難治性B細胞癌に対するCD19/CD22標的CAR-T免疫療法の臨床効果

//Brief communication//---
 As cell-based therapy, chimeric antigen receptor T cell(2-11), NK cell(12) targeting CD19 is the candidate for the patient with B cell malignancies relapsed or refractory against current chemotherapy. However, in also CAR-T cell therapy, 30-95% of the patients in B cell acute lymphoblastic leukemia experience relapses due to (acquired or intrinsic) loss of cell surface CD19(13). To make CAR-T cell therapy effective, high density target antigen expression is needed(14-18). Therefore, the target antigen aside from CD19 needs to be found, and CD22 is one of the candidates due to expression on most B-lineage malignancies(19-23). However, CD22 target CAR-T cell entails relapse like CD19 target one.
Jay Y. Spiegel, Shabnum Patel, Lori Muffly et al, analyze the effectiveness of CD19, CD22 bispecific target CAR-T cell for the patient with the refractory large B cell lymphoma or B cell acute lymphoblastic leukemia for durable immune response(1). However, bispecific CAR-T cell therapy cannot show significant positive clinical effect due to insufficient CD22 antigen function. In this study, it is difficult to get synergistic effect by bispecific antigen. Therefore, progression free survival of bispecific CAR-T antigen is similar to monospecific (CD19) antigen in refractory large B cell lymphoma. CAR-T cell bioengineering has much room to be technologically improved as follows(#1-4).
(#1): Prevention of tonic signaling(24).
(#2): Optimizing hinge length(25,26).
(#3): Hinge/transmembrane domain(27).  
(#4): Optimizing the distance between the target epitope and tumor cell membrane(20,28,29).
In the case where different antigen is expressed on the surface of T cell, some interactions between antigens and geometric issue including shielding of CD22 epitope by CD19 receptor(?) may limit functionality. Technological challenge may become high and complex in bispecific antigen compared to monospecific one.
 
(Reference)
(1)
Jay Y. Spiegel, Shabnum Patel, Lori Muffly, Nasheed M. Hossain, Jean Oak, John H. Baird, Matthew J. Frank, Parveen Shiraz, Bita Sahaf, Juliana Craig, Maria Iglesias, Sheren Younes, Yasodha Natkunam, Michael G. Ozawa, Eric Yang, John Tamaresis, Harshini Chinnasamy, Zach Ehlinger, Warren Reynolds, Rachel Lynn, Maria Caterina Rotiroti, Nikolaos Gkitsas, Sally Arai, Laura Johnston, Robert Lowsky, Robbie G. Majzner, Everett Meyer, Robert S. Negrin, Andrew R. Rezvani, Surbhi Sidana, Judith Shizuru, Wen-Kai Weng, Chelsea Mullins, Allison Jacob, Ilan Kirsch, Magali Bazzano, Jing Zhou, Sean Mackay, Scott J. Bornheimer, Liora Schultz, Sneha Ramakrishna, Kara L. Davis, Katherine A. Kong, Nirali N. Shah, Haiying Qin, Terry Fry, Steven Feldman, Crystal L. Mackall & David B. Miklos
CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
Nature Medicine (2021)
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Author information
Author notes
Rachel Lynn
Present address: Lyell Immunopharma, San Francisco, CA, USA
These authors contributed equally; Jay Y. Spiegel, Shabnum Patel, Lori Muffly.
These authors jointly supervised this work: Steven Feldman, Crystal Mackall, David B. Miklos.
Affiliations
Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA
Jay Y. Spiegel, Lori Muffly, John H. Baird, Matthew J. Frank, Parveen Shiraz, Juliana Craig, Maria Iglesias, Sally Arai, Laura Johnston, Robert Lowsky, Everett Meyer, Robert S. Negrin, Andrew R. Rezvani, Surbhi Sidana, Judith Shizuru, Wen-Kai Weng & David B. Miklos
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
Shabnum Patel, Lori Muffly, Bita Sahaf, Harshini Chinnasamy, Zach Ehlinger, Warren Reynolds, Rachel Lynn, Nikolaos Gkitsas, Robbie G. Majzner, Liora Schultz, Sneha Ramakrishna, Kara L. Davis, Katherine A. Kong, Steven Feldman, Crystal L. Mackall & David B. Miklos
Division of Hematology/Oncology, Loyola University Medical Center, Chicago, IL, USA
Nasheed M. Hossain
Department of Clinical Pathology, Stanford University School of Medicine, Stanford, CA, USA
Jean Oak, Sheren Younes, Yasodha Natkunam, Michael G. Ozawa & Eric Yang
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
John Tamaresis
Department of Pediatrics–Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA
Maria Caterina Rotiroti, Robbie G. Majzner, Liora Schultz, Sneha Ramakrishna, Kara L. Davis & Crystal L. Mackall
Adaptive Biotechnologies, Seattle, WA, USA
Chelsea Mullins, Allison Jacob & Ilan Kirsch
IsoPlexis, Brantford, CT, USA
Magali Bazzano, Jing Zhou & Sean Mackay
BD Biosciences, San Jose, CA, USA
Scott J. Bornheimer
Pediatric Oncology Branch Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
Liora Schultz, Nirali N. Shah, Haiying Qin & Terry Fry
Department of Pediatrics–Hematology/Oncology, University of Colorado Anschutz and Children’s Hospital Colorado, Denver, CO, USA
Terry Fry
(2)
Turtle, C. J. et al.
