scholarly journals CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiangzhou Shi ◽  
Zijian Zhang ◽  
Hong Cen ◽  
Han Wu ◽  
Shangkun Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cells ◽  
Clinical Success ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Normal Blood ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

AbstractCAR T cell therapy has shown dramatic clinical success in relapsed or refractory B-ALL and other hematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is strongly expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal blood cells. Moreover, T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide and without normal blood cells toxicity. We observed that our anti-CD99 CAR T cells showed robust cytotoxicity specifically against CD99+ T-ALL cell lines and primary tumor cells in vitro and significantly prolonged cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) models survival in vivo. Together, our results demonstrate that anti-CD99 CAR T cells could specifically recognize and efficiently eliminate CD99+ leukemia cells.

CAR T cells targeting CD99 as an approach to eradicate T-cell Acute Lymphoblastic Leukemia without normal blood cells toxicity

2021 ◽  
Author(s):  
Jiangzhou Shi ◽  
Zijian Zhang ◽  
Hong Cen ◽  
Han Wu ◽  
Shangkun Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Clinical Success ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Pilot Clinical Study

Abstract CAR T cell therapy has shown dramatic clinical success in relapsed or refractory (r/r) B-ALL and other haematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal bone marrow cells. T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide, maintained their cytotoxic function and mediated powerful antitumour effects. Subsequently, we conducted a pilot clinical study to evaluate the safety and feasibility of therapy with anti-CD99 CAR T cells in 4 patients with r/r T-LBL (n=1), AML (n=2) or myeloid sarcoma (MS) (n=1). The clinical overall response rate (ORR) was 50% (2/4 patients), and 1 patients (25%) achieved complete remission (CR) for 2 month. Mild cytokine release syndrome (CRS) occurred in 2 patients and the CRS no more than grade 2. Together, our results demonstrate that anti-CD99 CAR T cells specifically recognize and efficiently eliminate CD99+ leukemia cells.

scholarly journals Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for Adult Patients with Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 846-846
Author(s):  
Liang Huang ◽  
Na Wang ◽  
Chunrui Li ◽  
Yang Cao ◽  
Yi Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Antigen Loss

Abstract Clinical trials of second generation chimeric antigen receptor engineered T cells (CAR-T cells) have yielded unprecedented efficacy in refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), especially in children and young adult. However, antigen loss relapse has been observed in approximately 14% of patients in anti-CD19 CAR-T cell therapy across institutions, which emerges as a challenge for the long-term disease control of this promising immunotherapy. Recently, CD19/CD20 and CD19/CD22 dual antigen targeting have been proposed to overcome antigen loss relapse after the administration of anti-CD19 CAR-T cells. This strategy may result in enhanced anti-tumor activity, while safety concern regarding the risk of cytokine release syndrome (CRS) due to significant CAR-T cell activation and cytokine release needs to be addressed. Here, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells. We aimed to evaluate its safety and efficacy in adult patients with refractory or relapsed B-ALL. This trial is registered with ChiCTR, number ChiCTR-OPN-16008526. Between March 2016 and March 2017, 27 patients with refractory or relapsed B-ALL were enrolled in this clinical trial, with a median age of 30±12 years (range, 18-62 years). Thirteen patients (48.1%) had a history of at least two prior relapsed or primary refractory disease. Twenty-six patients received fludarabine and cyclophosphamide before the infusion of CAR-T cells. The median cell dosages of anti-CD22 and anti-CD19 CAR-T cells were 2.44 ± 1.02 × 106 /kg and 1.98 ± 1.05 × 106 /kg, respectively. 24/29 (88.9%) patients achieved CR or Cri, including 7 patients who received prior hematopoietic stem cell transplantation, and 13/27 (48.1%) patients achieved minimal residual disease negative (MRD-) CR accessed by flow cytometry. Sustained remission was achieved with a 6-month overall survival rate of 79% (95% CI, 66-97) and an event-free survival rate of 72% (95% CI, 55-95). 24/29 (88.9%) patients experienced CRS and 6/27 (22.2%) patients had reversible sever CRS (grade 3-4). And 3/27 (11.1%) patients developed neurotoxicity. Multi-color flow cytometry was used to screen and quantitate MRD in blood, bone marrow and cerebrospinal fluid. Antigen escape of CD19 and CD22 was not detected in any relapsed patient post-CAR-T cell therapy. Our results indicated that sequential infusion of third generation Anti-CD22 and Anti-CD19 CAR-T cell therapy is feasible and safe for patients with refractory/relapsed B-ALL. Dual antigen targeting should be a promising approach for overcoming antigen escape relapse, while needs to be further determined in our clinical trial. Disclosures No relevant conflicts of interest to declare.

