VOLUME
33
䡠
NUMBER
6
䡠
FEBRUARY
20
2015
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Are All Chimeric Antigen Receptors Created Equal? Jae H. Park and Renier J. Brentjens, Memorial Sloan Kettering Cancer Center, New York, NY See accompanying article on page 540
In the report accompanying this article, Kochenderfer et al1 discuss the efficacy of autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) in patients with relapsed diffuse large B-cell lymphoma. Although previous reports have demonstrated significant antitumor activity in low-grade B-cell malignancies and B-cell acute lymphoblastic leukemia (ALL),2-9 this is the first report to our knowledge to demonstrate the efficacy of CD19-targeted CAR T cells in patients with diffuse large B-cell lymphoma. A CAR is a recombinant receptor constructs composed of an extracellular single-chain variable fragment (scFv) derived from an antibody, linked to a transmembrane domain, which is further linked to one or more intracellular T-cell signaling domains (Fig 1). Because CARs combine the binding domain of an antibody and T-cell signaling moieties, they can redirect T-cell specificity to the tumor in an HLA-independent fashion and activate the CAR-modified T lymphocytes to lyse targeted tumor cells. Initial first-generation CARs were constructed through the fusion of an scFv-based antigen binding domain to an inert CD8 transmembrane domain, linked to a cytoplasmic signaling domain derived from the CD3- or Fc receptor ␥ chains (Fig 1). Although T cells expressing first-generation CARs effectively engaged the target antigens,10-12 limited T-cell proliferation and diminished cytolytic
First-generation CAR
Second-generation CAR
Third-generation CAR
mAB scFv TM domain
Hinge
CD3ζ or FCRγ One co-stimulatory domain (CD28, 4-1BB, OX-40)
Two co-stimulatory domains (CD28, 4-1BB, OX-40)
Fig 1. Structure of chimeric antigen receptors (CARs). First-generation CARs are composed of single-chain variable fragment (scFv) specific to tumorassociated antigen, fused to transmembrane (TM) domain, which is linked to cytoplasmic signaling domain of T-cell receptor (eg, CD3- or Fc receptor [FCR] ␥ chains). Second-generation CARs include costimulatory signaling domain (eg, CD28, 4-1BB, OX-40), and third-generation CARs contain tandem cytoplasmic signaling domains from two costimulatory receptors (eg, CD28-4-1BB, CD28OX40). Journal of Clinical Oncology, Vol 33, No 6 (February 20), 2015: pp 651-653
activities were observed because of the lack of T-cell costimulation.13,14 For optimal activation and proliferation, T cells require both T-cell receptor engagement and signaling (termed signal 1), as well as costimulatory signaling through costimulatory receptors (ie, CD28, 4-1BB, OX-40) on T cells binding to cognate ligands (ie, CD80/86, 4-1BBL, OX-40L) expressed either by the targeted tumor cell or professional antigen-presenting cells (termed signal 2). To overcome the lack of T-cell costimulation (signal 2), firstgeneration CARs were further modified by incorporating the cytoplasmic signaling domains of T-cell costimulatory receptors. These second-generation CARs (Fig 1) enhanced signaling strength and persistence of the modified T cells, leading to superior antitumor activity.13,15-17 However, it remains unclear whether any particular second-generation CAR design is superior to the other. In one study by Carpenito et al,18 both CD28- and 4-1BB– based CAR-modified T cells had the same antitumor activity, but the 4-1BB– based CAR enhanced in vivo persistence of T cells. In contrast, another study failed to demonstrate any significant difference between CD28- and 4-1BB– based second-generation CARs with regard to proliferation, potency, antitumor efficacy, and persistence of the T cells.19 More recently, third-generation CARs containing tandem cytoplasmic signaling domains from two costimulatory receptors (Fig 1) were tested in certain mouse models,18-21 but clinical experience so far has been limited.22 Initial clinical results with first-generation CD19-targeted CAR-modified T cells were disappointing, but second-generation CAR-modified T cells displayed significantly enhanced expansion and persistence in patients with B-cell