Donor-Derived Anti-CD19 Chimeric-Antigen-Receptor-Expressing T Cells Cause Regression Of Malignancy Persisting After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 151-151 ◽  
Author(s):  
James N Kochenderfer ◽  
Mark E. Dudley ◽  
Robert O. Carpenter ◽  
Sadik H Kassim ◽  
Jeremy J. Rose ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
B Cell Malignancies ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Progressive malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). To improve treatment of B-cell malignancies that persist despite alloHSCT, we conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Ten patients were treated on this trial. Four patients were recipients of human-leukocyte-antigen (HLA)-matched unrelated donor (URD) transplants and 6 patients were recipients of HLA-matched sibling transplants. T cells for genetic modification were obtained from each patient’s healthy alloHSCT donor. Patients received a single infusion of anti-CD19-CAR T cells. Cell doses ranged from 1x106 to 10x106 T cells/kg. A mean of 58% of the infused cells expressed the CAR. Patients did not receive chemotherapy or other anti-malignancy therapy with the CAR-T-cell infusions, so the responses observed in these patients are not confounded by the effects of chemotherapy. In contrast to other reports of successful treatment of B-cell malignancies with anti-CD19-CAR T cells, the patients on this study were not lymphocyte-depleted at the time of the CAR-T-cell infusions. Two patients with chronic lymphocytic leukemia (CLL) refractory to standard unmanipulated allogeneic donor lymphocyte infusions (DLIs) had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells. One of these CLL patients obtained a complete remission that is ongoing 9 months after treatment with allogeneic anti-CD19-CAR T cells. This patient also had complete eradication of blood B cells within 9 days after her CAR-T-cell infusion. Another patient had tumor lysis syndrome requiring rasburicase treatment as his CLL dramatically regressed in lymph nodes, bone marrow, and blood within 2 weeks of his anti-CD19-CAR-T-cell infusion. A patient with mantle cell lymphoma obtained a partial remission that is ongoing 3 months after infusion of anti-CD19-CAR T cells. A fourth patient with diffuse large B-cell lymphoma has ongoing stable disease 11 months after infusion of anti-CD19-CAR T cells. The other 6 treated patients all had short periods of stable malignancy or progressive disease after their CAR-T-cell infusions. Specific eradication of blood B cells occurred after infusion of CAR T cells in 3 of 4 patients with measurable blood B cells pretreatment. None of the patients treated on this study developed GVHD after their anti-CD19-CAR-T-cell infusions, despite the fact that 6 of 10 treated patients had experienced GVHD at earlier time-points after their most recent alloHSCT. One patient, who had a history of cardiac dysfunction with prior acute illnesses, had temporary cardiac dysfunction after infusion of anti-CD19-CAR T cells. The most prominent toxicities experienced by patients were fever and hypotension; these peaked 5 to 12 days after CAR-T-cell infusions and resolved within 14 days after the T-cell infusions. Two patients had Grade 3 fever, and 2 patients had Grade 3 hypotension. No patients experienced Grade 4 toxicities that were attributable to the CAR-T-cell infusions. Elevated levels of serum interferon gamma were detected in 3 patients at the time that they were experiencing toxicities. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. The peak blood levels of CAR T cells varied from undetec to 2.8% of peripheral blood mononuclear cells. The persistence of the CAR T cells in the blood of patients was limited to one month or less. When we assessed T cells from the blood of patients ex vivo, we found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 (PD-1) on CAR+ T cells compared to CAR-negative T cells. These results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after alloHSCT without causing GVHD. Malignancies that were resistant to standard DLIs regressed after anti-CD19-CAR-T-cell infusions. Future goals for improving this approach include enhancing the persistence of anti-CD19-CAR T cells and reducing toxicities. Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after alloHSCT. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2020 ◽  
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.

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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 99-99 ◽  
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.

scholarly journals Distribution of chimeric antigen receptor-modified T cells against CD19 in B-cell malignancies

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhitao Ying ◽  
Ting He ◽  
Xiaopei Wang ◽  
Wen Zheng ◽  
Ningjing Lin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Target Cells ◽  
B Cell Malignancies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Over Time

Abstract Background The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. Methods NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. Results CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7–21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. Conclusions CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. Trial registration The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421.

scholarly journals Pharmacodynamic Profile and Clinical Response in Patients with B-Cell Malignancies of Anti-CD19 CAR T-Cell Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2042-2042 ◽  
Author(s):  
Arianne Perez ◽  
Lynn Navale ◽  
John M. Rossi ◽  
Yueh-wei Shen ◽  
Yizhou Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Clinical Responses ◽  
Equity Ownership

