Effect of chimeric antigen receptor-modified T (CAR-T) cells on responses in children with non-CNS extramedullary relapse of CD19+ acute lymphoblastic leukemia (ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10507-10507 ◽  
Author(s):  
Mala Kiran Talekar ◽  
Shannon L. Maude ◽  
George E Hucks ◽  
Laura S Motley ◽  
Colleen Callahan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Prior History ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

10507 Background: Anti-CD19 CAR-T cell therapies have shown high efficacy in inducing durable marrow responses in patients with relapsed/refractory CD19+ ALL. We now report on outcome of 10 patients with extramedullary (EM) involvement of ALL treated with CAR-T, including 5 patients who had EM disease at time of infusion. Methods: We identified patients treated on pediatric phase 1/2a trials of murine (CTL019) or humanized (CTL119) anti-CD19 CAR-T cells for isolated EM or BM/EM relapse of ALL. EM relapse was defined as involvement of non-CNS site by imaging +/- pathology within 12 months (mos) of infusion. Post infusion, patients had diagnostic imaging done at 1, 3, 6, 9, and 12 mos. Results: Among 97 patients receiving CAR-T, ten (CTL019, n=6; CTL119, n=4) were identified who had EM involvement on average 2.3 mos (range 0-9 mos) prior to infusion; including 5/10 at time of infusion. Sites of EM relapses included testes, sinus, parotid, bone, uterus, kidney and skin, and 5 patients had multiple sites of EM involvement. Patients ranged from 2-4 relapses of their ALL pre-CAR-T. Two had isolated EM relapse (sites were parotid and multifocal bony lesions in one; testis and sinus in second). All 10 patients had undergone hematopoietic stem cell transplantation prior to EM relapse, 2 had received radiation directed to the EM site prior to CAR-T. Five patients evaluated by serial imaging had objective responses: 2 had resolution of EM disease by day 28; 2 had resolution by 3 mos; 1 had continued decrease in size of uterine mass at 3 and 6 mos and underwent hysterectomy at 8 mos with no evidence of disease on pathology. In the 4 patients with prior history of skin or testicular involvement, there was no evidence by exam at day 28. One patient had progressive EM disease within 2 weeks of CAR-T cell infusion and died at 6 weeks. Three relapsed with CD19+ disease [1 skin/medullary- died at 38 mos post CAR-T; 2 medullary (1 died at 17 mos, 1 alive at 28 mos)]. The remaining 6 are alive and well at median follow-up of 10 mos (range 3-16 mos) without recurrence of disease. Conclusions: Single agent CAR-T immunotherapy can induce potent and durable responses in patients with EM relapse of their ALL. Clinical trial information: NCT01626495, NCT02374333.

The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia (ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 103-103 ◽  
Author(s):  
Shannon L. Maude ◽  
George E Hucks ◽  
Alix Eden Seif ◽  
Mala Kiran Talekar ◽  
David T. Teachey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Lymphoblastic Leukemia ◽  
Prior History ◽  
Cell Detection ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
T Cell Expansion

