Cord Blood Derived CAR-T Cells in Refractory/Relapsed B Cell Malignancies

AbstractChimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

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Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies

Blood ◽

10.1182/blood.2020006770 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jordan Gauthier ◽

Evandro D. Bezerra ◽

Alexandre V. Hirayama ◽

Salvatore Fiorenza ◽

Alyssa Sheih ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Severe Toxicity ◽

B Cell Malignancies ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Grade 3

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

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Efficacy and Long Term Survival of Genetically Modified T Cells Targeting CD19 in a Syngeneic Immune Competent Transgenic Murine Tumor Model Is Dependent on Prior Lymphodepleting Chemotherapy.

Blood ◽

10.1182/blood.v110.11.2754.2754 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2754-2754

Author(s):

James Lee ◽

Yan Nikhamin ◽

Gavin Imperato ◽

Adam Cohen ◽

Michel Sadelain ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Clinical Setting ◽

Peripheral Blood ◽

Tumor Model ◽

B Cell Malignancies ◽

Car T Cells ◽

Human T Cells ◽

Car T

Abstract T cells may be genetically modified ex vivo to target specific antigens by retroviral transduction of genes encoding chimeric antigen receptors (CARs). We have previously constructed a CAR, termed 19z1, specific for the CD19 antigen expressed on most B cell malignancies. Human T cells modified to express the 19z1 CAR specifically eradicate systemic human CD19+ tumors in SCID-Beige mice. However, these models are limited by the xenogeneic nature of the human T cells and tumor cells and the immune compromised state of the host. Here, we studied the biology of adoptively transferred 19z1+ T cells in a syngeneic immune competent murine model designed to better mimic the clinical setting of patients with B cell malignancies. We utilized transgenic C57BL6 mice which lack expression of mouse CD19 (mCD19−/−) and have a single copy of the human CD19 (hCD19+/−) gene (C57BL6(mCD19−/− hCD19+/−)) kindly provided by Dr. T. Tedder, Duke University. These mice are functionally immune-competent with hCD19 expression restricted to the B cell population. To assess whether syngeneic 19z1+ T cells were capable of eradicating normal hCD19+ B cells, we infused C57BL6(mCD19−/− hCD19+/−) mice with either 19z1+ or control prostate specific membrane antigen-targeted (Pz1+) T cells. As assessed by flow cytometric analysis of peripheral blood, we neither found evidence of hCD19+ B cell aplasias in 19z1+ T cell treated mice nor were able to demonstrate the persistence of infused CAR+ T cells. To investigate whether the lack of 19z1+ T cell efficacy and persistence was due to an absence of homeostatic drive, we next lymphodepleted C57BL6(mCD19−/− hCD19+/−) mice with cyclophosphamide prior to T cell infusion. Mice lymphodepleted prior to 19z1+ T cell infusion demonstrated marked and sustained B cell aplasias when compared to lymphodepleted Pz1+ T cell and non-lymphodepleted T cell treated controls. Furthermore, while no CAR+ T cells were identifiable in the Pz1 and non-lymphodepleted control groups, 19z1+ T cells were consistently present in the peripheral blood of the cyclophosphamide pre-treated, 19z1+ T cell treated mice (3–5% of white blood cells). To assess the anti-tumor efficacy of the 19z1+ T cells, we next established a systemic tumor model utilizing mouse EL4 thymoma cells retrovirally modified to express hCD19 (EL4(hCD19)). C57BL6(mCD19−/− hCD19+/−) mice pre-treated with cyclophosphamide, subsequently infused systemically with EL4(hCD19) tumor, followed by systemic 19z1+ T cell infusion, had a significant survival advantage (80% survival at >120 days) over untreated controls or controls treated with Pz1+ T cells or 19z1+ T cells in the absence of lymphodepletion (0% survival). In conclusion, we have developed a syngeneic immune competent tumor model of hCD19 disease that is highly relevant to the clinical setting. Using this model, we demonstrate the significance of lymphodepletion on the prolonged in vivo persistence and anti-tumor efficacy of 19z1+ T cells. Data derived from this model will be correlated to findings obtained from a recently initiated clinical trial for patients with chronic lymphocytic leukemia, and will significantly impact the design of subsequent trials in the future.

