Implications of Minimal Residual Disease Negative Complete Remission (MRD-CR) and Allogeneic Stem Cell Transplant on Safety and Clinical Outcome of CD19-Targeted 19-28z CAR Modified T Cells in Adult Patients with Relapsed, Refractory B-Cell ALL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 682-682 ◽  
Author(s):  
Jae H Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Yvette Bernal ◽  
Terence Purdon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Residual Disease ◽  
Predictive Marker ◽  
Post Treatment ◽  
Adult Patients ◽  
Cell Transplant ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: We have previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 in adult patients with relapsed or refractory (R/R) ALL (Park et al. ASH 2014). Herein, we further report the long-term outcome of a larger cohort from our phase 1 clinical trial in adults with R/R ALL (NCT01044069) with a focused analysis on the role of post-treatment minimal residual disease (MRD) negativity as a predictive marker of survival as well as the effect of allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to or after CAR T cell infusion on safety and clinical outcome. Patients and Methods: Adult patients with R/R B-cell ALL (B-ALL) were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retroviral vector encoding a CAR comprising a CD19-specific scFv and CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 - 3x106 19-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells. Post-treatment MRD was assessed at day 14-28 by multiparameter flow cytometry in bone marrow (BM) samples. Results: 44 patients have been treated to date. The median age was 45 years (range, 22-74). 14 patients (32%) had Philadelphia chromosome positive (Ph+) ALL (T315I mutation in 5 patients), 17 patients (39%) had prior allo-HSCT, and 24 patients (55%) had ≥ 3 prior lines of ALL therapy. Of the 44 patients, 43 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 22 of the 43 patients (51%) had morphologic disease (≥5% blasts in BM or measurable extramedullary disease) and the remaining 21 patients had minimal disease (<5% blasts in BM). 36 patients (84%) were in complete remission (CR) after 19-28z CAR T-cell infusion. MRD analysis was performed in 35 of 36 CR patients, and 29 of these 35 patients (83%) achieved an MRD-negative CR (MRD-CR). As of July 13, 2015, the median follow-up was 4.2 months (range 1-45), with 16 patients having at least 6 months of follow-up. Responses appear durable with 7 patients remaining disease-free beyond 1 year up to 45 months. A median overall survival (OS) of all patients and patients who achieved MRD-CR is 8.5 months and 10.8 months, respectively. Post-treatment MRD status emerged as a strong predictive marker of OS: OS at 6 months was 76% (95% CI: 51-89) in the MRD-CR cohort vs. 14% (95% CI: 8-45) in the MRD+CR cohort. In contrast, allo-HSCT after achieving CR with CAR T cell infusion did not affect the survival rate. Of the 36 patients in CR following the T cell infusion, 12 patients underwent allo-HSCT. OS at 6 months was 70% (95% CI: 33-89) in patients who underwent post-CAR allo-HSCT vs. 64% (95% CI: 36-82) in patients who did not get allo-HSCT after CAR T cells. Comparing baseline disease characteristics of patients who had prior allo-HSCT before the CAR T cell treatment vs. no prior allo-HSCT, patients who had prior allo-HSCT (n=17) were similar in age (median age 45 vs. 46), but had higher disease burden (65% with morphologic disease vs. 44%), were more heavily pretreated (59% of patients with ≥4 lines of therapy vs. 15%), and included more high-risk disease (41% with Ph+ ALL vs. 26%). However, there was no statistically significant difference in CR rates (75%, CI: 48-93 vs. 89%, CI: 71-98), incidences of severe cytokine release syndrome (24% vs. 22%), and OS at 6 months (57% vs. 60%) between these two cohorts. Fewer patients who had prior allo-HSCT underwent another allo-HSCT following CAR T cell infusion: 2 patients vs. 10 patients with no prior all-HSCT. Although no obvious case of graft-versus-host disease (GvHD) was noted, one patient experienced a grade 3 gastrointestinal toxicity that may have been related to GvHD. Conclusions: These data confirm the potent anti-tumor efficacy of 19-28z CAR T cells (JCAR015) in adult patients with R/R ALL. MRD negativity following the 19-28z CAR T cell treatment is highly predictive of survival, and allo-HSCT post-CAR T cell infusion had no significant impact on survival. Furthermore, 19-28z CAR T cells appear to be safe in patients who had prior allo-HSCT, and may represent an attractive alternative option to second allo-HSCT. These findings are being confirmed in an ongoing multi-center, pivotal phase 2 trial evaluating JCAR015 in adult patients with R/R ALL. Disclosures Park: Amgen: Consultancy; Genentech: Research Funding; Juno Therapeutics: Other: Advisory Board, Research Funding. Riviere:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Curran:Juno Therapeutics: Consultancy. Sadelain:Juno Therapeutics: Consultancy, Equity Ownership, Other: Co-Founder, stockholder, Patents & Royalties: Licensed patents on CARs. Brentjens:Juno Therapeutics: Other: Co-founder, stockholder and consultant.

CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update

2018 ◽  
pp. e6-e15 ◽  
Author(s):  
Adam D. Cohen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Cellular Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non–gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date. Multiple antigen targets, including B-cell maturation antigen (BCMA), CD19, CD38, CD138, and SLAMF7, are being explored for myeloma, and BCMA has emerged as the most promising. Preliminary data from four phase I studies of BCMA CAR T cells, each using a different CAR construct, that involved 90 evaluable patients with relapsed/refractory disease have been reported. These data show response rates of 60% to 100%, including minimal residual disease (MRD)-negative complete remissions, at effective doses (> 108 CAR-positive cells) after lymphodepleting conditioning. Response durability has been more variable, likely related to differences in CAR T-cell products, lymphodepleting regimens, patient selection criteria, and/or underlying biology/prognostic factors. In the two most recent studies, however, most patients remained progression free with median follow-up time of 6 to 10 months; some ongoing remissions lasted more than 1 year. Toxicities are similar to those from CD19 CAR T cells and include cytokine release syndrome and neurotoxicity that is reversible but can be severe. Multiple BCMA CAR T-cell studies are ongoing. Future directions include combinations with immunomodulatory drugs, checkpoint inhibitors, or other CAR T cells, as well as use of gene-edited cellular products to enhance the safety and efficacy of this approach.

Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7516-7516 ◽  
Author(s):  
Michael Wang ◽  
Leo I. Gordon ◽  
Maria Lia Palomba ◽  
Jeremy S. Abramson ◽  
Charalambos Andreadis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Phase 1 ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

7516 Background: Most pts with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. We report initial dose-finding results from pts with R/R MCL treated with liso-cel (JCAR017), an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1 TRANSCEND study. Methods: Eligible pts had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior lines of therapy. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels (DL): DL1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Results: At data cutoff, 9 pts (DL1, n = 6; DL2, n = 3) had received liso-cel. The median (range) age was 66 (58‒78) years; 7 pts were male. Histologies included blastoid (n = 3) and pleiomorphic (n = 1) variants. 8 pts had documented Ki67 > 30% (40%‒80%); 1 pt had TP53 mutation. Pts had received a median of 5 (3‒7) prior therapies; 3 pts had received prior hematopoietic stem cell transplant. All 9 pts had prior ibrutinib; 4 had a best response of progressive disease on ibrutinib. 6/9 pts (67%) received bridging chemotherapy. 4/9 pts (44%) had serious treatment-emergent adverse events (TEAEs). 5/9 pts (56%) had grade (G) 3/4 TEAEs, primarily anemia, neutropenia, and hypophosphatemia (22% each). 3/9 pts (33%) had cytokine release syndrome (CRS); all were G1. Median time to CRS onset was 6 (2‒7) days; median time to resolution was 6 (2‒6) days. 1 pt received tocilizumab and corticosteroids. There were no neurological events. 4 pts died, all in DL1 (3 from disease progression; 1 after receiving new anticancer therapy post liso-cel). Overall response rate was 78% (7/9 pts; 4/6 in DL1, median follow-up 12.4 [95% CI: 9.2–12.4] mo; 3/3 in DL2, median follow-up 1.4 [95% CI: 1.0–1.4] mo). 2 pts in DL1 maintained a durable CR until last follow-up (day 281 and 378, respectively). Median time to peak CAR+ T cell expansion: 9.5 (9–10) days at DL1 and 17.5 (10–27) days at DL2. Conclusions: In this phase 1 study in pts with R/R MCL, liso-cel treatment showed tolerable toxicity and had clinical activity. Updated DL2 data and longer follow-up will be presented. Clinical trial information: NCT02631044.

TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7501-7501 ◽  
Author(s):  
Tanya Siddiqi ◽  
Kathleen Anne Dorritie ◽  
Jacob Drobnyk Soumerai ◽  
Deborah Marie Stephens ◽  
Jason A Dubovsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Complete Blood Count ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Cell Product ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

7501 Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10−4) and by NGS in bone marrow (BM; 10−6). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.

scholarly journals Safety and Efficacy of Low Dose CD19 Targeted Chimeric Antigen Receptor T (CAR-T) Cell Immunotherapy in 47 Cases with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 649-649 ◽  
Author(s):  
Biping Deng ◽  
Alex Hongsheng Chang ◽  
Junfang Yang ◽  
Jing Pan ◽  
Xian Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Low Dose ◽  
Residual Disease ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Pre Treatment

Abstract Abstract Introduction: Patients (pts) with relapsed refractory B-ALL are mostly incurable by chemotherapy. The disease free survival (DFS) is low even treatment with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We explored treatment of 47 cases of relapsed refractory B-ALL with low dose CD19 CAR-T cells and assessed the clinical safety and efficacy. Patients and Methods: (6-8)X107 pts' peripheral blood mononuclear cells(PBMCs) were activated with CD3 and CD28 antibodies for 24h, then transduced with the lentivirus encoding anti-CD19-CD3zeta-4-1BB CAR (Image1/Picture1) and cultured for 5-6 days in serum-free media containing IL2,IL7,IL15,IL21. All pts except one who had persistent cytopenia received cyclophosphamide 250 mg/m2/d X 3d, and fludarabine 30 mg/m2/d X 3d, then CAR-T cell infusion. Between Jul.31 2015 and Jul. 15 2016, a total of 47 cases were treated with CAR-T cells (Chart1). 37/47 cases had frank hematologically relapsed refractory B-ALL, who could not achieve complete remission (CR) after more than 1 cycles of chemotherapy. The median prior chemotherapy duration was 18 months. The median pre-treatment bone marrow blast percentage was 67% (6.5-98.5%). The most recently treated 15 cases had their PB blasts <30% and had no brain mass. 10/47 cases had persistent positive minimal residual disease (MRD) per flow cytometry (FCM) after more than 3 cycle of chemotherapy, except one who had severe pneumonia after 1 cycle of chemotherapy. The MRD pre-treatment were ranging from 0.01%-1.53%. Chart 1: Characteristics of Patients Pre-CAR-T Image 1/Picture 1: Results: The pts received a median of 10 (0.5-140) X104cells/kg CAR-T cells, and the most recently treated 15 cases all received 10 X 104cells/kg. The median observation period was 201 days (20-368 days). On day 16-20 after CAR-T infusion, 31/35 (88.6%) relapsed hematological refractory cases achieved CR or incomplete CR(Cri), and 29/35 cases (82.9%) achieved negative MRD by FCM(CMR: complete molecular remission). No extramedullary leukemia was detected in any cases with residual disease. The most recently treated 15 consecutive cases all achieved CR with only mild (<grade 2) cytokine release syndrome (CRS). 2 cases could not be evaluated for efficacy because 1 died from severe pancytopenia and 1 died from intracranial hemorrhage during the first month of the study. 4 cases did not achieve CR but all those pts only received less than 5x104/kg CAR-T cells. 15/17 CR cases were bridged into allo-HSCT and have remained in CMR with a median follow-up of 197 days (100-303 days). 25 CR cases have been followed up for more than 60 days, 5/25 pts had hematological relapse and 4/25 pts became MRD+ again. The median time to relapse was 64 days (52-193 days), with 5 pts CD19-, 2 CD19 dim and 2 CD19+ by FCM. The major side effect was CRS. The median time to development of CRS was 7 days (1-12) with median CRS grade 2 (1-5). 9/10 (90%) refractory MRD+ cases became MRD- after CAR-T treatment. The median time to development of CRS of this group of patients was at day 6 (day 6-7) with median CRS grade 1 (0-1). Conclusion: Our anti-CD19 CAR-T cell therapy can result in a high CR/CRi /CMR rate in pts with refractory B-ALL and could overcome pre-existing risk factors for poor outcomes, including complex chromosome abnormalities, poor gene mutations, inherited predisposing gene mutation, extramedullary leukemia etc. Pts could be safely bridged into allo-HSCT for potential cure. The dose of infused CAR-T cells in our patients was far lower than previously reported in the literature and the culture period was only 6-7 days, which could dramatically reduce the cost of the CAR-T therapy. 10X104cells/kg of CAR-T cells was a safe and effective number for treating B-ALL. The major complication was CRS and the severity of CRS was directly correlated with the number of malignant B cells in the PB. The efficacy of CAR-T therapy was correlated to the infused number of CAR-T cells. The most recently treated 15 consecutive cases all achieved CR without severe CRS suggesting that the optimal number of CAR-T cells and patient selection are important for the efficacy and safety. Table. Table. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