Donor-derived CD7 CAR T cells for T-cell acute lymphoblastic leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10001-10001
Author(s):  
Jing Pan ◽  
Jing Pan ◽  
Biping Deng ◽  
Zhuojun Ling ◽  
Weiliang Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cellular Immunotherapy ◽  
Hematologic Toxicity ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Grade 3

10001 Background: Despite the success of chimeric antigen receptor T cell therapy in B cell malignances, there is currently no proved CAR T treatment for T cell neoplasms. We provide first evidence support the use of donor derived CAR T cells in T cell leukemia. Methods: In this phase 1 trial, CD7 CAR T cells were manufactured with T cells from prior SCT prior to a single infusion at doses of 5 × 105 or 1 × 106 (± 30%) cells per kilogram of body weight. donors, or from new donors who were HLA-matched or haploidentical, via leukopheresis and transduced with a lentiviral vector which carries a CD7 CAR construct. The primary endpoint was safety. Short-term efficacy was also assessed. Results: Results of 20 enrolled patients who received infusion are reported. Of 20 patients, 12 received previous HSCT-donor derived CAR T cells and 8 received fresh haplo-identical donor derived CAR T cells and plan to received transplantation as consolidation after remission.Adverse events included grade 3-4 hematologic toxicity in all (100%), grade 3-4 and grade 1-2 cytokine release syndrome in 2 (10%) and in 18 (90%), grade 1 neurotoxicity in 3 (15%), grade 1-2 graft-versus-host disease in 12 (60%), and grade 1 viral activation in 3 (15%) patients. Nineteen (95%) patients had a response, including 18 (90%) with complete remission and 1 (5%) with partial remission. Of 19 responders, 7 were bridged to SCT and remained minimal residual disease (MRD)-negative until last visit; 12 were followed up at a medium of 4.4 months, among whom 9 remained MRD-negative, 1 had a relapse, 1 discontinued for other treatment, and 1 died of pulmonary fungal infection at 5.5 months. CAR cells mostly persisted beyond 3 months. Patient CD7-positive healthy T cells were depleted, while CD7-negative T cells increased. Conclusions: We report the initial toxicity profile and anti-leukemia activity of a donor-derived CD7-targeted cellular immunotherapy for patients with relapsed or refractory T-ALL. (Funded by the National Key R&D program; ChiCTR.org number, ChiCTR2000034762). Clinical trial information: ChiCTR2000034762. [Table: see text]

scholarly journals CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression

Leukemia ◽  
2020 ◽  
Vol 35 (1) ◽  
pp. 75-89 ◽  
Author(s):  
Kristen Fousek ◽  
Junji Watanabe ◽  
Sujith K. Joseph ◽  
Ann George ◽  
Xingyue An ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Tracking ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
B Lineage ◽  
Cd19 Expression

AbstractChimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(−) disease. We report that CD19(−) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(−) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(−) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.

scholarly journals Development of Novel Anti-CD10 Target Modules for Redirection of Universal CAR T Cells Against CD10-Positive Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5612-5612 ◽  
Author(s):  
Anja Feldmann ◽  
Stefanie Koristka ◽  
Claudia Arndt ◽  
Liliana Raquel Loureiro ◽  
Ralf Bergmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