lymphoma.17,23 Using either CD28or 4-1BB– based second-generation CD19-specific CARs, investigators at Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania, and the National Cancer Institute published initial promising results of phase I clinical trials, reporting durable antitumor efficacy in patients with indolent B-cell malignancies, including chronic lymphocytic leukemia (CLL),2,4,7,8,17 and more recently reporting dramatic clinical responses in patients with relapsed B-cell ALL.5,6,8 These trials varied significantly with respect to infused T-cell product; CAR design, including scFv and costimulatory domains (CD28 v 4-1BB); means of gene transfer (retrovirus v lentivirus); ex vivo T-cell expansion; T-cell dose; intensity of conditioning chemotherapy; degree of tumor burden at the time of therapy; and age of the treated patient population. All of these variables make it difficult to compare results from one trial with those of another and the efficacy of one CAR T cell with that of another. © 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
651
Park and Brentjens
In general, there seem to be three principle parameters by which investigators consistently assess CAR T cells in the clinical setting. The first parameter is clinical efficacy. Both CD28- and 4-1BB– containing CD19-specific second-generation CAR-modified T cells have demonstrated striking antitumor efficacy in patients with low-grade and aggressive B-cell malignancies, as reported by the National Cancer Institute,3,3a the University of Pennsylvania,7-9a and MSKCC.4,6 The second parameter is CAR T-cell persistence. Prolonged B-cell aplasia and CAR T-cell persistence have been reported in patients treated with both 4-1BB– and CD28-based CAR-modified T cells.3,8,9 However, even in the setting of limited persistence, CAR T-cell therapy nonetheless seems perfectly capable of inducing complete long-term (⬎ 1 year) molecular remissions in the absence of further therapy.6 Therefore, the relevance of the optimal length of CAR T-cell persistence and consequently the optimal length of CAR T-cell persistence remains largely unknown. The third parameter relevant to CAR design is patient safety. The immune-mediated rejection of normal tissues, referred to as ontarget, off-tumor toxicity, can range from B-cell aplasia induced by CD19-targeted CARs that can be effectively managed with intravenous immunoglobulins to a fatal toxicity reported after infusion of CAR-modified T cells targeting ERBB2, which is expressed at low levels in normal tissues, including heart and pulmonary vasculatures.24 Therefore, the careful selection of a tumor-specific target is essential in the CAR design to reduce off-tumor toxicities. Another major safety concern with the use of CARs is cytokine release syndrome (CRS), a potentially life-threatening toxicity associated with elevation of proinflammatory cytokines, such as interleukin-6 and interferon gamma.3,6-8 The anti–interleukin-6 receptor antibody tociluzumab, with or without a steroid, has been shown to effectively and quickly reverse CRS6,8 and has become a critical part of the CRS management algorithm in clinical trials using CAR T cells. REFERENCES 1. Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-549, 2015 2. Kochenderfer JN, Wilson WH, Janik JE, et al: Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116:4099-4102, 2010 3. Kochenderfer JN, Dudley ME, Feldman SA, et al: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:2709-2720, 2012 3a. Lee DW, Kochenderfer JN, StetlerStevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: A phase I dose-escalation trial. Lancet [epub ahead of print on October 10, 2014] 4. Brentjens RJ, Rivière I, Park JH, et al: Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817-4828, 2011 652
© 2015 by American Society of Clinical Oncology
