scholarly journals Identification of human CD4+ T cell populations with distinct antitumor activity

2020 ◽  
Vol 6 (27) ◽  
pp. eaba7443
Author(s):  
Michelle H. Nelson ◽  
Hannah M. Knochelmann ◽  
Stefanie R. Bailey ◽  
Logan W. Huff ◽  
Jacob S. Bowers ◽  
...  

How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies.

2020 ◽  
Author(s):  
Michelle H. Nelson ◽  
Hannah M. Knochelmann ◽  
Stefanie R. Bailey ◽  
Logan W. Huff ◽  
Jacob S. Bowers ◽  
...  

AbstractHow naturally arising human CD4+ T helper subsets impact tumor immunity is unknown. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumor malignancies. As CD26high T cells secrete type-17 cytokines and have been categorized as Th17 cells, we posited these helper populations would possess similar molecular properties. Herein, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from Th17 cells. Of clinical significance, CD26high T cells engineered with a chimeric antigen receptor (CAR) ablated large human tumors to a greater extent than enriched Th17, Th1, or Th2 cells. Moreover, CD26high T cells mediated curative responses in mice, even when redirected with a suboptimal CAR and without the aid of CD8+ CAR T cells. CD26high T cells co-secreted effector cytokines at heightened levels and robustly persisted. Collectively, our work reveals the potential of human CD4+ T cell populations to improve durability of solid tumor therapies.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2491-2491
Author(s):  
C.J.M. Halkes ◽  
I Jedema ◽  
H.M. van Egmond ◽  
L van der Fits ◽  
J.H.F. Falkenburg ◽  
...  

Abstract Abstract 2491 Alemtuzumab (ALT) is a monoclonal anti CD52 antibody used for the treatment of CD52 positive lymphoid malignancies and to deplete T cells in vivo and in vitro to prevent graft rejection or GVHD after allogeneic stem cell transplantation (alloSCT). Membrane CD52 expression depends on the presence of a glycosylphosphatidylinositol (GPI) anchor. GPI deficiency is frequently found in small populations of normal and malignant hematopoietic cells, including T and B cells (frequencies from <0.01 to 2%). These cells lack expression of GPI-linked proteins like CD52 as can be detected by absence of staining of FLAER, which is an aerolysin that specifically binds to mammalian GPI anchors. After alloSCT using ALT for T cell depletion, reconstitution of FLAER and CD52 double negative cells is seen, and outgrowth of CD52 negative malignant cell populations has been found after single agent treatment with ALT in malignant diseases. However, GPI deficient cells have been suggested to have a lower proliferative potential and a decreased survival due to their increased susceptibility to spontaneous complement mediated cell lysis, possibly explaining the infrequent dominant outgrowth of GPI deficient clones in healthy individuals. Sézary Syndrome (SS) is an aggressive cutaneous T cell lymphoma characterized by the presence of high numbers of neoplastic T cells expressing CD4 and CD52 in peripheral blood, lymph nodes and skin. Clinical responses in SS patients after single drug treatment with low dosed ALT have been described by several investigators. However, in 6 out of 6 patients analyzed, we found a small population of CD52 and FLAER negative Sézary cells, illustrating that a GPI negative subpopulation is frequently observed which may lead to outgrowth of CD52 negative Sézary cells. We treated 3 patients with successive courses of low dose ALT (10 mg subcutaneously once weekly until circulating malignant cells were < 1,000/mm3) and followed the kinetics of CD52- and CD52+ Sézary cells. Before ALT treatment, a CD4+CD52-FLAER- T cell population was found in all three patients (0.01–0.06% of all circulating CD4+ T cells). As expected, a rapid decrease in absolute numbers of CD4+CD52+FLAER+ cells was observed after ALT treatment (decrease 94 to 100%). Surprisingly, despite the absence of the CD52 target molecule, the absolute number of CD4+CD52-FLAER- T cells also decreased after the first and second treatment cycles in all three patients (decreases between 22 and 96%), indicating that the massive in vivo ALT mediated lysis of CD52+ Sézary cells coincided with collateral damage of CD52- Sézary cells. Between successive treatment courses in the absence of circulating ALT, the absolute numbers of CD4+CD52+FLAER+ T cells showed a more rapid increase compared to CD4+CD52-FLAER- T cells in all patients (median 193 fold increase (range 17–896) versus 9 fold increase (range 2–144) respectively), illustrating a decreased in vivo proliferative potential of these GPI negative cells. After repeated doses of ALT, one of the patients developed resistance to ALT treatment. Phenotype analysis revealed that 97% of the 23,000/mm3 circulating Sézary cells were CD4+CD52-FLAER-. Clonality analysis showed that CD4+CD52+FLAER+ and CD4+CD52-FLAER–Sézary cell populations expressed identical T cell receptor V-beta chains demonstrating that both cell populations are part of the same initial clone of Sézary cells. At present, one year after the start of ALT treatment, reponses are still observed in both other patients without overgrowth of a CD4+CD52-FLAER–Sézary cells. We conclude that despite presence of small populations of CD52 and GPI negative cells in patients with Sézary Syndrome, all patients respond to treatment with alemtuzumab. CD52 negative, GPI deficient Sézary cells showed high susceptibility to collateral damage during antibody treatment. During treatment intervals, CD52+ cells showed a faster recovery compared to CD52- cells, indicating a lower proliferative potential of the GPI deficient Sézary cells. Although, as shown in one patient, ultimate outgrowth of GPI deficient CD52- sezary cells can occur, the capacity to achieve long term control of both CD52+ and CD52- Sézary cells in several patients offers a rationale for treatment of SS with alemtuzumab, possibly in combination with a low dosed cytotoxic drug Disclosures: Off Label Use: Alemtuzumab for treatment of Sezary Syndrome.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-22-SCI-22 ◽  
Author(s):  
Dirk Hans Busch

