Abstract CT051: Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL

2020 ◽  
Author(s):  
Haneen Shalabi ◽  
Bonnie Yates ◽  
Shilpa Shahani ◽  
Haiying Qin ◽  
Steven L. HIghfill ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T ◽  
Children And Young Adults

scholarly journals Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults

Blood ◽  
2017 ◽  
Vol 129 (25) ◽  
pp. 3322-3331 ◽  
Author(s):  
Rebecca A. Gardner ◽  
Olivia Finney ◽  
Colleen Annesley ◽  
Hannah Brakke ◽  
Corinne Summers ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Car T Cells ◽  
Car T ◽  
Children And Young Adults ◽  
Intent To Treat

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Efficacy of Humanized CD19-Targeted Chimeric Antigen Receptor (CAR)-Modified T Cells in Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 217-217 ◽  
Author(s):  
Shannon L Maude ◽  
David M. Barrett ◽  
Susan R. Rheingold ◽  
Richard Aplenc ◽  
David T Teachey ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Previously Treated ◽  
Children And Young Adults

Abstract Background Targeted immunotherapy with CTL019, CD19-specific chimeric antigen receptor (CAR)-modified T cells, can produce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). However, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119). Design A pilot/phase 1 study of CAR-modified T cells containing a humanized anti-CD19 scFv domain (CTL119) enrolled children and young adults with relapsed/refractory B-ALL with or without prior exposure to a CAR T cell product. Patients previously treated with CD19-specific CAR-modified T cells were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response to prior CAR T cell therapy or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding a CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. The humanized scFv domain was developed by grafting the complementary determining regions of both the heavy and light chains onto human germline acceptor frameworks. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119. Results Thirty children and young adults aged 29 mo-24 yr were infused with CTL119. Eighteen patients had received prior allogeneic stem cell transplant (SCT). Eleven patients who previously received murine-derived CD19-specific CAR-modified T cells (CTL019, n=7; other, n=4) were retreated for B cell recovery (n=5), CD19+ relapse (n=5), or no response to prior CAR T cells (n=1). CNS disease or other extramedullary disease was the indication for enrollment in 6 and 3 patients, respectively. At assessment 1 month after infusion, 26/30 patients (87%) achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Of 11 patients previously treated with murine CD19-specific CAR-modified T cells, 7 (64%) achieved a CR at 1 month, 4 demonstrated no response. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in 5/7 responding patients. Two responding patients with positive MRD progressed to CD19+ relapse at 1.6 and 3 mo. In patients with no prior exposure to a CD19 CAR T cell product, MRD-negative CR was achieved in 19/19 patients (100%). One patient relapsed with CD19+ extramedullary disease at 2.8 mo. With a median follow-up of 4.2 mo (range, 1.0-14.1 mo) for all responding patients in both cohorts, 23/26 remain in remission with 1 proceeding to SCT in remission. B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 3 months or more in 11/18 patients with adequate follow-up: 1/6 retreatment, 10/12 CAR-naïve. Cytokine release syndrome (CRS) was observed in 28/30 patients and mild in most patients (grade 1, n=6; grade 2, n=18). Three patients experienced grade 3 CRS requiring supplemental oxygen or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Severe CRS was successfully managed with the IL6R antagonist tocilizumab in 3 patients. Neurologic toxicity included encephalopathy (n=5) and seizure (n=4) and was fully reversible. Conclusion In the first study of humanized anti-CD19 CAR T cells, CTL119 induced remissions in children and young adults with relapsed/refractory B-ALL, including 64% of patients previously treated with murine CD19-directed CAR T cells and 100% of CAR-naïve patients. Further investigation into CAR T cell persistence and anti-CAR responses will be vital to improve durable remission rates in this highly refractory population. Disclosures Maude: Novartis: Consultancy. Barrett:Novartis: Research Funding. Teachey:Novartis: Research Funding. Shaw:Novartis: Research Funding; Vitality Institute: Research Funding. Brogdon:Novartis: Employment. Scholler:Novartis: Patents & Royalties: Royalties, Research Funding. Marcucci:Novartis: Research Funding. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Frey:Amgen: Consultancy; Novartis: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. June:Novartis: Honoraria, Patents & Royalties, Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Grupp:Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding.