Unfortunately, varying definitions of CRS used to define toxicities in the published clinical trials,3a,6,9a it is currently not possible to reasonably assess if one CAR design is safer than another. Furthermore, investigators at MSKCC have reported a strong correlation between the severity of CRS and the tumor burden in patients with ALL.5,6 To this end, future published studies from all centers conducting clinical trials in this field need to carefully examine whether the development or degree of CRS is related to CAR design, tumor burden at the time of therapy, both, or neither. CD19-specific second-generation CAR-modified T cells have now demonstrated significant antitumor efficacy across multiple B-cell hematologic malignancies and serve as a strong proof of principle for this novel immune-based approach to cancer therapy across different tumor types. Whether one CAR design is superior to another is difficult to assess at this time, given the limited available published clinical trial data and heterogenous treated patient populations with differing age groups and disease prognosis. Are all CARs created equal? Perhaps they are. However, publication of larger cohorts of more homogeneous treated patient populations across multiple clinical trials at different centers with the uniformed categorization of toxicities will be required to answer this question in a sound and meaningful manner. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
5. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra138, 2013 6. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra225, 2014 7. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725-733, 2011 8. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013 9. Kalos M, Levine BL, Porter DL, et al: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73, 2011 9a. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014 10. Cooper LJ, Topp MS, Serrano LM, et al: T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-Blineage leukemia effect. Blood 101:1637-1644, 2003 11. Brocker T, Karjalainen K: Signals through T cell receptor-zeta chain alone are insufficient to prime
resting T lymphocytes. J Exp Med 181:1653-1659, 1995 12. Brentjens RJ, Latouche JB, Santos E, et al: Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9:279-286, 2003 13. Brentjens RJ, Santos E, Nikhamin Y, et al: Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13:5426-5435, 2007 14. Till BG, Jensen MC, Wang J, et al: Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112: 2261-2271, 2008 15. Milone MC, Fish JD, Carpenito C, et al: Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17:1453-1464, 2009 16. Kowolik CM, Topp MS, Gonzalez S, et al: CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66:10995-11004, 2006 17. Savoldo B, Ramos CA, Liu E, et al: CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121:1822-1826, 2011 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
Are All CARs Created Equal?
18. Carpenito C, Milone MC, Hassan R, et al: Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A 106:3360-3365, 2009 19. Zhong XS, Matsushita M, Plotkin J, et al: Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8⫹ T cellmediated tumor eradication. Mol Ther 18:413-420, 2010 20. Tammana S, Huang X, Wong M, et al: 4-1BB and CD28 signaling plays a synergistic role in redirecting
umbilical cord blood T cells against B-cell malignancies. Hum Gene Ther 21:75-86, 2010 21. Wang J, Jensen M, Lin Y, et al: Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 18:712-725, 2007 22. Till BG, Jensen MC, Wang J, et al: CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: Pilot clinical trial results. Blood 119:3940-3950, 2012 23. Jensen MC, Popplewell L, Cooper LJ, et al: Antitransgene rejection responses contribute to at-
tenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16:1245-1256, 2010 24. Morgan RA, Yang JC, Kitano M, et al: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18: 843-851, 2010
DOI: 10.1200/JCO.2014.57.5472; published online ahead of print at www.jco.org on January 20, 2015
■ ■ ■
Simplify Your Search With JCO Subject Collections Subject Collections are topic-specific archives of articles published on jco.org that make it easy for you to find the research you need. Instead of random, time-consuming keyword searches, JCO Subject Collections allow you to quickly browse your interest areas for articles on specific diseases and treatments. Best of all, by signing up for Collection Alerts, you’ll receive e-mail notification whenever JCO publishes an article in your interest area. Sign up today at jco.org/collections.