103 Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with relapsed B-ALL treated with murine (CTL019) or humanized (CTL119) anti-CD19 CAR T cells received 1-3 doses of the PD-1 inhibitor pembrolizumab (PEM) for partial/no response or prior history of poor CAR T cell persistence starting 14d-2mo post CAR T cell infusion. Results: PEM increased and/or prolonged detection of circulating CAR T cells in all 4 children, with objective responses in 2/4. It was well tolerated, with fever in 2 pts and no autoimmune toxicity. Pts 1-3 received CTL119 for CD19+ relapse after prior murine CD19 CAR T cells. Pt 1 had 1.2% CD19+ residual disease despite expansion with detectable CTL119 by D28 and received PEM at 2mo for progressive disease with decreasing circulating CTL119. CTL119 became detectable at 0.2% of CD3+ cells by flow cytometry, but disease progressed. Pt 2 had no response after initial CTL119 expansion with a rapid disappearance by D28. After CTL119 reinfusion with PEM added 14d later, circulating CAR T cells remained detectable at 4.4% by D28, but disease progressed with decreased CD19 expression. In Pt 3, prior treatment with both CTL019 and CTL119 produced CR with poor CAR T cell persistence followed by CD19+ relapse. CTL119 reinfusion combined with PEM at D14 resulted in CR with prolonged CTL119 persistence (detectable at D50 compared to loss by D36 after 1st CTL119 infusion). Pt 4 received PEM for widespread extramedullary (EM) involvement at D28 post CTL019 infusion despite marrow remission. Initial CTL019 expansion peaked at 63% at D10 and fell to 20% at D28. Resurgence of CTL019 expansion, with a 2nd peak of 70% 11d after PEM, was associated with dramatic reduction in PET-avid disease by 3mo post CTL019. Conclusions: PEM was safely combined with CAR T cells and increased or prolonged CAR T cell detection, with objective responses seen. Immune checkpoint pathways may impact response to CAR T cell treatments and warrant further investigation. Clinical trial information: NCT02374333, NCT02906371.

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.

scholarly journals Haploidentical Donor-Derived CAR-T Cells Are Safely and Effectively Co-Infused with the Haploidentical Graft, Depleted of Ab T Cells: Report of Case Series

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1736-1736
Author(s):  
Larisa Shelikhova ◽  
Olga Molostova ◽  
Arina Rakhteenko ◽  
Rimma Khismatullina ◽  
Julia Abugova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Introduction Autologous chimeric antigen receptor (CAR) T cells induce high rate of deep remissions among children with relapsed/refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL). In a significant proportion of patients true cure is achieved only with HSCT as post-CAR-T consolidation. Seeking to combine the cytoreductive and curative power of HSCT with the antigen-specific activity of CAR-T we devised an approach with simultaneous infusion of haploidentical ab T cell-depleted graft and CAR-T cells, derived from the same donor. The approach was offered to patients with R/R B-ALL on a compassionate use basis and here the first experience is summarized. Patients and methods A total of 11 patients with relapsed/refractory BCP-ALL (n-10) and Burkitt leukemia(n-1), (5 female, 6 male, median age 8,3 y) were treated. Three patients had relapsed BCP-ALL after both haploidentical HSCT and autologous CD19 CAR-T cell, 3 after haploidentical HSCT, 2 after autologous CD19 CAR-T cell, 3 after intensive chemotherapy +/- blinatumomab (n=2). Seven patients had CD19 and CD22 positive leukemic cells in bone marrow (MRD+ n=1, >20% blasts n=6), 2 pts had MRD-level disease with CD22 positive blast cells and 2 pts were in CR2. Peripheral blood mononuclear cells used to produce CAR T cells were provided by the patient's transplant donor. The CliniMACS Prodigy T cell transduction (TCT) process was used to produce CD19 and СD19/22CAR-T cells. Five (45%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 6 (55%) pts. GvHD prophylaxis included tocilizumab at 8 mg/kg on day -1 and abatacept at 10 mg/kg on day -1, +7, +14, +28. Final product was administered without cryopreservation to the patients: 10 pts received allogeneic CAR T cell with haploidentical (n=10) and match related (n=1) TCRαβ-depleted graft (CD19 CAR- T cell n=1 and CD19/22 CAR- T cell n=10). The CAR-T cell product was administered at a dose of 0,1*10 6/kg of CAR-T cells in all pts. The median dose of CD34+ cells was 8.5 x10 6/kg (range 5-15), αβ T cells - 56x10 3/kg (range 9-172). Results Primary engraftment was achieved in 10 of 11 pts (non-engraftment patient relapsed early), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. Cytokine release syndrome occurred in 7 patients (63%) and all were grade ≤3. Six patients (54%) had neurologic events (ICANS grade 3, n=1). No aGVHD 3-4 were observed, 4 pts developed grade 2 aGVHD (skin and gut). The median time to CAR-T cell peak expansion was 14 days (7-28). The median time to CAR-T cell persisted was 6 months (2-12) and B cell aplasia was 7 months. All engrafted patients achieved CR (MRD negative) at day +28 after CAR-T cell therapy, one patient died due to Mucormycosis at day +31. One patient relapsed after 2 months after HST. Eight patients are alive in CR with a median follow up 291 days (85-388). Conclusion Our early experience suggests that haploidentical CAR-T cells can be safely infused simultaneously with the hematopoietic stem cell graft on the platform of ab T cell depletion. The infusions did not compromise engraftment and GVHD control, while specific CAR-T toxicity was mild and manageable. We have documented allogeneic haploidentical CAR-T expansion and persistence. Prospective testing of the approach is warranted. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.