Minimal Residual Disease Negative Complete Remissions Following Anti-CD22 Chimeric Antigen Receptor (CAR) in Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 650-650 ◽  
Author(s):  
Nirali N Shah ◽  
Maryalice Stetler-Stevenson ◽  
Constance M. Yuan ◽  
Haneen Shalabi ◽  
Bonnie Yates ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Clinical Responses ◽  
Children And Young Adults

Abstract Background: Despite the success of anti-CD19 chimeric antigen receptor (CAR) therapy for relapsed/refractory ALL, not all respond and CD19-negative escape has been observed. To overcome this problem and to test an alternative target, we developed an anti-CD22 CAR. Widely expressed on B-lineage leukemia and lymphomas, CD22 represents an ideal target. The primary objectives of this phase I dose escalation study were to determine the feasibility of producing anti-CD22 CAR cells and to assess the safety of administering escalating doses of anti-CD22-CAR T cells in children and young adults with relapsed or refractory CD22+ B cell malignancies. Secondary objectives include determination of anti-leukemia effects, measurement of persistence of anti-CD22 CAR T cells, and evaluation of cytokine profiles. We report interim results based on the first 9 enrolled subjects in this first-in-human testing of anti-CD22 CAR therapy. Design: Children and young adults with relapsed/refractory CD22+ hematologic malignancies were eligible. Study endpoints included toxicity, feasibility, and clinical responses. All enrolled subjects underwent autologous leukopheresis for peripheral blood mononuclear cells. Cells were then CD3+ enriched and cultured in the presence of anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22 (M971BBz) CAR, with culture duration of 7-10 days. Subjects began lymphodepleting chemotherapy with fludarabine 25 mg/m2 on Days -4, -3 and -2 and cyclophosphamide 900 mg/m2 on day -2 followed by cell infusion on Day 0. Dose level 1(DL-1) started at 3 x 105 transduced T-cells/recipient weight (kg), with DL- 2 at 1 x 106transduced T cells/kg, respectively. Results: We report on outcomes for the first 9 subjects enrolled and treated. The median age was 20 years (range, 7-22 years), and all had CD22+ ALL. All 9 subjects had previously undergone at least one prior allogeneic hematopoietic stem cell transplant, and 2 patients had received 2 prior transplants. Seven subjects had previously received treatment with anti-CD19 CAR-T cell therapy of whom 6 had a CD19 negative/dim antigen escape. All subjects had CD22 expression on > 99% of their malignancy, with a median site density of 2589 molecules per cell (range 846-13452). Dose-escalation was as follows: 6 subjects treated at DL-1 due to expansion at this level following DLT in the second subject with grade 3 diarrhea; 3 subjects treated at DL-2 without DLT. CAR expansion and cytokine release syndrome (CRS) was seen in 6 patients with a maximum CRS grade 2. Anti-CD22 CAR cells were detected in the peripheral blood, CSF and bone marrow of all responders. Clinical responses were evaluated at day 28 (+/- 4 days). Four of 9 (44%) subjects evaluable for response attained a complete marrow remission, all of whom were MRD negative. This included all 3 subjects treated at the second dose level with a sustained remission at 3 months. Conclusions: This first-in-human anti-CD22 CAR T-cell therapy is safe, feasible and clinically active in patients with leukemia who have undergone prior CAR therapy. MRD negative complete remissions were seen in patients who were both CAR-naïve or had previously been treated with anti-CD19 CAR and were CD19 negative. Accrual is ongoing. Disclosures Lee: Juno: Honoraria. Mackall:NCI: Patents & Royalties: B7H3 CAR.

scholarly journals Outcomes of Children and Young Adults with Acute Lymphoblastic Leukaemia Administered Inotuzumab Pre CAR-T Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1743-1743
Author(s):  
Khushnuma Mullanfiroze ◽  
Giorgio Ottaviano ◽  
Avijeet K Mishra ◽  
Maria Gabelli ◽  
Arina Lazareva ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Children And Young Adults ◽  
The Uk