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
653
Park and Brentjens
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Are All Chimeric Antigen Receptors Created Equal? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jae H. Park Consulting or Advisory Role: Amgen Research Funding: Juno Therapeutics Renier J. Brentjens Employment: Juno Therapeutics Stock or Other Ownership: Juno Therapeutics
© 2015 by American Society of Clinical Oncology
Honoraria: Daiichi Sankyo Consulting or Advisory Role: Daiichi Sankyo, Juno Therapeutics Research Funding: Juno Therapeutics Patents, Royalties, Other Intellectual Property: CD19-targeted CAR Travel, Accommodations, Expenses: Juno Therapeutics
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
33
䡠
NUMBER
6
䡠
FEBRUARY
20
2015
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Are All Chimeric Antigen Receptors Created Equal? Jae H. Park and Renier J. Brentjens, Memorial Sloan Kettering Cancer Center, New York, NY See accompanying article on page 540
In the report accompanying this article, Kochenderfer et al1 discuss the efficacy of autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) in patients with relapsed diffuse large B-cell lymphoma. Although previous reports have demonstrated significant antitumor activity in low-grade B-cell malignancies and B-cell acute lymphoblastic leukemia (ALL),2-9 this is the first report to our knowledge to demonstrate the efficacy of CD19-targeted CAR T cells in patients with diffuse large B-cell lymphoma. A CAR is a recombinant receptor constructs composed of an extracellular single-chain variable fragment (scFv) derived from an antibody, linked to a transmembrane domain, which is further linked to one or more intracellular T-cell signaling domains (Fig 1). Because CARs combine the binding domain of an antibody and T-cell signaling moieties, they can redirect T-cell specificity to the tumor in an HLA-independent fashion and activate the CAR-modified T lymphocytes to lyse targeted tumor cells. Initial first-generation CARs were constructed through the fusion of an scFv-based antigen binding domain to an inert CD8 transmembrane domain, linked to a cytoplasmic signaling domain derived from the CD3- or Fc receptor ␥ chains (Fig 1). Although T cells expressing first-generation CARs effectively engaged the target antigens,10-12 limited T-cell proliferation and diminished cytolytic
First-generation CAR
Second-generation CAR
Third-generation CAR
mAB scFv TM domain
Hinge
CD3ζ or FCRγ One co-stimulatory domain (CD28, 4-1BB, OX-40)
Two co-stimulatory domains (CD28, 4-1BB, OX-40)
Fig 1. Structure of chimeric antigen receptors (CARs). First-generation CARs are composed of single-chain variable fragment (scFv) specific to tumorassociated antigen, fused to transmembrane (TM) domain, which is linked to cytoplasmic signaling domain of T-cell receptor (eg, CD3- or Fc receptor [FCR] ␥ chains). Second-generation CARs include costimulatory signaling domain (eg, CD28, 4-1BB, OX-40), and third-generation CARs contain tandem cytoplasmic signaling domains from two costimulatory receptors (eg, CD28-4-1BB, CD28OX40). Journal of Clinical Oncology, Vol 33, No 6 (February 20), 2015: pp 651-653
activities were observed because of the lack of T-cell costimulation.13,14 For optimal activation and proliferation, T cells require both T-cell receptor engagement and signaling (termed signal 1), as well as costimulatory signaling through costimulatory receptors (ie, CD28, 4-1BB, OX-40) on T cells binding to cognate ligands (ie, CD80/86, 4-1BBL, OX-40L) expressed either by the targeted tumor cell or professional antigen-presenting cells (termed signal 2). To overcome the lack of T-cell costimulation (signal 2), firstgeneration CARs were further modified by incorporating the cytoplasmic signaling domains of T-cell costimulatory receptors. These second-generation CARs (Fig 1) enhanced signaling strength and persistence of the modified T cells, leading to superior antitumor activity.13,15-17 However, it remains unclear whether any particular second-generation CAR design is superior to the other. In one study by Carpenito et al,18 both CD28- and 4-1BB– based CAR-modified T cells had the same antitumor activity, but the 4-1BB– based CAR enhanced in vivo persistence of T cells. In contrast, another study failed to demonstrate any significant difference between CD28- and 4-1BB– based second-generation CARs with regard to proliferation, potency, antitumor efficacy, and persistence of the T cells.19 More recently, third-generation CARs containing tandem cytoplasmic signaling domains from two costimulatory receptors (Fig 1) were tested in certain mouse models,18-21 but clinical experience so far has been limited.22 Initial