- Email: [email protected]
Is another antibody conjugate against ALL needed?
Comment
Treatment of adults with acute lymphoblastic leukaemia, especially those with relapsed or refractory disease, is challenging, not only because of the high prevalence of drug resistance, but also because of their poor tolerance to chemotherapy. Hence, there is a clear need to develop targeted treatments. Antibodybased treatment is one of the promising strategies that has been recently developed, and several methods have been used to target surface antigens commonly expressed on leukaemic lymphoblasts (CD19, CD20, CD22, and CD52).1 Rituximab, an unconjugated antibody against CD20, is regularly used for the treatment of adult lymphomas; however, CD20 is variably expressed on acute lymphoblastic leukaemia blast cells. CD19 is uniformly expressed on B-lineage acute lymphoblastic leukaemia blast cells and represents an excellent therapeutic target. However, studies have shown the emergence of leukaemia cells that no longer express the targeted antigen, which has been a cause of subsequent relapse, suggesting a need to target other leukaemiaassociated molecules. The development of effective antibody-based treatments against CD22 is a welcome addition to the armamentarium. In comparison with CD19, the level of CD22 expression is lower in B-cell lineage acute lymphoblastic leukaemia, although it is more rapidly internalised after antibody binding.2 The unconjugated antibody epratuzumab has shown limited single-drug activity in B-lineage acute lymphoblastic leukaemia.3 The potency of antibodybased treatments can be markedly augmented by conjugation to toxic moieties or linkage to cells of the immune system that are capable of mediating cytotoxicity. In a phase 2 trial of the anti-CD22 conjugate inotuzumab ozogamicin,4 58% of patients had a complete response, but hepatotoxicity was commonly reported, the most severe of which was veno-occlusive disease after allogeneic stem cell transplantation. Clinical trials targeting CD22 are in progress with the recombinant immunotoxin moxetumomab pasudotox and with chimeric antigen receptor transduced T cells (NCT01891981, NCT02227108, and NCT02315612). Radioisotope antibody conjugates have several theoretical advantages over other antibody-targeted treatments. Internalisation is not needed for activity, www.thelancet.com/haematology Vol 2 March 2015
and bystander effects might occur. Thus, high doses of radiation can be delivered not only to leukaemic cells that express the target antigen, but also to blast cells in close proximity that might be antigen negative. Similarly, cells of the microenvironment that can mediate resistance to chemotherapy5 might also be effectively targeted. Most commonly, β-emitters have been used in radioimmunotherapy trials. In comparison with other β-emitting radioisotopes, yttrium 90 (⁹⁰Y) has a longer path length (5 mm), shorter half-life (2·5 days), and higher energy delivery (2·3 MeV β-energy). When targeted to haematopoietic cells to treat haematological malignancies, radioimmunoconjugate drugs are concentrated in the bone marrow, which can lead to a high incidence of severe, treatment-limiting myelosuppression. In The Lancet Haematology, Patrice Chevallier and colleagues6 report the results of a phase 1 trial of ⁹⁰Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed acute lymphoblastic leukaemia. This study represents one of the first trials of radioimmunotherapy in the setting of acute lymphoblastic leukaemia. Three of 17 patients achieved a complete response (one of whom had incomplete platelet recovery) that lasted 7–12 months. Not surprisingly, the most common severe and life-threatening (ie, grade 3 and 4) adverse events were pancytopenia and infections, with one case of dose-limiting bone marrow aplasia lasting 8 weeks noted at the highest dose level. The authors concluded that this treatment was active and well tolerated. This study highlights both the potential, but also the limitations, of radioimmunoconjugates in the treatment of leukaemia. Targeting acute lymphoblastic leukaemia blast cells can induce remissions in chemotherapyrefractory disease. However, concentration of high-dose radiation to haematopoietic tissues can cause severe, prolonged myelosuppression. Thus, pancytopenia and infections are anticipated. One approach to circumvent these side-effects is to use radioimmunotherapy as part of myeloablative conditioning in the context of haematopoietic stem cell transplantation.7 Other important potential risks include radiation-associated secondary myelodysplasia8 and damage to the bone marrow stroma resulting in hypoplasia or fibrosis.
PR. J. Bernard/CNRI/Science Photo Library
Is another antibody conjugate against ALL needed?