Abstract Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. The definition of optimal targets and antigen receptors as well as the differentiation status of transferred T cells are emerging as crucial parameters for generating cell products with predictable efficacy and safety profiles. Our laboratory has demonstrated that defined subsets within the memory CD8+ T cell compartment fulfill all key characteristics of adult tissue stem cells and are essential for robust and long-term maintained responses upon adoptive transfer. We have developed clinical multi-parameter enrichment technologies to purify these memory stem cells for clinical applications. In my presentation I will report on the status of ongoing clinical trials using such purified cell products either as a primary T cell population for the treatment of infections upon allogeneic stem cell transplantation or after genetic modification with a CD19 CAR for the treatment of malignancies (collaboration with Stan Riddell, FHCC/Seattle). Infusing small numbers of T cells within a memory stem cell product can be highly effective therapeutically, but bears some risk of toxicity. Therefore, safeguards that allow selective depletion of transferred cells in the case of un-tolerable side effects may be needed to further improve adoptive immunotherapy. I will present results exploring the capacity of a truncated version of EGFR (EGFRt) co-expressed with T cells expressing a CD19-CAR. In pre-clinical mouse models we demonstrate that application of Cetuximab, which binds to EGFRt, confers selective depletion of adoptively transferred CAR-T cells in vivo. Long-term B cell aplasia, which is a main side effect of CD19-CAR T cell therapy, can be completely reverted with this strategy. Vaccination studies upon B cell recovery demonstrate full functionality of antigen-specific antibody formation. EGFRt co-expressing CD19-CAR T cells have been successfully transferred into first human patients, providing the option to test for the first time in a clinical setting whether treatment of B cell aplasia after long-term leukemia remission can be achieved by selective depletion. Disclosures Busch: STAGE cell therapeutics: Other: I was share holder of STAGE cell therapeutics, a company that was recently bought by Juno therapeutics.. Off Label Use: CD19 CAR T cells.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1737-1737
Author(s):  
Olga Molostova ◽  
Larisa Shelikhova ◽  
Yakov Muzalevsky ◽  
Alexey Kazachenok ◽  
Rimma Khismatullina ◽  
...  