clinical results with first-generation CD19-targeted CAR-modified T cells were disappointing, but second-generation CAR-modified T cells displayed significantly enhanced expansion and persistence in patients with B-cell lymphoma.17,23 Using either CD28or 4-1BB– based second-generation CD19-specific CARs, investigators at Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania, and the National Cancer Institute published initial promising results of phase I clinical trials, reporting durable antitumor efficacy in patients with indolent B-cell malignancies, including chronic lymphocytic leukemia (CLL),2,4,7,8,17 and more recently reporting dramatic clinical responses in patients with relapsed B-cell ALL.5,6,8 These trials varied significantly with respect to infused T-cell product; CAR design, including scFv and costimulatory domains (CD28 v 4-1BB); means of gene transfer (retrovirus v lentivirus); ex vivo T-cell expansion; T-cell dose; intensity of conditioning chemotherapy; degree of tumor burden at the time of therapy; and age of the treated patient population. All of these variables make it difficult to compare results from one trial with those of another and the efficacy of one CAR T cell with that of another. © 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
651
Park and Brentjens
In general, there seem to be three principle parameters by which investigators consistently assess CAR T cells in the clinical setting. The first parameter is clinical efficacy. Both CD28- and 4-1BB– containing CD19-specific second-generation CAR-modified T cells have demonstrated striking antitumor efficacy in patients with low-grade and aggressive B-cell malignancies, as reported by the National Cancer Institute,3,3a the University of Pennsylvania,7-9a and MSKCC.4,6 The second parameter is CAR T-cell persistence. Prolonged B-cell aplasia and CAR T-cell persistence have been reported in patients treated with both 4-1BB– and CD28-based CAR-modified T cells.3,8,9 However, even in the setting of limited persistence, CAR T-cell therapy nonetheless seems perfectly capable of inducing complete long-term (⬎ 1 year) molecular remissions in the absence of further therapy.6 Therefore, the relevance of the optimal length of CAR T-cell persistence and consequently the optimal length of CAR T-cell persistence remains largely unknown. The third parameter relevant to CAR design is patient safety. The immune-mediated rejection of normal tissues, referred to as ontarget, off-tumor toxicity, can range from B-cell aplasia induced by CD19-targeted CARs that can be effectively managed with intravenous immunoglobulins to a fatal toxicity reported after infusion of CAR-modified T cells targeting ERBB2, which is expressed at low levels in normal tissues, including heart and pulmonary vasculatures.24 Therefore, the careful selection of a tumor-specific target is essential in the CAR design to reduce off-tumor toxicities. Another major safety concern with the use of CARs is cytokine release syndrome (CRS), a potentially life-threatening toxicity associated with elevation of proinflammatory cytokines, such as interleukin-6 and interferon gamma.3,6-8 The anti–interleukin-6 receptor antibody tociluzumab, with or without a steroid, has been shown to effectively and quickly reverse CRS6,8 and has become a critical part of the CRS management algorithm in clinical trials using CAR T cells. REFERENCES 1. Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-549, 2015 2. Kochenderfer JN, Wilson WH, Janik JE, et al: Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116:4099-4102, 2010 3. Kochenderfer JN, Dudley ME, Feldman SA, et al: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:2709-2720, 2012 3a. Lee DW, Kochenderfer JN, StetlerStevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: A phase I dose-escalation trial. Lancet [epub ahead of print on October 10, 2014] 4. Brentjens RJ, Rivière I, Park JH, et al: Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817-4828, 2011 652
© 2015 by American Society of Clinical Oncology