Abstract Introduction: Immunotherapies like Inotuzumab ozogamicin (InO), Blinatumomab and Chimeric antigen receptor T cell therapy (CAR-T) have revolutionized outcomes in patients with Relapse/Refractory Acute Lymphoblastic Leukaemia (R/R ALL) with event free survival (EFS) of 50% at 1 year (Maude et al. 2018). Optimal phasing of these agents has not been clearly defined and depends on antigen expression on blasts, CNS status, T cell number and prior disease response. InO, a CD22 targeting antibody-drug conjugate has proven efficacy in adults (Kantarjian et al., 2016) and children as a bridge to allogeneic stem cell transplantation (allo-SCT) with a favourable toxicity profile (Brivio et al. 2021). However, outcomes following the use of InO prior to CAR-T therapy are still not established. This study provides a retrospective analysis of children and young adults who received InO as part of pre-CAR-T management (before leucapheresis or as bridging therapy to CAR-T infusion). Methods: Patients aged 0-25years with R/R ALL were eligible for the study if they received InO pre-CAR-T therapy. Retrospective data collection was performed using a standardised form from CAR-T centres in the UK. Response to CAR-T therapy and/or relapse was evaluated at 1, 3, 6, 12 months or at last follow-up. Results were compared to a control cohort of R/R ALL patients treated with tisagenlecleucel but without preceding InO, over a contemporaneous period, at the largest paediatric CAR-T centre in the UK. Results: Fourteen patients from 5 paediatric and young adult centres in the UK received InO after screening for CAR-T therapy. InO was used pre-leucapheresis, as bridging and for both in 2, 11 and 1 respectively. Two were excluded from outcome analysis (1 adolescent with Trisomy 21 and transfusion induced hepatic siderosis died due to VOD while awaiting CAR-T production and 1 failed CAR-T manufacture despite achieving an adequate T cell harvest as per manufacturer guidance). Twelve (85%) patients were able to receive CAR-T infusion at a median of 1 month (range 0.7-5.6 months) from first InO dose. InO was well tolerated with 21% developing febrile neutropenia and grade 4 cytopenias. Use of InO pre-leucapheresis led to successful manufacture of CAR-T cells in 2/3 (66%). InO group was compared with 27 children who received CAR-T without preceding InO over the same time period. Table 1 summarises patient and CAR-T characteristics of the two groups which were comparable. Median follow-up of the InO and non-InO groups was 10 months (range 2.8- 30.1 months). In the InO group(n=12), 3 (25%) remained leukemia free at last follow up. Nine patients (75%) relapsed. All relapses occurred within 6 months from CAR-T infusion. Seven (58%) of those who relapsed died at a median of 7.8 months post CAR-T infusion and 2 (16.6%) were salvaged with further therapy. Subsequent therapy (alternate CAR-T and/or allo-SCT) was carried out in 4/12 (33%) patients in the InO group and in 5/27 (18.5%) in the non-InO group (p= 0.2). EFS was significantly higher in the non-InO group (53% vs 12%, p=0.0009), as was OS (86% vs 13%, p=0.004) (Figure 1). Conclusion: This study provides a direct comparison between two contemporaneously treated cohorts with R/R ALL receiving CAR-T therapy. InO prior to CAR T cell therapy was well tolerated despite the cohort being heavily pre-treated except for one patient who developed fatal VOD prior to CAR T cell infusion. InO was given for disease debulking, rather than to achieve MRD negativity and hence majority of the cohort (75%) received only 1 dose of InO in bridging rather than the usual schedule of three doses weekly per cycle. Outcomes for the non-InO group were comparable to those treated on the ELIANA study but the OS of the InO group was significantly lower (13% vs 86% p= 0.004). Potential reasons include an impact of InO on function of CAR-T cells in vivo or a deleterious effect of InO on the B cell compartment such that CAR-T cells prove less effective. Due to the retrospective nature of the study, it is possible there was an inherent bias to use InO in patients with more resistant disease, although the very comparable pre CAR-T bone marrow disease burden in each group suggests this was not the case. The small size of the cohorts may also have exaggerated differences in outcome. Ultimately, randomised controlled studies of InO pre-CAR-T are required before firm conclusions about its impact on outcomes post CAR-T therapy can be ascertained. Figure 1 Figure 1. Disclosures Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Nicholson: BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; Pfizer: Consultancy. Amrolia: ADC Therapeutics: Other: Named inventor on a patent which is being transferred to ADCT.; Autolus: Patents & Royalties. Ghorashian: Novartis: Honoraria; UCLB: Patents & Royalties.