Abstract This study is supported in part by funding from the CooperativeResearch and Development Agreement (CRADA) between the National Cancer Institute and Kite Pharma Introduction: Chimeric antigen receptor (CAR) engineered autologous T-cell therapy has shown promising efficacy in B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Anti-CD19 CAR T-cell product characteristics and potential pharmacodynamic markers from patients in this study were evaluated together with updated clinical responses. Methods: In this National Cancer Institute (NCI) clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by 1-2 x 106/kg anti-CD19 CAR T cells engineered with a CAR expressing CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the serum of patients prior to conditioning and CAR T-cell infusion, and during an interval of 4 weeks post-CAR T-cell infusion. EMD Millipore Luminex® xMAP® multiplex assays were used to measure all analytes. A Luminex 200™ instrument and xPONENT® 3.1 software were used for data acquisition and analysis. Major T-cell phenotypic markers including CD4, CD8, CD45RA and CCR7 were evaluated by multicolor flow cytometry on CAR-expressing T cells prior to and post-infusion, using a BD FACSCanto II. FlowJo software was used for data analysis. T-cell marker expression, as well as cytokine and chemokine levels were analyzed together with the clinical response to anti-CD19 CAR T cells. Maximum fold increase (MFI) was defined as the maximum fold change of measured analytes above baseline (pre-conditioning, day -5) across sampling timepoints. Results: Anti-CD19 CAR T-cell products, PBMCs from 12 patients, and serum samples from 15 patients have been evaluated. In 12 patient lots evaluated to date, the median CD4+/CD8+ CAR T-cell ratio was 0.48 (range 0.02-6.12). In addition, the median ratio between naïve (TN) plus central memory T cells (TCM), and more differentiated effector memory (TEM) plus effector cells (TE), was 0.48 (range 0.1-16.8). Post-hoc analyses adjusted for multiple comparisons showed that the frequency of CD4+ TN and TCM cells in the 6-8 day T-cell lots was significantly greater than that of CD4+ TN and TCM cells in the 10 day T-cell lots. The corresponding frequencies of CD8+ TN and TCM cells in the 6-8 day T-cell lots compared to 10 day T-cell lots approached significance, but did not meet the threshold after multiplicity adjustment. Clinical responses were seen across broad ranges of CD4+/CD8+ and (TN+TCM)/(TEM+TE) ratios in the CAR T-cell product. CAR T cells upregulated T-cell activation and immune modulating markers, as well as released measurable levels of cytokines and chemokines in response to CAR engagement of CD19 in vitro, or post-infusion. Cytokine and chemokine levels achieved their peak 3-10 days post T-cell infusion and returned to baseline generally within 3 weeks. Key pro-inflammatory cytokines and markers were upregulated: IL-6 median fold increase (MFI) at peak of 66 (interquartile range 5-152), IFN-g MFI 57 (13-126), C-reactive protein MFI 6 (4-42); immune homeostatic cytokines IL-15 MFI 19 (7-54), IL-2 MFI 20 (4-22), IL-10 MFI 10 (4-15); chemokines monocyte chemotactic protein (MCP)-1 MFI 7 (5-9), MCP-4 MFI 4 (2-5); and the immune effector molecules granzyme A MFI 7 (6-17) and granzyme B MFI 5 (3-9). Further analyses are ongoing. Conclusion: Clinical responses were observed irrespective of the CD4+/CD8+ ratio in the CAR T cell product. Cytokines and immune effector mediators peaked and cleared within 3 weeks. This pharmacodynamic profile reveals a rapid and coordinated sequence of T cell activation underlying durable responses in patients with B-cell malignancies. Disclosures Perez: Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Bot:Kite Pharma: Employment, Equity Ownership.

scholarly journals SILAC phosphoproteomics reveals unique signaling circuits in CAR-T cells and the inhibition of B cell-activating phosphorylation in target cells

2021 ◽  
Author(s):  
Alijah A. Griffith ◽  
Kenneth P. Callahan ◽  
Nathan Gordo King ◽  
Qian Xiao ◽  
Xiaolei Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