Unfortunately, varying definitions of CRS used to define toxicities in the published clinical trials,3a,6,9a it is currently not possible to reasonably assess if one CAR design is safer than another. Furthermore, investigators at MSKCC have reported a strong correlation between the severity of CRS and the tumor burden in patients with ALL.5,6 To this end, future published studies from all centers conducting clinical trials in this field need to carefully examine whether the development or degree of CRS is related to CAR design, tumor burden at the time of therapy, both, or neither. CD19-specific second-generation CAR-modified T cells have now demonstrated significant antitumor efficacy across multiple B-cell hematologic malignancies and serve as a strong proof of principle for this novel immune-based approach to cancer therapy across different tumor types. Whether one CAR design is superior to another is difficult to assess at this time, given the limited available published clinical trial data and heterogenous treated patient populations with differing age groups and disease prognosis. Are all CARs created equal? Perhaps they are. However, publication of larger cohorts of more homogeneous treated patient populations across multiple clinical trials at different centers with the uniformed categorization of toxicities will be required to answer this question in a sound and meaningful manner. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
5. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra138, 2013 6. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra225, 2014 7. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725-733, 2011 8. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013 9. Kalos M, Levine BL, Porter DL, et al: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73, 2011 9a. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014 10. Cooper LJ, Topp MS, Serrano LM, et al: T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-Blineage leukemia effect. Blood 101:1637-1644, 2003 11. Brocker T, Karjalainen K: Signals through T cell receptor-zeta chain alone are insufficient to prime
resting T lymphocytes. J Exp Med 181:1653-1659, 1995 12. Brentjens RJ, Latouche JB, Santos E, et al: Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9:279-286, 2003 13. Brentjens RJ, Santos E, Nikhamin Y, et al: Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13:5426-5435, 2007 14. Till BG, Jensen MC, Wang J, et al: Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112: 2261-2271, 2008 15. Milone MC, Fish JD, Carpenito C, et al: Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17:1453-1464, 2009 16. Kowolik CM, Topp MS, Gonzalez S, et al: CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66:10995-11004, 2006 17. Savoldo B, Ramos CA, Liu E, et al: CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121:1822-1826, 2011 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
Are All CARs Created Equal?
18. Carpenito C, Milone MC, Hassan R, et al: Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A 106:3360-3365, 2009 19. Zhong XS, Matsushita M, Plotkin J, et al: Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8⫹ T cellmediated tumor eradication. Mol Ther 18:413-420, 2010 20. Tammana S, Huang X, Wong M, et al: 4-1BB and CD28 signaling plays a synergistic role in redirecting
umbilical cord blood T cells against B-cell malignancies. Hum Gene Ther 21:75-86, 2010 21. Wang J, Jensen M, Lin Y, et al: Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 18:712-725, 2007 22. Till BG, Jensen MC, Wang J, et al: CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: Pilot clinical trial results. Blood 119:3940-3950, 2012 23. Jensen MC, Popplewell L, Cooper LJ, et al: Antitransgene rejection responses contribute to at-
tenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16:1245-1256, 2010 24. Morgan RA, Yang JC, Kitano M, et al: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18: 843-851, 2010
DOI: 10.1200/JCO.2014.57.5472; published online ahead of print at www.jco.org on January 20, 2015
■ ■ ■
Simplify Your Search With JCO Subject Collections Subject Collections are topic-specific archives of articles published on jco.org that make it easy for you to find the research you need. Instead of random, time-consuming keyword searches, JCO Subject Collections allow you to quickly browse your interest areas for articles on specific diseases and treatments. Best of all, by signing up for Collection Alerts, you’ll receive e-mail notification whenever JCO publishes an article in your interest area. Sign up today at jco.org/collections.
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on March 7, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
653
Park and Brentjens
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Are All Chimeric Antigen Receptors Created Equal? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jae H. Park Consulting or Advisory Role: Amgen Research Funding: Juno Therapeutics Renier J. Brentjens Employment: Juno Therapeutics Stock or Other Ownership: Juno Therapeutics
© 2015 by American Society of Clinical Oncology
Honoraria: Daiichi Sankyo Consulting or Advisory Role: Daiichi Sankyo, Juno Therapeutics Research Funding: Juno Therapeutics Patents, Royalties, Other Intellectual Property: CD19-targeted CAR Travel, Accommodations, Expenses: Juno Therapeutics
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