scholarly journals IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1 LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR, AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORS AND DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii360-iii360
Author(s):  
Nicholas Vitanza ◽  
Juliane Gust ◽  
Ashley Wilson ◽  
Wenjun Huang ◽  
Francisco Perez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Signs And Symptoms ◽  
Preliminary Evidence ◽  
Cns Tumors ◽  
Disease Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract We report preliminary results of three Phase 1 trials of repetitively dosed locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3 (BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary endpoints are feasibility and safety. Successful CAR T cell manufacture occurred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions; S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not begun treatment. None of the subjects developed new neurologic toxicities, although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No objective radiographic responses have been observed. Both BrainChild-01 subjects had transient systemic CRP elevations following infusions (S-001: peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week 1), possibly indicating an inflammatory response. Both subjects had post-infusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg, IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF) without concurrent systemic changes. In summary, we provide preliminary evidence of safety and feasibility of intracranial delivery of CAR T cells for pediatric CNS tumors.

Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia (AML)

Blood ◽  
2021 ◽  
Author(s):  
Hardikkumar Jetani ◽  
Almudena Navarro-Bailón ◽  
Marius Maucher ◽  
Silke Frenz ◽  
Christina Mathilde Verbruggen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Novel Target

Acute myeloid leukemia (AML) is attractive for the development of CAR T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic-acid-binding immunoglobulin-like lectin (Siglec)-6 as a novel target for CAR T-cells in AML. We designed a Siglec-6-specific CAR with a targeting-domain derived from a human monoclonal antibody JML‑1. We found that Siglec-6 is prevalently expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6-CAR T-cells confers specific anti-leukemia reactivity that correlates with Siglec-6-expression in pre-clinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6-expression on transformed B-cells in chronic lymphocytic leukemia (CLL) and show specific anti-CLL-reactivity of Siglec-6-CAR T-cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSC/P) and that treatment with Siglec-6-CAR T-cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6-CAR T-cell therapy may be used to effectively treat AML without a need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B-cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lacking expression of Siglec-6 on normal HSC/P is a key differentiator from other Siglec-family members (e.g. Siglec-3=CD33) and other CAR target antigens, e.g. CD123, that are under investigation in AML and warrants the clinical investigation of Siglec-6-CAR T-cell therapy.

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.

Updated results from ZUMA-3, a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy, in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3024-3024 ◽  
Author(s):  
Bijal D. Shah ◽  
William G. Wierda ◽  
Gary J. Schiller ◽  
Michael Russell Bishop ◽  
Januario E. Castro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Disease Burden ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