Abstract Introduction CD19 CAR-T is a highly effective therapy among children with relapsed/refractory B-ALL. The optimal approach to delivery of this therapy and the best post-remission strategy remain to be established. We have tested in a prospective academic trial CD19 CAR-T cells manufactured at the point-of-care based on the automatic bioreactor platform. Based on the results of the first part of the trial, a toxicity mitigation strategy with conditional split dosing and refined post-remission therapy based on allogeneic HSCT was implemented. We report here the results of toxicity mitigation strategy approach as well as the long-term outcome with regard to the HSCT consolidation. Patients and methods A total of 57 pts with relapsed/refractory B-ALL were screened, 54 pts were included in the trial, and additional 3 pts were eligible for compassionate use of CD19 CAR-T cell therapy. The CliniMACS Prodigy T-cell transduction process with lentiviral second generation CD19.4-1BB zeta vector (Lentigen, Miltenyi Biotec) was used for CAR-T manufacturing. All patients received prophylactic tocilizumab before CAR-T cells infusion. In the first part of trial 33 pts received lymphodepleting chemotherapy containing cyclophosphamide (750 mg/m2) and fludarabine (120 mg/m2), CAR-T cells was administered in dose-escalating regimen (0.1, 0.5, 1, and 3х10 6/kg b.w.). After the interim analysis, treatment scheme was modified to adapt the lymphodepletion therapy and the starting CAR-T dose to the leukemia burden. Twenty-four consecutive pts were divided into "low leukemia burden" (n=10) and "highleukemia burden" (n=14) groups, based on the threshold of 15% leukemic cells in the bone marrow. Patients with low leukemia burden received the same lymphodepletion chemotherapy as in the first part of the trial, and a single fixed dose of CAR-T cells at 1x10 6/kg b.w. Patients with high leukemia burden received an escalated lymphodepletion (fludarabine 120 mg/m 2, cyclophosphamide 750 mg/m 2, cytarabine 900 mg/m 2, etoposide 450 mg/m 2, dexamethasone 30 mg/m 2) and a divided dose of CAR-T. Day 0 CAR-T dose was set at 0.1 x10 6/kg. The second dose of 0.9x10 6/kg b.w. was administered between day 7 and day 14 if the following criteria were met: bone marrow leukemia burden by flow cytometry &lt; 15% and CRS and/or ICANS grade within 3 previous days does not exceed grade 2. Results Thirty patients included in the first part of the trial, were evaluable for response at day 28, and 27 (90%) of them had MRD-negative remission. Interim analysis showed that grade 3-5 CRS and neurotoxicity were associated exclusively with large leukemia burden (&gt;15% blasts in the bone marrow) at the enrollment (p=0,003). With the risk-adapted strategy (part 2 of the trial), 8 patients (80%) with low leukemic burden achieved CR at day 28, and all patients (100%) with high leukemic burden achieved complete remission on day 28. In the high burden cohort 4 patients received the second CAR-T infusion, while the remaining 10 patients did not receive second dose due to either toxicity grade ³2 (4 pts), or persistence of &gt;15% blast cells in bone marrow (6 pts). There were no cases of grade IV-V toxicity among patients with high leukemia burden, Table 1. For all patients the median follow-up for survivors was 490 days (287-1193), the cumulative incidence of relapse after initial response was 69.6%, median time to relapse was 250 days (58-696). HSCT during the CR was performed in 15 patients. The median time between first CAR-T infusion and HSCT was 96 days (41-292). Three patients (20%) relapsed early after HSCT (88, 114 and 155 days). Event-free and overall survival for the total cohort was 19.6% and 56.4%, respectively. Among the 34 pts, who did not receive HSCT in CR after CAR-T therapy, EFS and OS were 14.7% and 55.7%. Among the 15 pts, who received HSCT as consolidation, EFS and OS were 86.1% and 80%, p-value for HSCT vs no HSCT 0.125 (OS) and 0.0001 (EFS). Conclusion Low doses of non-cryopreserved CAR-T cells (0.1*10 6/kg), manufactured at the point-of-care, demonstrated high efficacy in patients with high initial leukemia burden, as well as favorable profile of life-threatening toxicity. The proposed risk-adapted strategy of CAR-T dosing allows to achieve high remission rate in all patients (with high and low leukemic mass). HSCT is likely to be a necessary modality for consolidation and long-term maintenance of remission after CAR-T therapy among a majority of patients with advanced B-ALL. Figure 1 Figure 1. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.


2021 ◽  
Author(s):  
Jan Joseph Melenhorst ◽  
Gregory M Chen ◽  
Meng Wang ◽  
David . L Porter ◽  
Peng Gao ◽  
...  

The adoptive transfer of T lymphocytes reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term potential and the clonal stability of the infused cells. Here, we studied the longest persisting CD19 redirected chimeric antigen receptor (CAR) T cells to date in two chronic lymphocytic leukemia (CLL) patients who achieved a complete remission in 2010. CAR T-cells were still detectable up to 10+ years post-infusion, with sustained remission in both patients. Surprisingly, a prominent, highly activated CD4+ population developed in both patients during the years post-infusion, dominating the CAR T-cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T-cells with a repertoire dominated by few clones. Single cell multi-omics profiling via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) with TCR sequencing of CAR T-cells obtained 9.3 years post-infusion demonstrated that these long-persisting CD4+ CAR T-cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Our data provide novel insight into the CAR T-cell characteristics associated with long-term remission in leukemia.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 591-591 ◽  
Author(s):  
Cesar Sommer ◽  
Bijan Boldajipour ◽  
Julien Valton ◽  
Roman Galetto ◽  
Trevor Bentley ◽  
...  

