CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

被引：418

作者：

Spiegel, Jay Y. ^{[1
]}

Patel, Shabnum ^{[2
]}

Muffly, Lori ^{[1
,2
]}

Hossain, Nasheed M. ^{[3
]}

Oak, Jean ^{[4
]}

Baird, John H. ^{[1
]}

Frank, Matthew J. ^{[1
]}

Shiraz, Parveen ^{[1
]}

Sahaf, Bita ^{[2
]}

Craig, Juliana ^{[1
]}

Iglesias, Maria ^{[1
]}

Younes, Sheren ^{[4
]}

Natkunam, Yasodha ^{[4
]}

Ozawa, Michael G. ^{[4
]}

Yang, Eric ^{[4
]}

Tamaresis, John ^{[5
]}

Chinnasamy, Harshini ^{[2
]}

Ehlinger, Zach ^{[2
]}

Reynolds, Warren ^{[2
]}

Lynn, Rachel ^{[2
,12
]}

Rotiroti, Maria Caterina ^{[6
]}

Gkitsas, Nikolaos ^{[2
]}

Arai, Sally ^{[1
]}

Johnston, Laura ^{[1
]}

Lowsky, Robert ^{[1
]}

Majzner, Robbie G. ^{[2
,6
]}

Meyer, Everett ^{[1
]}

Negrin, Robert S. ^{[1
]}

Rezvani, Andrew R. ^{[1
]}

Sidana, Surbhi ^{[1
]}

Shizuru, Judith ^{[1
]}

Weng, Wen-Kai ^{[1
]}

Mullins, Chelsea ^{[7
]}

Jacob, Allison ^{[7
]}

Kirsch, Ilan ^{[7
]}

Bazzano, Magali ^{[8
]}

Zhou, Jing ^{[8
]}

Mackay, Sean ^{[8
]}

Bornheimer, Scott J. ^{[9
]}

Schultz, Liora ^{[2
,6
,10
]}

Ramakrishna, Sneha ^{[2
,6
]}

Davis, Kara L. ^{[2
,6
]}

Kong, Katherine A. ^{[2
]}

Shah, Nirali N. ^{[10
]}

Qin, Haiying ^{[10
]}

Fry, Terry ^{[10
,11
]}

Feldman, Steven ^{[2
]}

Mackall, Crystal L. ^{[2
,6
]}

Miklos, David B. ^{[1
,2
]}

机构：

[1] Stanford Univ, Div Blood & Marrow Transplantat & Cellular Therap, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Stanford Canc Inst, Ctr Canc Cell Therapy, Sch Med, Stanford, CA 94305 USA

[3] Loyola Univ Med Ctr, Div Hematol Oncol, Chicago, IL USA

[4] Stanford Univ, Dept Clin Pathol, Sch Med, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Biomed Data Sci, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Pediat Hematol Oncol, Sch Med, Stanford, CA 94305 USA

[7] Adapt Biotechnol, Seattle, WA USA

[8] IsoPlexis, Brantford, CT USA

[9] BD Biosci, San Jose, CA USA

[10] NIH, Pediat Oncol Branch Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA

[11] Univ Colorado Anschutz & Childrens Hosp Colorado, Dept Pediat Hematol Oncol, Denver, CO USA

[12] Lyell Immunopharma, San Francisco, CA USA

来源：

NATURE MEDICINE | 2021年 / 27卷 / 08期

基金：

美国国家卫生研究院;

关键词：

SURFACE-ANTIGEN; TUMOR-ANTIGEN; RECEPTOR; EFFICACY; LYMPHOMA; THERAPY; REMISSIONS; EXPRESSION; EXPANSION; ESCAPE;

D O I：

10.1038/s41591-021-01436-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

引用

页码：1419 / +

页数：27

共 70 条

[1] 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 [J].

Abramson, Jeremy S. ;

Palomba, Maria Lia ;

Gordon, Leo I. ;

Lunning, Matthew A. ;

Wang, Michael L. ;

Arnason, Jon E. ;

Mehta, Amitkumar ;

Purev, Enkhtsetseg ;

Maloney, David G. ;

Andreadis, Charalambos ;

Sehgal, Alison R. ;

Solomon, Scott R. ;

Ghosh, Nilanjan ;

Albertson, Tina ;

Garcia, Jacob ;

Kostic, Ana ;

Li, Daniel ;

Kim, Yeonhee ;

Siddiqi, Tanya .

BLOOD, 2019, 134

[2] T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma [J].

Ali, Syed Abbas ;

Shi, Victoria ;

Maric, Irina ;

Wang, Michael ;

Stroncek, David F. ;

Rose, Jeremy J. ;

Brudno, Jennifer N. ;

Stetler-Stevenson, Maryalice ;

Feldman, Steven A. ;

Hansen, Brenna G. ;

Fellowes, Vicki S. ;

Hakim, Frances T. ;

Gress, Ronald E. ;

Kochenderfer, James N. .

BLOOD, 2016, 128 (13) :1688-1700

[3] Phase I Study of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-Cell Therapy Targeting CD19 and CD22, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia Study [J].