3024 Background: Promising results have been observed with KTE-C19, an anti-CD19 CAR T cell therapy, in refractory aggressive NHL in the ZUMA-1 trial (Blood 2016;128:LBA-6). We present here updated results from the ZUMA-3 phase 1 trial of KTE-C19 in adult patients (pts) with R/R ALL. Methods: Adult (≥18 y) pts with R/R ALL (Ph+ eligible), ≥25% bone marrow (BM) blasts, adequate organ function and ECOG status 0-1 received 1 or 2×106 CAR T cells/kg after conditioning with cyclophosphamide + fludarabine. Phase 1 primary endpoint is incidence of dose-limiting toxicity (DLT). Secondary endpoints include efficacy outcomes and biomarker associations. Results: As of Nov 1, 2016, 11 pts were enrolled; 10 received KTE-C19. One pt had a serious adverse event (SAE) prior to dosing and was not treated. KTE-C19 was successfully manufactured in all pts across a broad range of baseline absolute lymphocyte counts in 6 days in a centralized facility, with an approximate 2-week turnaround time. Pts were 60% men with 1-4 prior lines of therapy and high disease burden (median, 70% BM blasts). No pt (0/3) experienced a DLT at the 2×106 dose. Phase 1 was expanded to 6 pts at the same dose; 1 grade (Gr) 5 AE (multiorgan failure due to cytokine release syndrome [CRS]) was observed. Subsequent pts (4) received 1×106 CAR T cells/kg. Overall, the most common Gr≥3 AEs were cytopenias (80%), febrile neutropenia (50%), pyrexia (40%), and transaminitis (40%). Gr≥3 CRS and neurologic events (NEs) were reported in 20% and 40% of pts, respectively. Cerebral edema was not observed. All CRS (except Gr5) and 5 of 6 NEs (1 Gr3 ongoing at cut-off) resolved. Of the 8 efficacy evaluable pts, 6 achieved an MRD-negative (MRD–) complete response (CR, or CR + partial or incomplete hematopoietic recovery). Updated results will include additional pt follow-up and biomarker data. Conclusions: No DLTs were observed with KTE-C19 in adult pts with high BM disease burden; one pt had G5 CRS after the DLT cohort. Manufacturing was successful in all pts; most pts achieved an MRD– CR. Based on these results, ZUMA-3 continues to enroll pts with additional measures implemented to further enhance safety. Clinical trial information: NCT02614066.

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.