CD19 CAR-T cells of defined CD4 + :CD8 +  composition in adult B cell ALL patients.
J. Clin. Invest. 126, 2123–2138 (2016).
(3)
Locke, F. L. et al.
Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial.
Lancet Oncol. 20, 31–42 (2019).
(4)
Neelapu, S. S. et al.
Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.
N. Engl. J. Med. 377, 2531–2544 (2017).
(5)
Schuster, S. J. et al.
Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.
N. Engl. J. Med. 380, 45–56 (2019).
(6)
Hay, K. A. et al.
Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy.
Blood 133, 1652–1663 (2019).
(7)
Maude, S. L. et al.
Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.
N. Engl. J. Med. 378, 439–448 (2018).
(8)
Park, J. H. et al.
Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia.
N. Engl. J. Med. 378, 449–459 (2018).
(9)
Nastoupil, L. J.
Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium.
J. Clin. Oncol. 38, 3119–3128 (2020).
(10)
Abramson, J. S. et al.
Pivotal safety and efficacy results from Transcend   NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel  (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas.
Blood 134,  241 (2019).
(11)
Lee, D. W. et al.
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.
Lancet 385, 517–528 (2015).
(12)
Liu, E. et al.
Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors.
N. Engl. J. Med. 382, 545–553 (2020).
(13)
Majzner, R. G. & Mackall, C. L.
Tumor antigen escape from CAR T-cell therapy.
Cancer Discov. 8, 1219–1226 (2018).
(14)
Majzner, R. G. et al.
CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors.
Clin. Cancer Res. 25, 2560–2574 (2019).
(15)
Watanabe, K. et al.
Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8 +  T cells.
J. Immunol. 194, 911–920 (2015).
(16)
Hombach, A. A. et al.
Superior therapeutic index in lymphoma therapy: CD30 +  CD34 +  hematopoietic stem cells resist a chimeric antigen receptor T-cell attack.
Mol. Ther. 24, 1423–1434 (2016).
(17)
Walker, A. J. et al.
Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase.
Mol. Ther. 25, 2189–2201 (2017).
(18)
Majzner, R. G. et al.
Tuning the antigen density requirement for CAR T-cell activity.
Cancer Discov. 10, 702–723 (2020).
(19)
Shah, N. N. et al.
Characterization of CD22 expression in acute lymphoblastic leukemia.
Pediatr. Blood Cancer 62, 964–969 (2015).
(20)
Haso, W. et al.
Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia.
Blood 121, 1165–1174 (2013).
(21)
Tedder, T. F., Poe, J. C. & Haas, K. M.
CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction.
Adv. Immunol. 88, 1–50 (2005).
(22)
Raponi, S. et al.
Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk.
Lymphoma 52, 1098–1107 (2011).
(23)
Olejniczak, S. H., Stewart, C. C., Donohue, K. & Czuczman, M. S.
A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry.
Immunol. Invest. 35, 93–114 (2006).
(24)
Lynn, R. C. et al.
c-Jun overexpression in CAR T cells induces exhaustion resistance.
Nature 576, 293–300 (2019).
(25)
Guest, R. D. et al.
The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens.
J. Immunother. 28, 203–211 (2005).
(26)
Hudecek, M. et al.
Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells.
Clin. Cancer Res. 19, 3153–3164 (2013).
(27)
Majzner, R. G. et al.
Tuning the antigen density requirement for CAR T-cell activity.
Cancer Discov. 10, 702–723 (2020).
(28)
Long, A. H., Haso, W. M. & Orentas, R. J.
Lessons learned from a highly-active CD22-specific chimeric antigen receptor.
Oncoimmunology 2, e23621 (2013).
(29)
Li, D. et al.
Persistent polyfunctional chimeric antigen receptor T cells that target glypican 3 eliminate orthotopic hepatocellular carcinomas in mice.
Gastroenterology 158, 2250–2265.e20 (2020).