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Clinical Responses In Patients Infused With T Lymphocytes Redirected To Target κ-Light Immunoglobulin Chain

Blood ◽

10.1182/blood.v122.21.506.506 ◽

2013 ◽

Vol 122 (21) ◽

pp. 506-506 ◽

Cited By ~ 6

Author(s):

Carlos A. Ramos ◽

Barbara Savoldo ◽

Enli Liu ◽

Adrian P. Gee ◽

Zhuyong Mei ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

B Cell ◽

Light Chain ◽

Stable Disease ◽

Research Funding ◽

B Cell Malignancies ◽

Car T Cells ◽

Car T

Abstract Adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, causes sustained depletion of normal B cells and consequent severe hypogammaglobulinemia. In order to target B-cell malignancies more selectively, we exploited the clonal restriction of mature B-cell malignancies, which express either a κ or a λ-light immunoglobulin (Ig) chain. We generated a CAR specific for κ-light chain (CAR.κ) to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the reciprocal λ-light chain, thus minimizing the impairment of humoral immunity. After preclinical validation, we designed a phase I clinical trial in which patients with refractory/relapsed κ+ non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) are infused with autologous T cells expressing a CAR.κ that includes a CD28 costimulatory domain. The protocol also included patients with multiple myeloma with the aim of targeting putative myeloma initiating cells. Three dose levels (DL) are being assessed, with escalation determined by a continual reassessment method: 0.2 (DL1), 1 (DL2) and 2 (DL3) ×108 T cells/m2. Repeat infusions are allowed if there is at least stable disease after treatment. End points being evaluated include safety, persistence of CAR+T cells and antitumor activity. T cells were generated for 13 patients by activating autologous PBMC with immobilized OKT3 (n=5) or CD3/CD28 monoclonal antibodies (n=8). In 2 patients with >95% circulating leukemic cells, CD3 positive selection was performed using CliniMACS. After transduction, T cells (1.2×107±0.5×107) were expanded ex vivo for 18±4 days in the presence of interleukin (IL)-2 to reach sufficient numbers for dose escalation. CAR expression was 81%±13% by flow cytometry (74,112±23,000 transgene copy numbers/mg DNA). Products were composed predominantly of CD8+ cells (78%±10%), with a small proportion of naïve (5±4%) and memory T cells (17%±12%). CAR+ T cells specifically targeted κ+ tumors as assessed by 51Cr release assays (specific lysis 79%±10%, 20:1 E:T ratio) but not κ–tumors (11%±7%) or the NK-sensitive cell line K562 (26%±13%). Ten patients have been treated: 2 on DL1, 3 on DL2 and 5 on DL3. Any other treatments were discontinued at least 4 weeks prior to T-cell infusion. Patients with an absolute leukocyte count >500/µL received 12.5 mg/kg cyclophosphamide 4 days before T-cell infusion to induce mild lymphopenia. Infusions were well tolerated, without side effects. Persistence of infused T cells was assessed in blood by CAR.κ-specific Q-PCR assay and peaked 1 to 2 weeks post infusion, remaining detectable for 6 weeks to 9 months. Although the CAR contained a murine single-chain variable fragment (scFv), we did not detect human anti-mouse antibodies following treatment and CAR.κ+T cell expansion continued to be observed even after repeated infusions. We detected modest (<20 fold) elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells, but systemic inflammatory response syndrome (cytokine storm) was absent. No new-onset hypogammaglobulinemia was observed. All 10 patients are currently evaluable for clinical response. Of the patients with relapsed NHL, 2/5 entered complete remission (after 2 and 3 infusions at dose level 1 and 3, respectively), 1/5 had a partial response and 2 progressed; 3/3 patients with multiple myeloma have had stable disease for 2, 8 and 11 months, associated with up to 38% reduction in their paraprotein; and 2/2 patients with CLL progressed before or shortly after the 6-week evaluation. In conclusion, our data indicate that infusion of CAR.κ+ T cells is safe at every DL and can be effective in patients with κ+ lymphoproliferative disorders. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Rooney:Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

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Therapy of B Cell Malignancies with CD19-Specific Chimeric Antigen Receptor-Modified T Cells of Defined Subset Composition

Blood ◽

10.1182/blood.v124.21.384.384 ◽

2014 ◽

Vol 124 (21) ◽

pp. 384-384 ◽

Cited By ~ 11

Author(s):

