two groups at 5 years was not significantly different. Among patients with a high–intermediate risk, eventfree survival and overall survival were significantly higher for the group given high-dose therapy than for those given CHOP (56% vs 28% and 74% vs 44%, respectively). “This is a well-conducted phase III trial and the results are important”, notes Norbert Schmitz (University of Kiel, Germany). However, he cautions that there are several aspects that need careful consideration: first, the trial included 15 patients with anaplastic lymphoma, which usually has a better prognosis than the more common diffuse large B-cell lymphoma. Second, “there were 23 patients who had diffuse, aggressive unclassifiable lymphoma—a subentity that I do not know how to judge”, Schmitz adds. In addition, Schmitz points out that this is the only study that has excluded high-risk patients in favour of the low, low–intermediate, or high–intermediate risk of death method of classification. “The finding that there was no difference in overall survival in any subgroup except the high–intermediate group may be because of the
Glycoproteins could be new antibody targets.
Cheng’s group also presented data showing that 35 antibodies, selected from the Marasco single-chain Fv phage display library, caused a 30–40% inhibition of FAP enzymatic activity in vitro. “Antibodies have an inherent advantage in that they can specifically target FAP and not other proteins”, notes Cheng. “Although the antibody we have studied so far has had only modest results, we are making some modifications to our existing antibodies to improve the molecule’s ability to block FAP’s action.” The researchers hope that further animal studies involving modified versions of these antibodies will provide additional insights into the potential of this new antibodydirected therapy. Rachel Liddle
THE LANCET Oncology Vol 5 May 2004
For personal use. Only reproduce with permission from The Lancet.
http://oncology.thelancet.com