CD19-Targeted 19-28z CAR Modified Autologous T Cells Induce High Rates of Complete Remission and Durable Responses in Adult Patients with Relapsed, Refractory B-Cell ALL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 382-382 ◽  
Author(s):  
Jae H Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Yvette J Bernal ◽  
Sarah Yoo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adult Patients ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and dismal prognosis with a median overall survival (OS) < 6 months and 5-year OS ≤10%. We have previously reported a high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19 in adult patients with CLL and ALL (Brentjens R et al. Blood 2011; Davila M et al. Sci Transl Med2014). Herein, for the first time, we further report the long-term outcome of our phase I clinical trial in adults with relapsed/refractory (R/R) ALL (NCT01044069) with analysis on potential predictive markers of response and neurological toxicities. Patients and Methods: Adult patients with R/R B-ALL were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retrovirus encoding a CAR construct composed of anti-CD19 scFV linked to CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 – 3x10619-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells in ALL. Post-treatment minimal residual disease (MRD) was assessed at day 14-28 by multiparameter flow cytometry and deep sequencing in the bone marrow (BM) samples (Adaptive Biotech Corp.) Results: 24 patients have been treated. The median age was 56 years (range, 23-74). 6 patients (25%) had Ph+ B-ALL (T315I mutation in 2 patients), 6 patients (25%) had prior allogeneic hematopoietic stem cell transplant (allo-HSCT), and 11 patients (46%) had 3 or more prior lines of ALL therapy before receiving the 19-28z CAR T cell therapy. Of the 24 patients, 22 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 12 of 22 patients had morphologic disease (6 to 97% blasts in the BM) and the remaining 10 patients had MRD. Twenty out of 22 patients (91%) were in complete remission (CR) after 19-28z CAR T-cell infusion, and 18 of these 20 patients (90%) achieved an MRD-negative CR. Ten of the 13 transplant eligible patients (77%) successfully underwent allo-HSCT following the 19-28z CAR T cell therapy. As of July 1, 2014, the median follow-up was 7.4 months (range 1-34), with 13 patients having at least 6 months of follow-up. Responses appear durable with 6 patients remaining disease-free beyond 1 year (range 12.6 – 34 months). Median overall survial (OS) is 9 months. 5 patients relapsed during the follow-up, including 1 patient with CD19 negative relapse. Three of the relapsed patients were treated again with the 19-28z CAR T cells, and two patients achieved a second CR. Comparing responders to non-responders, no association was observed between response and age (<60 vs. ≥60), prior allo-HSCT, number of prior therapies, or pre-treatment blast percentage. While none of the 10 patients with MRD at the time of T cell infusion developed cytokine release syndrome (CRS), 9 of 13 patients with morphologic disease at the time of the T cell infusion developed CRS with or without neurological symptoms that required intervention with an IL-6R antagonist or corticosteroid. A detailed analysis of serum cytokines demonstrated a consistent peak of IL-6 (22.2 to 553-fold increase) immediately prior to the development of neurological toxicities. Based on these data, we have developed a multi-disciplinary CRS management algorithm for patients at high risk in order to reduce the severity of CRS and improve safety of the 19-28z CAR T cell therapy. Conclusions: While longer follow-up is needed to confirm the durability of the observed responses, the potent induction of MRD-negative responses and successful long-term outcomes, including subsequent allo-HSCT without apparent additional post-transplant toxicities, strongly support the use of 19-28z CAR T cells in adult patients with B-ALL. A temporal relationship between serum IL-6 levels and neurological toxicities indicates that early intervention with IL-6 directed therapy may be more effective in ameliorating neurological toxicities in patients with morphologic disease at the time of T-cell infusion. These findings will need to be evaluated systematically and confirmed in a larger phase 2 trial. Disclosures Park: Juno Therapeutics: Research Funding. Riviere:Juno Therapeutics: Consultancy, scientific co-founders Other. Sadelain:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other.

Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7008-7008 ◽  
Author(s):  
Jae Hong Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Brigitte Senechal ◽  
Yongzeng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Burden ◽  
Adult Patients ◽  
Term Survival ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

7008 Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-ALL. However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL (NCT01044069) with a focus to identify those patients who optimally benefit from 19-28z CAR T cell therapy with durable long-term survival and reduced toxicities. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR following conditioning chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion; patients with < 5% blasts were classified as minimal residual disease (MRD) cohort vs. patients ≥5% blasts as morphologic disease cohort. Response assessment occurred at 4 weeks. Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p = 0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 – 36.2) (p = 0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p = 0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p = 0.0326 and p = 0.0001, respectively). Conclusions: Despite comparable initial CR rates regardless of pre-treatment disease burden, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Clinical trial information: NCT01044069.

scholarly journals IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL NEUROTOXICITY CORRELATES WITH PRETREATMENT AND ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii360-iii360
Author(s):  
Juliane Gust ◽  
Ashley Wilson ◽  
Olivia Finney ◽  
Kendra Jae Hartsuyker ◽  
Prabha Narayanaswamy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pediatric Patients ◽  
Cell Transplant ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Baseline Serum ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract OBJECTIVE Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is complicated by neurotoxicity in approximately 40% of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAP and S100b. We now hypothesize that NFL is also a useful biomarker of neuronal injury related to abnormal blood-brain-barrier and glial function. METHODS We used the Mesoscale Discovery platform to measure CSF and serum NFL levels in a consecutive cohort of 43 pediatric patients with B cell ALL who received CD19-directed CAR T cells. In addition, we will present expansion cohort measurements of NFL and GFAP (N=95). RESULTS CSF NFL levels prior to CAR T cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 for severe vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338) and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum, pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL, range 1–7.5pg/mL). However, there was no correlation with neurotoxicity, history of CNS radiation, peripheral neuropathy, stem cell transplant, or number of prior chemotherapies. Day 7 serum NFL levels did not change significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254). CONCLUSION We conclude that CSF NFL is promising biomarker of CAR T neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.

New technologies to improve CAR T cell generation and biomanufacturing will lead to safer, more therapeutically effective cells

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
T Cells ◽  
T Cell ◽  
New Technologies ◽  
Residual Disease ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Individual Site ◽  
Car T ◽  
Manufacturing Techniques

Clinical trials, including chimeric antigen receptor (CAR) T cell therapy for a range of terminal tumors, are now ongoing in several locations across the world, and the commercialization of some of these therapies is likely to begin in the near future. Because of the FDA's approval of CD19-directed CAR T cells for the treatment of relapsed/refractory ALL and DLBCL, a multibillion-dollar industry of potentially curative cell-based immunotherapies has sprung up around the treatment of cancer. Although these successes have been achieved, CAR T cell efficacy in both hematopoietic and non-hematopoietic cancers is frequently hampered by low therapeutic levels of CAR T cell expansion, a lack of long-term persistence of these cells, failure to achieve deep molecular remissions (defined as incomplete elimination of minimal residual disease), and decreased anti-tumor function/survival in the patient. There is no doubt that the application of several new technologies aimed at improving CAR T cell development and biomanufacturing that are successful in increasing anti-tumor potency, preventing resistance, mitigating severe adverse events, and lowering financial toxicity will result in safer, more clinically effective CAR T cells that are more affordable and therefore more widely available. In the end, careful management of CAR T cell centers on an individual site basis, anticipating regulatory challenges, and coordinating manufacturing techniques will all contribute to the faster integration of these medications into standard cancer treatment.