The common acute lymphoblastic leukemia antigen CD10 is a marker for several hematological malignancies, including acute lymphoblastic leukemia as well as T and B cell lymphomas, Burkitt lymphomas, and some solid tumors like renal cell carcinomas, pancreatic tumors and melanomas. Because of its tumor related expression pattern, CD10 is an attractive target for adoptively transferred T cells that are genetically modified to express chimeric antigen receptors (CARs). Recently, conventional CAR T cell therapy targeting CD19-positive hematological malignancies was clinically approved because of its impressive effectiveness in patients. However, CAR T cells can also cause severe side effects like on-target, off-tumor reactions, tumor lysis syndrome and cytokine release syndrome. Most critically, activity of conventional CAR T cells cannot be controlled, once they are applied in patients. As CD10 is also widely expressed on normal tissues, CAR T cell reactivity has to be controllable in order to stop CAR T cell therapy in case of on-target, off-tumor toxicities occur. Especially for this purpose, we have recently established a switchable, modular and universal CAR platform technology, named UniCAR system, which can be repeatedly turned on and off. In contrast to conventional CARs, that directly recognize a tumor-associated antigen (TAA) on the tumor cell surface via their extracellular single-chain variable fragment (scFv), the UniCAR system is structured in a modular manner of two components. The first component are T cells genetically engineered to express UniCARs and the second component are target modules (TMs). Most importantly, UniCARs cannot directly bind to a TAA because their extracellular scFv is directed against the peptide epitope E5B9 which is not present on the surface of living cells. Consequently, UniCAR armed T cells are per se inert. They can be redirected towards tumor cells only via a TM. TMs consist of a scFv targeting a TAA and the epitope E5B9 recognized by UniCARs allowing a cross-linkage of UniCAR T cells with tumor cells which results in T cell activation. As TMs have a very short half-life, UniCAR T cell activity can be controlled by dosing of the TM. Once the TM is administered, UniCAR T cells can be switched on, but once the TM injection is stopped and the TM is eliminated, UniCAR T cells are switched off immediately. Here, we show proof of concept for functionality of the UniCAR system targeting CD10-positive malignancies. Therefor, a novel anti-CD10 TM was constructed which is able to redirect UniCAR T cells to eliminate CD10-expressing tumor cells. In summary, we have established a universal, switchable, modular UniCAR platform technology that can be used to target CD10-positive malignancies. Disclosures Koristka: Intellia Therapeutics: Employment. Bachmann:GEMoaB Monoclonals: Equity Ownership, Patents & Royalties.

Modeling Retreatment of Acute Lymphoblastic Leukemia with Anti-CD19 Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2806-2806 ◽  
Author(s):  
Yinmeng Yang ◽  
Mark Eric Kohler ◽  
Terry J Fry
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Immune Rejection ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Post Infusion