Published Online February 25, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00024-1 See Articles page e108
e87
Comment
Targeting CD22 might offer advantages over other lineage-restricted surface antigens. So far, loss of CD22 expression with targeted treatment has not been described.4 Furthermore, maintenance of CD22 expression in human acute lymphoblastic leukaemia murine xenografts that were established with limited numbers of blast cells suggests that CD22 might be a target on acute lymphoblastic leukaemia initiating stem cells.9 Ultimately, combinations that target several antigens will probably be needed to prevent or overcome relapse related to loss of antigen expression. Therefore, there probably remains a need for additional antibody conjugates against acute lymphoblastic leukaemia.
ASW has received research support, honoraria, and travel support from MedImmune; has received honoraria and travel support for serving on advisory boards from Spectrum and Kite Pharma; and holds a patent for methods of treating paediatric acute lymphoblastic leukaemia with an anti-CD22 immunotoxin. C-HP declares no competing interests. 1 2
3
4
5
6
*Alan S Wayne, Ching-Hon Pui Children’s Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA (ASW); Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA (CHP) [email protected]
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Ai J, Advani A. Current status of antibody therapy in ALL. Br J Haematol 2015; 168: 471–80. Du X, Beers R, Fitzgerald DJ, Pastan I. Differential cellular internalization of anti-CD19 and -CD22 immunotoxins results in different cytotoxic activity. Cancer Res 2008; 68: 6300–05. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study. J Clin Oncol 2008; 26: 3756–62. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 2013; 119: 2728–36. Ehsanipour EA, Sheng X, Behan JW, et al. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine. Cancer Res 2013; 73: 2998–3006. Chevallier P, Eugene T, Robillard N, et al. ⁹⁰Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study. Lancet Haematol 2015; published online February 25. http://dx.doi. org/10.1016/S2352-3026(15)00020-4. Matthews DC, Appelbaum FR, Eary JF, et al. Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood 1995; 85: 1122–31. Tarella C, Gianni AM. Myeloablative doses of yttrium-90-ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia. Cancer 2011; 117: 5074–84. Morisot S, Wayne AS, Bohana-Kashtan O, et al. High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias. Leukemia 2010; 24: 1859–66.
www.thelancet.com/haematology Vol 2 March 2015
Treatment of adults with acute lymphoblastic leukaemia, especially those with relapsed or refractory disease, is challenging, not only because of the high prevalence of drug resistance, but also because of their poor tolerance to chemotherapy. Hence, there is a clear need to develop targeted treatments. Antibodybased treatment is one of the promising strategies that has been recently developed, and several methods have been used to target surface antigens commonly expressed on leukaemic lymphoblasts (CD19, CD20, CD22, and CD52).1 Rituximab, an unconjugated antibody against CD20, is regularly used for the treatment of adult lymphomas; however, CD20 is variably expressed on acute lymphoblastic leukaemia blast cells. CD19 is uniformly expressed on B-lineage acute lymphoblastic leukaemia blast cells and represents an excellent therapeutic target. However, studies have shown the emergence of leukaemia cells that no longer express the targeted antigen, which has been a cause of subsequent relapse, suggesting a need to target other leukaemiaassociated molecules. The development of effective antibody-based treatments against CD22 is a welcome addition to the armamentarium. In comparison with CD19, the level of CD22 expression is lower in B-cell lineage acute lymphoblastic leukaemia, although it is more rapidly internalised after antibody binding.2 The unconjugated antibody epratuzumab has shown limited single-drug activity in B-lineage acute lymphoblastic leukaemia.3 The potency of antibodybased treatments can be markedly augmented by conjugation to toxic moieties or linkage to cells of the immune system that are capable of mediating cytotoxicity. In a phase 2 trial of the anti-CD22 conjugate inotuzumab ozogamicin,4 58% of patients had a complete response, but hepatotoxicity was commonly reported, the most severe of which was veno-occlusive disease after allogeneic stem cell transplantation. Clinical trials targeting CD22 are in progress with the recombinant immunotoxin moxetumomab pasudotox and with chimeric antigen receptor transduced T cells (NCT01891981, NCT02227108, and NCT02315612). Radioisotope antibody conjugates have several theoretical advantages over other antibody-targeted treatments. Internalisation is not needed for activity, www.thelancet.com/haematology Vol 2 March 2015