Abstract Autologous chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) have demonstrated promising clinical activity, inducing durable responses in patients with relapsed/refractory multiple myeloma (MM). Development of autologous CAR T therapies is however limited by logistical challenges and the time required for manufacturing, which has to be done for each patient. In addition, manufacturing may not be feasible in some patients. An allogeneic approach that utilizes engineered cells from a healthy donor could potentially expand patient access to these therapies by providing a readily available off-the-shelf product. We have previously described the screening of a library of single chain variable fragments (scFvs) with high affinity to human BCMA and the identification of candidate BCMA CARs with potent antitumor activity. Here we sought to further characterize ALLO-715, our lead allogeneic BCMA CAR T cell product, for its specificity to human BCMA, antitumor efficacy in vitro using a long-term killing assay and in xenograft mouse models with physiologic levels of human IL-7 and IL-15, and suitability for scale-up manufacturing. Allogeneic ALLO-715 CAR T cells were generated by lentiviral transduction with a second generation CAR construct incorporating a novel scFv derived from a fully-human antibody with high affinity to BCMA (KD value ~ 5 nM, determined at 37°C) and featuring a rituximab-driven off-switch. Transduced T cells were then transfected with mRNAs encoding Transcription Activator-Like Effector Nucleases (TALEN®) designed to specifically disrupt the T cell receptor alpha chain and CD52 loci. These modifications result in a cell product with a lower risk of TCR-mediated graft-versus-host disease and resistance to the CD52 antibody alemtuzumab, a lymphodepleting agent. BCMA CAR T cells exhibited robust cell expansion, with low levels of tonic signaling that resulted in minimal differentiation (> 50% Tscm/Tcm phenotype). In in vitro assays, ALLO-715 CAR T cells displayed potent cytotoxic activity when co-cultured with the target cell lines MM.1S, Molp-8, and BCMA-REH but negligible cytotoxicity against BCMA-negative REH cells. The high proliferative potential indicated by the high frequency of memory T cells was validated in long-term killing assays, where ALLO-715 CAR T cells showed substantial expansion in the presence of MM.1S cells with no evidence of exhaustion or diminished cytolytic activity after seven days of continuous exposure to target. The potency of ALLO-715 CAR T cells was unaffected by high concentrations of soluble BCMA (>10 ug/mL), which has been shown previously to interfere with the activity of some BCMA-specific CARs. In MM xenograft mouse models, ALLO-715 CAR T cells were highly efficacious at single dose. High serum IL-15 levels have been associated with CAR T cell expansion in clinical trials. To evaluate the impact of homeostatic cytokines on CAR T cell survival and antitumor activity in our xenograft models, mice were administered adeno-associated viruses (AAV) for the expression of human IL-7 and IL-15. In the presence of physiological concentrations of these cytokines, enhanced BCMA CAR T cell expansion and anti-tumor activity were observed. To assess potential off-target interactions of ALLO-715 CAR, tissue cross-reactivity studies were carried out on standard human tissue panels using a scFv-human IgG fusion protein. Consistent with the limited expression pattern of BCMA, reactivity was seen on scattered cells in lymphoid tissues such as tonsil and abundantly on BCMA-expressing cell lines, but no appreciable staining was detected in other tissues. We examined BCMA CAR T cells manufactured following a proprietary GMP-like clinical scale process and found that cell expansion and viability, T cell phenotype and in vivo antitumor efficacy were preserved. These results demonstrate the potential of ALLO-715 as a novel allogeneic BCMA CAR T therapy for the treatment of relapsed/refractory MM and other BCMA-positive malignancies. Disclosures Sommer: Allogene Therapeutics: Employment, Equity Ownership, Patents & Royalties. Boldajipour:Pfizer Inc.: Employment, Patents & Royalties. Valton:Cellectis.Inc: Employment, Equity Ownership, Patents & Royalties. Galetto:Cellectis SA: Employment, Equity Ownership, Patents & Royalties. Bentley:Allogene Therapeutics: Employment, Equity Ownership. Sutton:Allogene Therapeutics: Employment, Equity Ownership. Ni:Allogene Therapeutics: Employment, Equity Ownership. Leonard:Allogene Therapeutics: Employment, Equity Ownership. Van Blarcom:Allogene Therapeutics: Employment, Equity Ownership. Smith:Cellectis. Inc: Employment, Patents & Royalties. Chaparro-Riggers:Pfizer Inc.: Employment, Patents & Royalties. Sasu:Allogene Therapeutics: Employment, Equity Ownership, Patents & Royalties.