Abstract Tremendous progress has been achieved employing immunotherapy for B cell acute lymphoblastic leukemia (ALL), a leading cause of death in children from cancer. Recent trials using chimeric antigen receptor T cells (CART) targeting the B cell restricted antigen, CD19, that utilize the autologous transfer of patients' T cells, have demonstrated remarkable remission rates of 80% against relapsed or refractory ALL. Despite initial clearance of tumor, relapse with CD19 antigen loss ALL and with CD19 expressing ALL can occur. Attempts at retreatment of patients who have received CD19 CAR T cell therapy suggests that most patients will not respond to a second infusion of CD19 CAR T cells. It has been proposed that failure to respond to a second infusion of CAR T cells may be due to immunogenicity of the foreign CAR protein and elimination of CAR T cells due to immunological targeting. To evaluate the mechanism of retreatment failure in the setting of persistent antigen, we utilized a murine second-generation anti-CD19 scfv/CD28/CD3ζ CAR transduced into mouse CD8 and CD4 polyclonal cells and tested against murine pre-B ALL in a syngeneic system. To investigate the issue of immunogenicity against CAR constructs, we immunized the mice with irradiated CAR T cells prior to CAR treatment to allow for anti-CAR T cell immunity. Following immunization, we inoculated the mice with leukemia on day 0 and treated the mice with 1 x 106 CAR T cells on day 4. CAR treatment was able to clear leukemia and CAR T cell-reactive antibodies were not detected in the serum of the mice, suggesting that a mechanism other than classic host mediated immune rejection of CAR T cells may underlie CAR T cell retreatment failure. To further model the failure of CAR T cell retreatment, we evaluated the ability of a second CAR T cell infusion to eliminate a second leukemic challenge. Leukemia bearing mice were treated with a curative dose of CD19 CAR T cells post lymphodepleting regimen. 30 days after clearance of the primary leukemic challenge, the mice were rechallenged with leukemia and subsequently treated with mock T cells or CD19 CAR T cells. Mice treated with CAR T cells followed by retreatment with mock T cells demonstrated persistence of CAR T cells from the first treatment, which were able to expand and clear the second leukemia challenge. In mice treated with a second dose of CAR T cells, CAR T cells from the second infusion briefly expanded 10 days post infusion, but could not be detected at day 20 post infusion. In contrast, CAR T cells from the initial infusion were still detectable at both time points. These results demonstrate that CAR T cells are able to persist, and, in a model of leukemic relapse, are able to expand and clear leukemia. However, CAR T cells infused into mice with CAR T cells persisting after a prior infusion fail to persist and quickly contract without evidence of host immune rejection of CAR T cells. Our data suggests that the inability to successfully retreat CD19+ relapsed leukemia with subsequent doses of CAR T cells may also involve mechanisms beyond immune recognition and clearance of CAR T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells

Blood ◽  
2019 ◽  
Vol 133 (20) ◽  
pp. 2212-2221 ◽  
Author(s):  
Philipp Karschnia ◽  
Justin T. Jordan ◽  
Deborah A. Forst ◽  
Isabel C. Arrillaga-Romany ◽  
Tracy T. Batchelor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Presentation ◽  
Massachusetts General Hospital ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with <7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.

scholarly journals Short-Interval Sequential CAR-T Cell Infusion May Enhance Prior CAR-T Cell Expansion to Augment Anti-Lymphoma Response in B-NHL

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuan Meng ◽  
Biping Deng ◽  
Luan Rong ◽  
Chuo Li ◽  
Weiliang Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Short Interval ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Sequential Administration ◽  
Car T

Chimeric antigen receptor (CAR)-T cell therapy emerges as a new treatment for refractory or relapsed (r/r) B-cell non-Hodgkin lymphoma (B-NHL); however, the overall response rate (ORR) of which in the B-NHL patients is much lower compared to the patients with r/r B acute lymphoblastic leukemia (B-ALL). We previously confirmed that sequential infusions of CD20 and CD22 CAR-T cells significantly improved the prognosis of the B-NHL patients, while some advanced patients still progressed to death during these CAR-T cell treatments. In this study, we showed that timely sequential administration of the second CAR-T cells could enhance expansion of prior CAR-T cells with stronger tumor-killing capacity in vitro and in vivo. We further conducted compassionate treatments on two advanced B-NHL patients with short-interval sequential infusions of CD19/22/20 CAR-T cells. Disease progression was observed in both patients after primary CAR-T cell infusion but robust re-expansion of prior CAR-T cells and anti-tumor effects was induced by infusion of a secondary CAR-T cells. These results indicate sequential infusions of CAR-T cells with a short interval may improve therapeutic efficacy in the B-NHL patients by promoting expansion of prior CAR-T cells.

scholarly journals The Decrease of Anti-CD3 Antibody Concentration Improved the Cytotoxicity of Chimeric Antigen Receptor (CAR) T Cells in the Treatment of Chronic Lymphoblastic Leukemia (CLL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4792-4792
Author(s):  
Sanmei Wang ◽  
Yilian Yang ◽  
Yu Zhu ◽  
Lei Fan ◽  
Michael Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Antibody Concentration ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T