and bystander effects might occur. Thus, high doses of radiation can be delivered not only to leukaemic cells that express the target antigen, but also to blast cells in close proximity that might be antigen negative. Similarly, cells of the microenvironment that can mediate resistance to chemotherapy5 might also be effectively targeted. Most commonly, β-emitters have been used in radioimmunotherapy trials. In comparison with other β-emitting radioisotopes, yttrium 90 (⁹⁰Y) has a longer path length (5 mm), shorter half-life (2·5 days), and higher energy delivery (2·3 MeV β-energy). When targeted to haematopoietic cells to treat haematological malignancies, radioimmunoconjugate drugs are concentrated in the bone marrow, which can lead to a high incidence of severe, treatment-limiting myelosuppression. In The Lancet Haematology, Patrice Chevallier and colleagues6 report the results of a phase 1 trial of ⁹⁰Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed acute lymphoblastic leukaemia. This study represents one of the first trials of radioimmunotherapy in the setting of acute lymphoblastic leukaemia. Three of 17 patients achieved a complete response (one of whom had incomplete platelet recovery) that lasted 7–12 months. Not surprisingly, the most common severe and life-threatening (ie, grade 3 and 4) adverse events were pancytopenia and infections, with one case of dose-limiting bone marrow aplasia lasting 8 weeks noted at the highest dose level. The authors concluded that this treatment was active and well tolerated. This study highlights both the potential, but also the limitations, of radioimmunoconjugates in the treatment of leukaemia. Targeting acute lymphoblastic leukaemia blast cells can induce remissions in chemotherapyrefractory disease. However, concentration of high-dose radiation to haematopoietic tissues can cause severe, prolonged myelosuppression. Thus, pancytopenia and infections are anticipated. One approach to circumvent these side-effects is to use radioimmunotherapy as part of myeloablative conditioning in the context of haematopoietic stem cell transplantation.7 Other important potential risks include radiation-associated secondary myelodysplasia8 and damage to the bone marrow stroma resulting in hypoplasia or fibrosis.
PR. J. Bernard/CNRI/Science Photo Library
Is another antibody conjugate against ALL needed?
Published Online February 25, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00024-1 See Articles page e108
e87
Comment
Targeting CD22 might offer advantages over other lineage-restricted surface antigens. So far, loss of CD22 expression with targeted treatment has not been described.4 Furthermore, maintenance of CD22 expression in human acute lymphoblastic leukaemia murine xenografts that were established with limited numbers of blast cells suggests that CD22 might be a target on acute lymphoblastic leukaemia initiating stem cells.9 Ultimately, combinations that target several antigens will probably be needed to prevent or overcome relapse related to loss of antigen expression. Therefore, there probably remains a need for additional antibody conjugates against acute lymphoblastic leukaemia.
ASW has received research support, honoraria, and travel support from MedImmune; has received honoraria and travel support for serving on advisory boards from Spectrum and Kite Pharma; and holds a patent for methods of treating paediatric acute lymphoblastic leukaemia with an anti-CD22 immunotoxin. C-HP declares no competing interests. 1 2
3
4
5
6
*Alan S Wayne, Ching-Hon Pui Children’s Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA (ASW); Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA (CHP) [email protected]
e88
7
8
9
Ai J, Advani A. Current status of antibody therapy in ALL. Br J Haematol 2015; 168: 471–80. Du X, Beers R, Fitzgerald DJ, Pastan I. Differential cellular internalization of anti-CD19 and -CD22 immunotoxins results in different cytotoxic activity. Cancer Res 2008; 68: 6300–05. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study. J Clin Oncol 2008; 26: 3756–62. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 2013; 119: 2728–36. Ehsanipour EA, Sheng X, Behan JW, et al. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine. Cancer Res 2013; 73: 2998–3006. Chevallier P, Eugene T, Robillard N, et al. ⁹⁰Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study. Lancet Haematol 2015; published online February 25. http://dx.doi. org/10.1016/S2352-3026(15)00020-4. Matthews DC, Appelbaum FR, Eary JF, et al. Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood 1995; 85: 1122–31. Tarella C, Gianni AM. Myeloablative doses of yttrium-90-ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia. Cancer 2011; 117: 5074–84. Morisot S, Wayne AS, Bohana-Kashtan O, et al. High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias. Leukemia 2010; 24: 1859–66.
www.thelancet.com/haematology Vol 2 March 2015