Cameron J Turtle ◽

Daniel Sommermeyer ◽

Carolina Berger ◽

Michael Hudecek ◽

David M Shank ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cd4 T Cells ◽

Research Funding ◽

T Cell Subsets ◽

B Cell Malignancies ◽

T Cell Therapy ◽

Car T Cells ◽

Car T

Abstract BACKGROUND: The adoptive transfer of CD19-specific chimeric antigen receptor-modified (CD19 CAR) T cells is a promising strategy for treating patients with CD19+ B cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). Dramatic responses have been observed in a subset of patients receiving CD19 CAR T cell therapy, and prior studies suggest that persistence of transferred T cells may correlate with the extent of tumor regression. The use of unselected T cells to prepare CAR T cells results in variation in the phenotypic composition of the infused product in individual patients, making it difficult to determine whether particular T cell subsets contribute to efficacy and/or toxicity. Studies in our lab demonstrated that genetically modified effector T cells derived from purified T cell subsets differ in the capacity to persist in vivo after adoptive transfer, and that a combination of CAR-modified CD8+ central memory (TCM) and CD4+ T cells provides optimal antitumor activity in tumor xenograft models. Based on these data, we designed the first clinical trial in which patients with CD19+ B cell malignancies receive CD19 CAR T cells comprised of a defined composition of CD8+ TCM and CD4+T cells engineered to express a CD19 CAR. METHODS: Patients with relapsed or refractory CD19+ ALL, CLL or NHL are eligible for this phase I/II study. CD8+ TCM and CD4+ T cells were separately enriched by immunomagnetic selection from a leukapheresis product from each patient, and cryopreserved. The CD8+ TCM and CD4+ T cells were stimulated in independent cultures with anti-CD3/anti-CD28 paramagnetic beads, and transduced with a lentivirus encoding the murine FMC63 anti-CD19 scFv, 4-1BB and CD3 zeta signaling domains. After in vitro expansion, the cell product for infusion was formulated in a 1:1 ratio of CD4+:CD8+ CAR+ T cells. A truncated non-functional human epidermal growth factor receptor (EGFRt) encoded in the transgene cassette allowed identification of transgene-expressing T cells by flow cytometry. Lymphodepleting chemotherapy was administered followed by infusion of EGFRt+ CAR T cells at one of three dose levels (2 x 105 EGFRt+ cells/kg, 2 x 106 EGFRt+ cells/kg, 2 x 107 EGFRt+cells/kg). RESULTS: Twenty patients with relapsed or refractory ALL (n = 9), NHL (n = 10) or CLL (n = 1), including those who failed prior autologous (n = 4) or allogeneic (n = 4) stem cell transplant have been treated on the trial. Fifteen of 20 treated patients received a product that conformed to the prescribed CD8+ TCM:CD4 composition. Five patients received a product manufactured using a modified strategy either due to low blood lymphocyte counts (n = 3) or due to failure to propagate T cells in culture (n = 2). CD8+ TCM and CD4+ T cells have been isolated from 12 additional patients and cryopreserved for therapy. Patients have been treated at all three dose levels without acute infusional toxicity. Severe cytokine release syndrome (sCRS) consisting of fever, hypotension, and reversible neurotoxicity associated with elevated serum IFN-γ and IL-6 was only observed in ALL patients with a high tumor burden. One ALL patient treated at the highest cell dose died of complications associated with sCRS. None of the NHL patients had sCRS. Of patients who are >6 weeks after CD19 CAR T cell therapy, best responses included complete (n=1) or partial (n=5) remission in 6/9 patients with NHL and complete remission in 5/7 patients with ALL. Both CD4+ and CD8+ CAR-T cells expanded in vivo and could be detected in blood, marrow and CSF. The peak level and duration of persistence of both CD4+ and CD8+ EGFRt+ T cells were associated with clinical response. TCRBV gene sequencing of flow sorted CD4+ and CD8+ EGFRt+CAR T cells from 2 patients showed that proliferating CAR T cells were polyclonal. A subset of NHL patients in whom CAR T cells became undetectable developed a T cell immune response to sequences in the murine CD19-specific scFv component of the CAR transgene. CONCLUSION: Adoptive immunotherapy with CD19 CAR T cells of defined subset composition is feasible and safe in a majority of heavily pretreated patients with refractory B cell malignancies and has potent anti-tumor activity. Persistence of CAR-T cells may be limited in some patients by transgene product immunogenicity. Data from this ongoing clinical trial will be updated at the meeting. Disclosures Turtle: Juno Therapeutics: Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Hudecek:Juno Therapeutics: Patents & Royalties. Jensen:Juno: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Riddell:Juno Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Maloney:Juno Therapeutics: Research Funding.

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Allogeneic T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor Cause Remissions of B-Cell Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation without Causing Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v126.23.99.99 ◽

2015 ◽

Vol 126 (23) ◽

pp. 99-99 ◽

Cited By ~ 1

Author(s):

Jennifer N Brudno ◽

Robert Somerville ◽

Victoria Shi ◽

Jeremy J. Rose ◽

David C. Halverson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

B Cell ◽

B Cell Malignancies ◽

Hematopoietic Stem ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Peak Blood