scholarly journals A Phase 1 Study with Point-of-Care Manufacturing of Dual Targeted, Tandem Anti-CD19, Anti-CD20 Chimeric Antigen Receptor Modified T (CAR-T) Cells for Relapsed, Refractory, Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4193-4193 ◽  
Author(s):  
Nirav N Shah ◽  
Fenlu Zhu ◽  
Carolyn Taylor ◽  
Dina Schneider ◽  
Winfried Krueger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Third Party ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Abstract Background: CAR-T cell therapy directed against the CD19 antigen is a breakthrough treatment for patients (pts) with relapsed/refractory (R/R) B-cell NHL. Despite impressive outcomes, not all pts respond and many that respond still relapse. Affordability and accessibility are further considerations that limit current commercial models of CAR-T products. Commercial CAR-T manufacturing is complex, time consuming, and expensive with a supply chain starting at the treating center with apheresis of mononuclear cells, cryopreservation, and shipping to and from a centralized third-party manufacturing site. We addressed these limitations in a Phase 1 clinical trial evaluating a first-in-human bispecific tandem CAR-T cell directed against both CD19 and CD20 (CAR-20.19-T) antigens for pts with R/R B-cell NHL. Through dual targeting we hope to improve response rates and durability of response while limiting antigen escape. We eliminated third party shipping logistics utilizing the CliniMACS Prodigy, a compact tabletop device that allows for automated manufacturing of CAR-T cells within a GMP compliant environment within the hospital. Most materials and reagents used to produce the CAR-T cell product were single-sourced from the device manufacturer. Methods: Phase 1 (NCT03019055), single center, dose escalation + expansion study to demonstrate feasibility and safety of locally manufactured second generation 41BB + CD3z CAR-20.19-T cells via the CliniMACS Prodigy. Feasibility was measured by ability to generate a target CAR-20.19-T cell dose for a minimum of 75% of subjects. Safety was assessed by the presence of dose limiting toxicities (DLTs) through 28 days post-infusion. Dose was escalated in a 3+3 fashion with a starting dose of 2.5 x 10^5 cells/kg, a target DLT rate <33%, and a goal treatment dose of 2.5 x 10^6 cells/kg. Adults with R/R Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) were eligible. CAR-T production was set for a 14-day manufacturing process. Day 8 in-process testing was performed to ensure quality and suitability of CAR-T cells for a potential fresh infusion. On Day 10, pts eligible for a fresh CAR-T infusion initiated lymphodepletion (LDP) chemotherapy with fludarabine 30 mg/m2 x 3 days and cyclophosphamide 500 mg/m2 x 1 day, and cells were administered after harvest on Day 14. Pts ineligible for fresh infusion received cryopreserved product and LDP was delayed accordingly. Results: 6 pts have been enrolled and treated with CAR-20.19-T cells: 3 pts at 2.5 x 10^5 cells/kg and 3 pts at 7.5 x 10^5 cells/kg. Median age was 53 years (48-62). Underlying disease was MCL in 3 pts, DLBCL in 2 pts, and CLL in 1 patient. Baseline data and prior treatments are listed in Table 1. CAR-T production was successful in all runs and all pts received their target dose. Three pts received fresh CAR-T cells and 3 pts received CAR-T cells after cryopreservation. To date there are no DLTs to report. No cases of Grade 3/4 cytokine release syndrome (CRS) or neurotoxicity (NTX) were observed. One patient had Grade 2 CRS and Grade 2 NTX requiring intervention. The other had self-limited Grade 1 CRS and Grade 1 NTX. Median time to development of CRS was Day +11 post-infusion. All pts had neutrophil recovery (ANC>0.5 K/µL) by Day 28. Response at Day 28 (Table 2) is as follows: 2/6 pts achieved a complete response (CR), 2/6 achieved a partial response (PR), and 2/6 had progressive disease (PD). One subject with a PR subsequently progressed at Day 90. The 3 pts who did progress all underwent a repeat biopsy, and all retained either CD19 or CD20 positivity. Pts are currently being enrolled at the target dose (2.5 x 10^6 cells/kg) and updated results will be provided at ASH. Conclusions: Dual targeted anti-CD19 and anti-CD20 CAR-T cells were successfully produced for all pts demonstrating the feasibility of a point-of-care manufacturing process via the CliniMACS Prodigy device. With no DLTs or Grade 3-4 CRS or NTX to report, and 2/6 heavily pre-treated pts remaining in CR at 3 and 9 months respectively our approach represents a feasible and promising alternative to existing CAR-T models and costs. Down-regulation of both target antigens was not identified in any patient following CAR-T infusion, and in-process studies suggest that a shorter manufacturing timeline is appropriate for future trials (10 days). Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Geron: Equity Ownership; Exelexis: Equity Ownership. Zhu:Lentigen Technology Inc., A Miltenyi Biotec Company: Research Funding. Schneider:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Krueger:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Worden:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; ADC Therapeutics: Research Funding. Johnson:Miltenyi: Research Funding. Dropulic:Lentigen, A Miltenyi Biotec company: Employment. Orentas:Lentigen Technology Inc., A Miltenyi Biotec Company: Other: Prior Employment. Hari:Takeda: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Sanofi: Honoraria, Research Funding.