AbstractChimeric antigen receptor (CAR) is a single-pass transmembrane receptor designed to specifically target and eliminate cancers. While CARs prove highly efficacious against B cell malignancies, the intracellular signaling events which promote CAR T cell activity remain elusive. To gain further insight into both CAR T cell signaling and the potential signaling response of cells targeted by CAR, we analyzed phosphopeptides captured by two separate phopshoenrichment strategies from third generation CD19-CAR T cells cocultured with SILAC labeled Raji B cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we report that CD19-CAR T cells upregulated several key phosphorylation events also observed in canonical T cell receptor (TCR) signaling while Raji B cells exhibited a significant decrease in B cell receptor-signaling related phosphorylation events in response to coculture. Our data suggest that CD19-CAR stimulation activates a mixture of unique CD19-CAR-specific signaling pathways and canonical TCR signaling while global phosphorylation in Raji B cells is reduced after association with the CD19-CAR T cells.

scholarly journals Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

2016 ◽  
Vol 113 (4) ◽  
pp. E459-E468 ◽  
Author(s):  
David T. Rodgers ◽  
Magdalena Mazagova ◽  
Eric N. Hampton ◽  
Yu Cao ◽  
Nitya S. Ramadoss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Recombinant Antibody ◽  
Cytokine Release ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

Review of therapeutic approaches for B-cell malignancies with immune checkpoint blockade and chimeric antigen receptor t-cell therapies: Development, benefits, and limitations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14069-e14069
Author(s):  
Priya Hays
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Immune Checkpoint ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

e14069 Background: Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as approaches to treat B-cell malignancies. Methods: PubMed/NCBI/MEDLINE databases were accessed with keywords "immune checkpoint inhibitors and B-cell malignancies" "CAR T-cell and B-cell malignancies", and various permutations including "clinical data" "toxicities", "reviews", "quality of life", and "adverse effects". Results: The first-in-class approved immune checkpoint inhibitor was ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen. Thereafter, nivolumab was also approved for use in the treatment of Hodgkin's lymphoma in 2016. In phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma received the anti-PD-1 monoclonal antibody nivolumab. Eighty-one patients were treated and drug-related adverse events occurred in 51 (63%) patients. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma and other hematologic malignancies. Clinical trial results describing CD19-targeted CAR T-cell therapy of patients with relapsed B-ALL were published in 2015. In this study, all five patients treated with CAR T cells achieved minimal residual disease negative complete remission. Updated results describing the treatment of 16 patients with relapsed or refractory B-ALL treated with CAR T cells were published: the overall CR rate in this trial was 88% and 12 of 14 patients were classified as minimal residual disease negative. 44% of these patients went on to standard-of- care allogeneic hematopoietic stem cell transplant. Initial studies also reported potent anti-leukemic effects of CD19 CAR T cell therapy in three patients with refractory chronic lymphocytic leukemia where two of the three patients achieved MRD-CR. Infused CAR T cells proliferated up to 10,000-fold and persisted in recipients for at least 6 months and shown to retain antitumor activity after six months. Costs for CAR T-cell therapies remain exorbitant, reaching over $1M (USD) per patient. Conclusions: Clinical data reveal safety and efficacy, and also associated toxicities for both approaches.

scholarly journals Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease

2016 ◽  
Vol 34 (10) ◽  
pp. 1112-1121 ◽  
Author(s):  
Jennifer N. Brudno ◽  
Robert P.T. Somerville ◽  
Victoria Shi ◽  
Jeremy J. Rose ◽  
David C. Halverson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
B Cell Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Purpose Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. Methods We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed 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. Results Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease–negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Conclusion Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.