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis

2021 ◽  
Author(s):  
Nicholas A. Vitanza ◽  
Adam J. Johnson ◽  
Ashley L. Wilson ◽  
Christopher Brown ◽  
Jason K. Yokoyama ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Interim Analysis ◽  
Cns Tumors ◽  
Car T Cells ◽  
Car T ◽  
Children And Young Adults

CD19-targeted chimeric antigen receptor (CAR) T cells in CNS relapsed acute lymphoblastic leukemia (ALL).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10511-10511 ◽  
Author(s):  
Haley Newman ◽  
Allison Emily Barz Leahy ◽  
Yimei Li ◽  
Hongyan Liu ◽  
Regina M Myers ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
T Cell ◽  
Cns Disease ◽  
Car T Cells ◽  
Car T Cell ◽  
Cns Relapse ◽  
Cranial Radiation ◽  
Car T ◽  
Children And Young Adults

10511 Background: CNS relapse of B-ALL is difficult to treat after cranial radiation or multiple relapses. Durable remissions of relapsed/refractory (r/r) B-ALL have been seen with CD19 CAR T cells; however, most trials excluded patients with active CNS disease. As we observed CAR trafficking into the CSF, we hypothesized that CD19 CAR T cells could control CNS B-ALL. Methods: We identified children and young adults with r/r CNS B-ALL treated on 4 clinical trials of CD19 CAR T cells, CTL019 or CTL119. NCT01626495 and NCT02435849 excluded active CNS disease, while the former in an amendment as well as NCT02374333 and NCT02906371 permitted active CNS disease controlled on therapy. All trials permitted CNS disease that cleared and excluded bulky intracranial disease that did not improve. We analyzed outcomes (CR, RFS) and safety. Results: We identified 65 patients 1-29y (median 10y) with r/r CNS B-ALL (CNS+) of 182 treated with CTL019/CTL119. There were no differences in age, sex, history of SCT or neurologic comorbidities in the CNS+ and CNS- cohorts. CNS+ patients were more likely to be in ≥2nd relapse (74% vs 46%, p < 0.01), to have received cranial radiation (58% vs 11%, p < 0.01), to have detectable CNS disease (p = 0.02) and less bone marrow disease pre-infusion (p < 0.01). At 1 mo post infusion, 62 (95%) CNS+ and 110 (94%) CNS- patients were in CR; 1 in each cohort died of sequelae of CRS and was inevaluable for response. All patients with CNS disease detected pre-infusion cleared by mo 3, including 9 in the CNS+ cohort [5 CNS2 ( < 5 CSF WBC with blasts), 4 CNS3 ( > 5 CSF WBC with blasts or exam/imaging evidence)] and 8 in the CNS- cohort (isolated CNS2 status pre-infusion). There was no difference in RFS (p = 0.28) in the CNS+ and CNS- cohorts [24-mo RFS: 61% (95% CI 46-73%) and 60% (95% CI 48-70%)]. There were 4 CNS relapses in the CNS+ cohort, and 1 in the CNS- cohort. Encephalopathy rate and grade was similar in the CNS+ and CNS- cohorts (52% vs 40% any grade; 12% vs 11% grade 3/4; p = 0.41). There were no deaths due to neurotoxicity (NT) and no statistically significant differences in incidence or severity of any NT or CRS in the CNS+ and CNS- cohorts. Conclusions: The CD19 CAR T cell therapies CTL019/CTL119 are effective at clearing CNS disease and inducing durable remissions in children and young adults with r/r CNS B-ALL. CNS relapse rates are low ( < 3%). Most CD19 CAR T cell trials excluded patients with active CNS disease, primarily due to the risk of NT. We show that patients with r/r CNS B-ALL that is adequately controlled prior to infusion can be safely treated with CD19 CAR T cells, with no increased risk of NT. Clinical trial information: NCT01626495, NCT02435849, NCT02374333, NCT02906371.

Sign in / Sign up

Export Citation Format

Share Document