scholarly journals A Feasibility and Safety Study of Non-Viral Genome Targeting Anti-CD19 CAR-T in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Yi Wang ◽  
Hui Wang ◽  
Ying Gao ◽  
Ding Zhang ◽  
Yan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: It has been made great clinical progresses in hematological malignancies by chimeric antigen receptor (CAR) T cell therapy which utilizes virus vector for manufacture. However, there're still issues unresolved, for instance, sophisticated virus production process, deadly Cytokine Release Syndrome (CRS) side-effect, and high recurrence rate, which probably limit the availability of CAR-T therapy. Non-viral Genome Targeting CAR-T (nvGT CAR-T) may provide a feasible solution to those unmet needs mentioned above. We used CRISPR-Cas9 and non-viral vector to insert anti-CD19 CAR DNA to a specific genome locus in human T cells, which in theory, produces more moderate CAR-T cells compared with conventional CAR-T cells. The efficacy of anti-CD19 nvGT CAR-T cells had been demonstrated in our previous pre-clinical studies, and in this Phase I clinical trial (ChiCTR2000031942), its safety and efficacy in relapsed/refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL) patients were explored. Objective: The primary objective of this Phase I trial is to assess safety, including evaluation of adverse events (AEs) and AEs of special interest, such as CRS and neurotoxicity. Secondary objective is to evaluate efficacy as measured by the ratio of complete remission (CR). Method: Peripheral blood mononuclear cells were collected from patients or allogeneic donors, then CD3+ T cells were selected and modified by nvGT vector to produce anti-CD19 CAR-T, then administrated to patients with r/r B-ALL. Up to July 2020, twelve patients with r/r B-ALL had been enrolled in this study and 8 patients completed their treatments and entered follow-up period. For 8 patients with follow-up data, the median age was 33 years (range, 13 to 61), and the median number of previous regimens was 5 (range, 2 to 11). The median baseline percentage of bone marrow (BM) blast is 72% (range, 24.5% to 99%). Among those subjects, 2 patients once have been conducted autologous or allogeneic hematopoietic stem cell transplantation (Auto-HSCT or Allo-HSCT), and 2 patients experienced serious infection before CAR-T infusion. No patient has been treated by any other CAR-T therapy before enrollment. Baseline characteristics refer to Table 1. Administering a lymphodepleting chemotherapy regimen of cyclophosphamide 450-750 mg/m2 intravenously and fludarabine 25-45 mg/m2 intravenously on the fifth, fourth, and third day before infusion of anti-CD19 nvGT CAR-T, all patients received an infusion at dose of 0.55-8.21×106/kg (Table 1). Result: Until day 30 post CAR-T cell infusion, 8/8 (100%) cases achieved CR and 7/8 (87.5%) had minimal residual disease (MRD)-negative CR (Table 1). Anti-bacterial and anti-fungal were performed in patients SC-3, SC-4 and SC-5 after CAR-T cell infusion, which seems no influence on efficacy. Patient SC-7 was diagnosed as T-cell Acute Lymphoblastic Leukemia before Allo-HSCT but with recent recurrence of B-ALL, which was MRD-negative CR on day 21 post nvGT CAR-T therapy. Up to July 2020, all cases remain CR status. CRS occurred in all patients (100%) receiving anti-CD19 nvGT CAR-T cell, including 1 patient (12.5%) with grade 3 (Lee grading system1) CRS, two (25%) with grade 2 CRS, and 5 (62.5%) with grade 1 CRS. There were no cases of grade 4 or higher CRS (Table 1). The median time to onset CRS was 9 days (range, 1 to 12 days) and the median duration of CRS was 6 days (range, 2 to 9 days). None developed neurotoxicity. No fatal or life-threatening reactions happened and no Tocilizumab and Corticosteroids administered following CAR-T treatment. Data including body temperature (Figure 1), CAR-positive T cell percentage (Figure 2), Interleukin-6 (IL-6) and Interleukin-8 (IL-8) (Figure 3 and 4), C-reactive Protein (CRP) (Figure 5), Lactate Dehydrogenase (LDH) (Figure 6), and Procalcitonin (PCT) (Figure 7), are in accordance with the trend of CRS. Conclusion: This Phase I clinical trial primarily validates the efficacy of this novel CAR-T therapy, however, it still needs time to prove its durability. Surprisingly, we find that nvGT CAR-T therapy is seemingly superior than viral CAR-T therapy in terms of safety. All subjects which are high-risk patients with high tumor burden had low grade CRS, even a few patients sent home for observation post infusion with limited time of in-patient care. Furthermore, patients could tolerate a higher dose without severe adverse events, which probably bring a better dose-related efficacy. Disclosures No relevant conflicts of interest to declare.

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