Introduction Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies are often treated with infusions of unmanipulated donor lymphocytes (DLIs) from the transplant donor. DLIs are frequently not effective at eradicating malignancy, and DLIs often cause graft-versus-host disease (GVHD), which is a potentially lethal allogeneic immune response against normal recipient tissues. Methods We conducted a clinical trial of allogeneic T cells that were genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. The CAR was encoded by a gamma-retroviral vector and included a CD28 costimulatory domain. Patients with B-cell malignancies after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor. Findings Eight of 20 treated patients obtained remissions, including 6 complete remissions (CR) and 2 partial remissions. The response rate was highest for acute lymphoblastic leukemia with 4/5 patients obtaining minimal-residual-disease-negative CRs, but responses also occurred in chronic lymphocytic leukemia (CLL) and lymphoma. The longest ongoing CR is 30+ months in a patient with CLL. No patient developed new-onset acute GVHD after CAR T-cells were infused. Toxicities included fever, tachycardia, and hypotension. Median peak blood CAR T-cell levels were higher in patients who obtained remissions (39 CAR+ cells/mL) than in patients who did not obtain remissions (2 CAR+ cells/mL, P=0.001). Presence of endogenous normal or malignant blood B lymphocytes before CAR T-cell infusion was associated with higher post-infusion median blood CAR T-cell levels (P=0.04). Compared to patients who did not obtain a remission of their malignancies, patients obtaining remissions had a higher CD8:CD4 ratio of blood CAR+ T cells at the time of peak CAR T-cell levels (P=0.007). The mean percentage of CAR+CD8+ T cells expressing the programmed cell death-1 (PD-1) protein increased from 12% at the time of infusion to 82% at the time of peak blood CAR T-cell levels (P<0.0001). The mean percentage of CAR+CD4+ T cells expressing PD-1 increased from 32% at the time of infusion to 91% at the time of peak blood CAR T-cell levels (P<0.0001). Interpretation Infusion of allogeneic anti-CD19 CAR T cells is a promising approach for treating B-cell malignancies after alloHSCT. Our findings point toward a future in which antigen-specific T-cell therapies will be an important part of the field of allogeneic hematopoietic stem cell transplantation. Table. PatientNumber Malignancy Transplant type Total T cellsinfused/kg Anti-CD19CAR-expressingT cells infused/kg Malignancyresponseat last follow-up(interval from infusion to last follow-up in months) 1 CLL URD 10/10 HLA match 1x106 0.4x106 SD (3) 2 DLBCL Sibling 2x106 0.7x106 SD (1) 3 CLL Sibling 4x106 2.4x106 PD 4 DLBCL Sibling 4x106 2.2x106 SD (31+) 5 CLL URD 10/10 HLA match 1.5x106 1.0x106 CR (30+) 6 MCL Sibling 7x106 4.6x106 SD (3) 7 CLL URD 10/10 HLA match 1x106 0.7x106 PD 8 MCL Sibling 7x106 3.9x106 SD (24+) 9 MCL URD 10/10 HLA match 4x106 2.2x106 PR (3) 10 MCL Sibling 10x106 7.8x106 SD (2) 11 CLL URD 9/10 HLA match 5x106 3.1x106 PR (12+) 12 ALL Ph+ Sibling 7x106 5.2x106 MRD-negative CR (15+) 13 MCL Sibling 10x106 7.1x106 SD (9) 14 ALL Ph-neg Sibling 10x106 7.0x106 MRD-negative CR (5) 15 ALL Ph-neg Sibling 10x106 6.9x106 MRD-negative CR (3) 16 ALL Ph-neg Sibling 7x106 5.6x106 PD 17 DLBCL Sibling 10x106 8.2x106 CR (6+) 18 DLBCL Sibling 10x106 3.1x106 SD (2) 19 FL transformed to DLBCL URD 10/10 HLA match 5x106 4.3x106 PD 20 ALL Ph-neg URD 9/10 HLA match 5x106 4.2x106 MRD-negative CR (3+)^ CLL, chronic lymphocytic leukemia; ALL Ph+, Philadelphia chromosome positive acute lymphoblastic leukemia; ALL Ph-neg, Philadelphia chromosome negative acute lymphoblastic leukemia; MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; Sibling, human leukocyte antigen-matched sibling donor; URD, unrelated donor; HLA, human leukocyte antigen; PD, progressive disease; SD, stable disease; PR, partial remission; CR, complete remission; MRD-negative, minimal residual disease negative. ^Patient 20 underwent a second alloHSCT 3.5 months after anti-CD19 CAR T-cell infusion while in MRD-negative CR. Disclosures Goy: Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma.

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CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies

Science Translational Medicine ◽

10.1126/scitranslmed.aaw9414 ◽

2019 ◽

Vol 11 (511) ◽

pp. eaaw9414 ◽

Cited By ~ 15

Author(s):

Hong Qin ◽

Zhenyuan Dong ◽

Xiuli Wang ◽

Wesley A. Cheng ◽

Feng Wen ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Specific Marker ◽

Antitumor Effects ◽

B Cell Malignancies ◽

T Cell Therapy ◽

Car T Cells ◽

Car T ◽

Antigen Loss

CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell–specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient–derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.

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