scholarly journals Allogeneic Anti-CD19 CAR T Cells Manufactured from Healthy Donors Provide a Unique Cellular Product with Distinct Phenotypic Characteristics Compared to CAR T Cells Generated from Patients with Mature B Cell Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3228-3228 ◽  
Author(s):  
Charlotte Graham ◽  
Agnieszka Jozwik ◽  
Ruby Quartey-Papafio ◽  
Nikolaos Ioannou ◽  
Ana M Metelo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Malignancies ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Despite the success of autologous anti-CD19 CAR T cell therapy in B-Acute lymphoblastic leukaemia (B-ALL) and Diffuse Large B Cell Lymphoma (DLBCL), treatment failures occur. One contributing factor may be the intrinsic T cell fitness of the CAR T cell product that is influenced by the underlying malignancy and prior treatments. With the advent of gene editing, 'off the shelf' non-HLA matched healthy donor (HD) CAR T cells are under investigation for the treatment of patients (pts) in clinical trials. UCART19 (S68587) is a first-in-class allogeneic CAR T cell product expressing a second generation anti-CD19 CAR with TALEN®-mediated gene knockouts of T cell receptor alpha chain (TRAC) and CD52 to prevent graft versus host disease and to render them resistant to anti-CD52 antibody used for lymphodepletion. Preliminary clinical trial data on the use of UCART19 in B-ALL was previously reported at ASH (Benjamin et al, 2018). The phenotypic and functional characteristics of CAR T cell products manufactured from B-ALL, Chronic Lymphocytic Leukaemia (CLL) and DLBCL pts were compared to young adult healthy donor (HD) CAR T cell products. In addition, potential effects related to knocking out TRAC in HD TCR-CAR T cells were examined. Thawed PBMCs from B-ALL, CLL, DLBCL pts and HDs underwent T cell enrichment, activation with anti-CD3/CD28 beads and IL-2, followed by transduction with anti-CD19 4-1BB CD3ζ lentiviral CAR construct and expansion. HD TCR- CAR T cells were manufactured by electroporation of HD CAR T cells with mRNA coding for TRAC TALEN® and residual TCRαβ+cells were removed by magnetic bead selection. CAR expression levels, T cell subsets, and exhaustion markers were examined by flow cytometry. Expression of activation markers CD25 and CD69 was measured in response to co-culture with the CD19+cell line NALM-6. Cytotoxicity against NALM-6 and Raji was assessed and antigen-mediated proliferation measured over 14 days. HD CAR T cells (n=11) expanded significantly more during manufacture than CAR T cells derived from B-ALL (n=9), CLL (n=8) or DLBCL (n=8) pts. As expected, the electroporation step resulted in a transient decrease in viability which recovered over time in culture (n=10). Median CAR expression level was higher on CLL CAR T cell products compared to those from B-ALL pts and HDs, thought to be due to a higher CD4:CD8 ratio in some CLL products. As a consequence of TCR knockout, CD3 expression was lost on HD TCR- CAR T cells (n=10), apart from a small population of γδ CAR T cells. CLL and DLBCL CD8+CAR+cells expressed higher levels of PD1 than HD CD8+CAR+cells. DLBCL CD4+CAR+cells also expressed significantly higher levels of PD1 than HD or HD TCR-CD4+CAR+T cells. CAR+CD8+CD27+PD1- T cells have been previously described as a functionally important population that correlated with clinical outcome in pts who received CLL CAR T cells (Fraietta et al, 2018). We found HD (n=13) and HD TCR- (n=10) CAR T cells had significantly more CD8+CD27+PD1- CAR T cells compared to those derived from CLL (n=8) and DLBCL (n=6) pts, but similar levels to B-ALL pts (n=10). In the absence of CD19 antigen, DLBCL CAR+CD8+ T cells (n=6) had greater expression of CD25 and CD69. However, in response to stimulation with CD19+ NALM-6 cells, HD (n=12), HD TCR- (n=10) and B-ALL (n=10) CAR T cells had higher fold increase in CD69+ cells compared to DLBCL (n=6) CAR T cells. On paired analysis (n=6), no difference was seen in activation in response to CD19 antigen on HD compared to HD TCR- CAR T cells. All CAR T cell products demonstrated comparable cytotoxicity against NALM-6 and Raji cell lines in short term in vitro assays. However, long-term cytotoxicity will be evaluated in a murine model. We performed a detailed comparison of the phenotypic and functional characteristics of CAR T cells derived from pts with B-cell malignancies and HDs. DLBCL CAR T cells showed lower antigen specific activation but higher baseline activation which could lead to more differentiated exhausted T cells. CAR T cells derived from HDs show a higher proportion of the therapeutically relevant CAR+CD8+CD27+PD1- cells compared to patients with mature B cell malignancies (CLL and DLBCL), which is maintained after TRAC knockout. This suggests allogeneic CAR T cells, such as UCART19, may provide a more effective product for pts with T cell dysfunction. Disclosures Graham: Gillead: Other: Funding to attend educational meeting; Servier: Research Funding. Jozwik:Servier: Research Funding. Metelo:Pfizer: Research Funding; Allogene: Research Funding. Almena-Carrasco:Servier: Employment. Peranzoni:Servier: Employment. Ramsay:Celgene Corporation: Research Funding; Roche Glycart AG: Research Funding. Dupouy:Servier: Employment. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Patten:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Roche: Honoraria, Research Funding. Benjamin:Amgen: Honoraria; Allogene: Research Funding; Gilead: Honoraria; Servier: Research Funding; Eusapharm: Consultancy; Pfizer: Research Funding; Takeda: Honoraria; Novartis: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document