Abstract Purpose: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated impressive responses in refractory and relapsed acute lymphoblastic leukemia (ALL) and non-hodgkin's lymphoma (NHL), however, the outcome among chronic lymphoblastic leukemia (CLL) seems to be inferior compared to other lymphoblastic malignancies, indicating that efficacy of CAR-T cell therapy may be attributed to inherent T cell defects that are characteristic of CLL which impaired their proliferative capacity and sustained persistence in vivo. Thereby, infusion of less-differentiated T cells which have the capacity to persist and engraft long-term in vivo may enhance the anti-tumor activity. Materials and methods: On day 0, cryopreserved PBMCs from healthy donors (HDs) and CLL patients were thawed and seeded on anti-CD3 antibody (0.1μg/ml vs 1μg/ml) in combination with anti-CD28 antibody (1μg/ml) coated 24-well plates. On day 3, activated T cells (ATCs) supplied with retroviral supernatant of the third-generation RV-SFG.CD19.CD28.4-1BBzeta vector were transferred into 24-well plates previously coated with retronectin. Transduction efficiencies and phenotypes of CAR-T cells were evaluated on days 7, 10 and 14 after transduction using flow cytometry analysis. On a functional level, chromium 51 (Cr-51) release assay and intracellular staining (ICS) analysis were performed to explore the altered cytotoxic capability of CAR-T cells. Results: We observed that the decrease of anti-CD3 antibody concentration (0.1μg/ml) showed no influence on viability, expansion, transduction efficiency of CAR-T cells generated from HDs or CLL patients compared to standard anti-CD3 antibody concentration (1μg/ml). Moreover, the decrease of anti-CD3 antibody (0.1μg/ml)-mediated T cell activation resulted in an enrichment of less-differentiated naïve (CD45RA +CCR7 +) and central memory (CD45RA -CCR7 +)-like T cells both among CD4 + and CD8 + CAR-T cells. Additionally, cytokines-production (TNF-α, IFN-γ) were dramatically increased evaluated with ICS analysis from HDs and CLL patients in two different concentrations (0.1μg/ml vs. 1μg/ml) . Notably, CAR-T cells derived from HDs displayed decreased cytotoxic capability while CLL patients-derived CAR-T cells demonstrated increased cytotoxicity with lower anti-CD3 antibody concentration (0.1μg/ml) in the assessment of Cr-51 release assay, indicating that the proliferative capacity and sustained persistence of CAR-T cells derived from CLL patients were obtained in vivo. Conclusion: Anti-CD3 antibody-mediated activation of T cells altered anti-tumor efficiency of CAR-T cells before the transduction of ACTs with virus vectors. Consequently, when exploring the strategies to improve the efficacy of CAR-T cells, especially among CLL patients with inherent T cell defects, improvement of the functionality of T cells has to be taken into account. Figure 1 Figure 1. Disclosures Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel grants, Research Funding; Bluebird Bio: Other: Travel grants.

scholarly journals Emerging Therapeutic Options in Acute Lymphoblastic Leukemia

2020 ◽  
Vol 18 (12.5) ◽  
pp. 1781-1784
Author(s):  
Patrick A. Brown
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Therapeutic Options ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Immunotherapies have dramatically increased response rates in the relapsed/refractory setting of acute lymphoblastic leukemia. These emerging therapeutic options include blinatumomab, a bispecific T-cell engager construct; inotuzumab, an antibody–drug conjugate; and CAR T cells. Despite significantly improved rates of response, however, CAR T-cell therapy is the only approach associated with durable survival in a significant proportion of patients. Immunotherapies come with characteristic toxicity profiles. Inotuzumab is associated with hepatotoxicity, and blinatumomab and CAR T cells are associated with both cytokine release syndrome and neurotoxicity. Furthermore, immunotherapy is not always successful. Several mechanisms of failure exist, including failure to manufacture the CAR product, failure to engraft or lack of persistence of CAR T cells, endogenous T cell or CAR T-cell exhaustion, and antigen escape.

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