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.

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.

Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Sham Mailankody ◽  
Andrzej J. Jakubowiak ◽  
Myo Htut ◽  
Luciano J. Costa ◽  
Kelvin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Phase 1 ◽  
Objective Response ◽  
Bridging Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

8504 Background: Orva-cel is an investigational, BCMA-directed CAR T cell product with a fully human binder. Over 100 pts have been treated in the EVOLVE phase 1 study. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). We now report results of the higher dose levels (DLs) in 51 pts who received orva-cel manufactured using the process intended to support commercial use. Methods: Pts with RRMM who had ≥3 prior regimens, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb), received orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide. Results: Median pt age was 61 (range, 33–77) y; median time from diagnosis was 7.0 (range, 1.7–23.6) y, with a median of 6 (range, 3–18) prior regimens. Overall, 92% of pts were penta-exposed (2 IMiDs, 2 PIs, and an mAb); 61% of pts received bridging therapy (77% were refractory to bridging therapy). Two pts had dose-limiting toxicities: grade 3 neurological event (NE) for >7 d at 300 × 106 CAR+ T cells and grade 4 neutropenia for >28 d at 450 × 106 CAR+ T cells. Key efficacy and safety outcomes are shown in the Table. Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). Grade ≥3 anemia, neutropenia, and thrombocytopenia at 29 d occurred in 21%, 55%, and 44% of pts (median time to resolution to grade ≤2 of any cytopenia, ≤2.1 mo). Grade ≥3 infections occurred in 14%. After a median follow-up (F/U) of 5.9 mo, median progression-free survival was not reached. Conclusions: Orva-cel at 300, 450, and 600 × 106 CAR+ T cells demonstrated manageable safety (CRS grade ≥3: 2%; NE grade ≥3: 4%) and compelling efficacy in heavily pretreated pts with RRMM, with a 91% objective response rate (ORR) and 39% complete response (CR)/stringent CR (sCR) rate. Updated results will be presented, including minimal residual disease, durability of response, and recommended phase 2 dose. Clinical trial information: NCT03430011 . [Table: see text]

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.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (>40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Aimee C Talleur ◽  
Renee M. Madden ◽  
Amr Qudeimat ◽  
Ewelina Mamcarz ◽  
Akshay Sharma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Allogeneic Hct ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p<0.01). The remaining 6 patients developed recurrent detectable leukemia within 2 to 9 months post-CAR T-cell infusion (1 patient detectable by NGS only). Notably, recurring leukemia remained CD19+ in 4 of 5 evaluable patients. All 4 patients with CD19+ relapse received a 2nd CAR T-cell infusion (one in combination with pembrolizumab) and 2 achieved MRDneg/CR. There were no significant differences in outcome between SJCAR19 study participants and patients who received tisagenlecleucel. With a median follow up of one year, the 12 month event free survival (EFS) of all 22 patients is 25% (median EFS: 3.5 months) and the 12 month overall survival (OS) 70% (median OS not yet reached). In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.

scholarly journals B Cell Maturation Antigen-Specific CAR T Cells for Relapsed or Refractory Multiple Myeloma: A Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3113-3113 ◽  
Author(s):  
Nico Gagelmann ◽  
Francis Ayuketang Ayuk ◽  
Djordje Atanackovic ◽  
Nicolaus Kroeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Overall Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

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.

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