Interventions and Outcomes of Adult Patients with B-ALL Progressing After CD19 Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2021 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Jessica R Flynn ◽  
Isabelle Rivière ◽  
Mithat Gonen ◽  
Xiuyan Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Adult Patients ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has become a breakthrough treatment for patients with relapsed/refractory B acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult B-ALL patients who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T therapy was 5.5 months. Median survival after post-CAR T progression was 7.4 months. A high disease burden at the time of CAR T cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment for post-CAR T disease progression and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 of 12 patients (58.3%) achieved CR after blinatumomab and/or inotuzumab administered after post-CAR T failure. Multivariate analysis demonstrated longer remission duration from CAR T cells was associated with superior survival after progression following CAR T therapy. In conclusion, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor though a subset of patients achieved sustained remissions to salvage treatments including blinatumomab, inotuzumab and re-infusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T therapy and improve outcomes of these patients.

scholarly journals Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI

2021 ◽  
Author(s):  
Veronica P. Dubois ◽  
Olivia C. Sehl ◽  
Paula J. Foster ◽  
John A. Ronald
Keyword(s):  
T Cells ◽  
T Cell ◽  
Field Strength ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
3 Tesla ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Purpose Chimeric antigen receptor (CAR) T cell cancer immunotherapies have shown remarkable results in patients with hematological malignancies and represent the first approved genetically modified cellular therapies. However, not all blood cancer patients respond favorably, serious side effects have been reported, and the treatment of solid tumors has been a challenge. An imaging tool for visualizing the variety of CAR-T cell products in use and being explored could provide important patient-specific data on CAR-T cell location to inform on potential success or failure of treatment as well as off-target toxicities. Fluorine-19 (19F) magnetic resonance imaging (MRI) allows for the noninvasive detection of 19F perfluorocarbon (PFC) labeled cells. Our objective was to visualize PFC-labeled (PFC +) CAR-T cells in a mouse model of leukemia using clinical field strength (3 Tesla) 19F MRI and compare the cytotoxicity of PFC + versus unlabeled CAR-T cells. Procedures NSG mice (n = 17) received subcutaneous injections of CD19 + human B cell leukemia cells (NALM6) expressing firefly luciferase in their left hind flank (1 × 106). Twenty-one days later, each mouse received an intratumoral injection of 10 × 106 PFC + CD19-targeted CAR-T cells (n = 6), unlabeled CD19-targeted CAR-T cells (n = 3), PFC + untransduced T cells (n = 5), or an equivalent volume of saline (n = 3). 19F MRI was performed on mice treated with PFC + CAR-T cells days 1, 3, and 7 post-treatment. Bioluminescence imaging (BLI) was performed on all mice days − 1, 5, 10, and 14 post-treatment to monitor tumor response. Results PFC + CAR-T cells were successfully detected in tumors using 19F MRI on days 1, 3, and 7 post-injection. In vivo BLI data revealed that mice treated with PFC + or PFC − CAR-T cells had significantly lower tumor burden by day 14 compared to untreated mice and mice treated with PFC + untransduced T cells (p < 0.05). Importantly, mice treated with PFC + CAR-T cells showed equivalent cytotoxicity compared to mice receiving PFC − CAR-T cells. Conclusions Our studies demonstrate that clinical field strength 19F MRI can be used to visualize PFC + CAR-T cells for up to 7 days post–intratumoral injection. Importantly, PFC labeling did not significantly affect in vivo CAR-T cell cytotoxicity. These imaging tools may have broad applications for tracking emerging CAR-T cell therapies in preclinical models and may eventually be useful for the detection of CAR-T cells in patients where localized injection of CAR-T cells is being pursued.

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