Amrolia, Persis J. ;

Wynn, Robert ;

Hough, Rachael E. ;

Vora, Ajay ;

Bonney, Denise ;

Veys, Paul ;

Chiesa, Robert ;

Rao, Kanchan ;

Clark, Liz ;

Al-Hajj, Muhammad ;

Cordoba, Shaun P. ;

Onuoha, Shimobi ;

Kotsopoulou, Ekaterini ;

Khokhar, Nushmia Z. ;

Pule, Martin ;

Peddareddigari, Vijay G. R. .

BLOOD, 2019, 134

[4] Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19 [J].

Asnani, Mukta ;

Hayer, Katharina E. ;

Naqvi, Ammar S. ;

Zheng, Sisi ;

Yang, Scarlett Y. ;

Oldridge, Derek ;

Ibrahim, Fadia ;

Maragkakis, Manolis ;

Gazzara, Matthew R. ;

Black, Kathryn L. ;

Bagashev, Asen ;

Taylor, Deanne ;

Mourelatos, Zissimos ;

Grupp, Stephan A. ;

Barrett, David ;

Maris, John M. ;

Sotillo, Elena ;

Barash, Yoseph ;

Thomas-Tikhonenko, Andrei .

LEUKEMIA, 2020, 34 (04) :1202-1207

[5] CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum [J].

Bagashev, Asen ;

Sotillo, Elena ;

Tang, Chih-Hang Anthony ;

Black, Kathryn L. ;

Perazzelli, Jessica ;

Seeholzer, Steven H. ;

Argon, Yair ;

Barrett, David M. ;

Grupp, Stephan A. ;

Hu, Chih-Chi Andrew ;

Thomas-Tikhonenko, Andrei .

MOLECULAR AND CELLULAR BIOLOGY, 2018, 38 (21)

[6] CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma [J].

Baird, John H. ;

Frank, Matthew J. ;

Craig, Juliana ;

Patel, Shabnum ;

Spiegel, Jay Y. ;

Sahaf, Bita ;

Oak, Jean S. ;

Younes, Sheren F. ;

Ozawa, Michael G. ;

Yang, Eric ;

Natkunam, Yasodha ;

Tamaresis, John ;

Ehlinger, Zachary ;

Reynolds, Warren D. ;

Arai, Sally ;

Johnston, Laura ;

Lowsky, Robert ;

Meyer, Everett ;

Negrin, Robert S. ;

Rezvani, Andrew R. ;

Shiraz, Parveen ;

Sidana, Surbhi ;

Weng, Wen-Kai ;

Davis, Kara L. ;

Ramakrishna, Sneha ;

Schultz, Liora ;

Mullins, Chelsea ;

Jacob, Allison ;

Kirsch, Ilan ;

Feldman, Steven A. ;

Mackall, Crystal L. ;

Miklos, David B. ;

Muffly, Lori .

BLOOD, 2021, 137 (17) :2321-2325

[7] Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma [J].

Bielamowicz, Kevin ;

Fousek, Kristen ;

Byrd, Tiara T. ;

Samaha, Hebatalla ;

Mukherjee, Malini ;

Aware, Nikita ;

Wu, Meng-Fen ;

Orange, Jordan S. ;

Sumazin, Pavel ;

Man, Tsz-Kwong ;

Joseph, Sujith K. ;

Hegde, Meenakshi ;

Ahmed, Nabil .

NEURO-ONCOLOGY, 2018, 20 (04) :506-518

[8] Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia [J].

Blaeschke, Franziska ;

Stenger, Dana ;

Kaeuferle, Theresa ;

Willier, Semjon ;

Lotfi, Ramin ;

Kaiser, Andrew Didier ;

Assenmacher, Mario ;

Doering, Michaela ;

Feucht, Judith ;

Feuchtinger, Tobias .

CANCER IMMUNOLOGY IMMUNOTHERAPY, 2018, 67 (07) :1053-1066

[9] Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification [J].

Cheson, Bruce D. ;

Fisher, Richard I. ;

Barrington, Sally F. ;

Cavalli, Franco ;

Schwartz, Lawrence H. ;

Zucca, Emanuele ;

Lister, T. Andrew .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (27) :3059-+

[10] Analytical evaluation of the clonoSEQ Assay for establishing measurable (minimal) residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma [J].

Ching, Travers ;

Duncan, Megan E. ;

Newman-Eerkes, Tera ;

McWhorter, Mollie M. E. ;

Tracy, Jeffrey M. ;

Steen, Michelle S. ;

Brown, Ryan P. ;

Venkatasubbarao, Srivatsa ;

Akers, Nicholas K. ;

Vignali, Marissa ;

Moorhead, Martin E. ;

Watson, Drew ;

Emerson, Ryan O. ;

Mann, Tobias P. ;

Cimler, B. Melina ;

Swatkowski, Pamela L. ;

Kirsch, Ilan R. ;

Sang, Charles ;

Robins, Harlan S. ;

Howie, Bryan ;

Sherwood, Anna .

BMC CANCER, 2020, 20 (01)

← 1 2 3 4 5 6 7 →