2021 ◽  
Author(s):  
Zhiliang Bai ◽  
Steven Woodhouse ◽  
Dongjoo Kim ◽  
Stefan Lundh ◽  
Hongxing Sun ◽  
...  

Chimeric antigen receptor modified (CAR) T cells targeting CD19 have mediated dramatic responses in relapsed or refractory acute lymphoblastic leukemia (ALL), yet a notable number of patients have CD19-positive relapse within one year of treatment. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes prior to treatment. Herein we present 101,326 single cell transcriptomes and surface protein landscape from the CAR T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR mediated activation and controls. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of Th2 function was associated with CD19 positive relapsed patients (median remission 9.6 months) compared with very durable responders (remission over 54 months). Proteomic profiles also revealed that the frequency of early memory T cell subsets, rather than activation or co-inhibitory signatures could distinguish CD19-positive relapse. Additionally, a deficit of type 1 helper and cytotoxic effector function and an enrichment for terminally differentiated CD8+ T cells exhibiting low cytokine polyfunctionality was associated with initial non-responders. By contrast, the single-cell transcriptomic data of unstimulated or TCR-activated CAR T cells failed to predict clinical responses. In aggregate, our results dissect the landscape of CAR-specific activation states in infusion products that can identify patients who do not develop a durable response to the therapy, and unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long term remission.


2020 ◽  
Vol 8 (2) ◽  
pp. e001133
Author(s):  
Esmé TI van der Gracht ◽  
Mark JA Schoonderwoerd ◽  
Suzanne van Duikeren ◽  
Ayse N Yilmaz ◽  
Felix M Behr ◽  
...  

BackgroundAdenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8+ T cells elicited upon immunization with adenoviral vectors.MethodsAdenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (107, 108 or 109 infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.ResultsThe adenoviral vaccines elicited inflationary E7-specific memory CD8+ T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8+ T cells in the circulation related to the development of E7-specific CD8+ tissue-resident memory T (TRM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8+ T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8+ TRM cells. Moreover, the formation of CD8+ TRM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.ConclusionsTogether, these data show that adenoviral vector-induced CD8+ T cell inflation promotes protective TRM cell populations, and this can be enhanced by targeting CTLA-4.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Kathryn Cappell ◽  
Richard Mark Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle Vanasse ◽  
...  

3012 Background: T cells expressing anti-CD19 chimeric antigen receptors (CARs) can cause complete remissions of relapsed lymphoma. We conducted the first clinical trial of anti-CD19 CAR T cells to show responses against lymphoma. This CAR was later developed as axicabtagene ciloleucel. Here, we aimed to assess the long-term durability of remissions and the long-term adverse effects after anti-CD19 CAR T-cell therapy. Methods: Between 2009 and 2015, we treated 43 patients with anti-CD19 CAR T cells preceded by conditioning chemotherapy of cyclophosphamide plus fludarabine (NCT00924326). Three patients were re-treated for a total of 46 CAR T-cell treatments. Twenty-eight patients had aggressive lymphoma (diffuse large B-cell lymphoma or primary mediastinal B cell lymphoma), eight patients had low-grade lymphoma (five with follicular lymphoma and 1 each with splenic marginal zone lymphoma, mantle cell lymphoma, and unspecified low-grade non-Hodgkin lymphoma), and seven patients had chronic lymphocytic leukemia (CLL). Patients were treated in three cohorts that differed in the CAR T-cell production process and conditioning chemotherapy dose. Results: Of the 43 treated patients, 63% had chemotherapy-refractory lymphoma. Patients had received a median of 4 previous lines of therapy. The median CAR+ T cell dose per kilogram was 2X10^6. The overall remission rate was 76% with 54% complete remissions (CR) and 22% partial remissions (PR). Patients with CR had higher median peak blood CAR levels (86 CAR+ cells/µL) than those who did not have CR (16 CAR+ cells/µL, P= 0.0041). Long-term adverse effects were rare except for B-cell depletion and hypogammaglobulinemia, which both improved over time. Conclusions: This is the longest follow-up study of patients who received anti-CD19 CAR T cells. Anti-CD19 CAR T cells cause highly durable remissions of relapsed B-cell lymphoma and CLL, and long-term adverse effects of anti-CD19 CAR T cells were rare and usually mild. Clinical trial information: NCT00924326 . [Table: see text]


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