scholarly journals Refractory Cytokine Release Syndrome in Recipients of Chimeric Antigen Receptor (CAR) T Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2296-2296 ◽  
Author(s):  
Noelle V. Frey ◽  
Bruce L. Levine ◽  
Simon F. Lacey ◽  
Stephan A. Grupp ◽  
Shannon L Maude ◽  
...  
Keyword(s):  
T Cells ◽  
Research Funding ◽  
Disease Burden ◽  
High Dose ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Remission Rates ◽  
Significant Disease ◽  
Durable Remission

Abstract CTLO19 cells are CAR-modified T cells which recognize CD19 and produce high durable remission rates for pts with relapsed or refractory acute lymphoblastic leukemia (ALL). Cytokine Release Syndrome (CRS) has emerged as the major treatment related effect from CTL019, with symptoms that include high fevers and malaise but can progress to capillary leak, hypoxia and hypotension. CRS occurs hours to days after CTL019 infusion and correlates with rapid in vivo CTL019 expansion and marked elevation of serum IL6. In most cases, CRS is self-limited or rapidly reversed with anti-cytokine directed therapies. Here we report 3 cases of refractory CRS in adult pts with ALL. Our experience offers insight into clinical and investigational parameters describing this syndrome; highlights the variance of CRS across disease types and illustrates complexities of CRS management during concurrent infectious illness. As of 7/1/14, 97 pts (30 pediatric ALL, 12 adult ALL, 41 CLL, 14 NHL) have been treated with CTLO19. To capture clinical manifestations of CRS across protocols, we developed a novel CRS grading scale which will be described. Severe CRS (Gr 3-5) occurred in 27 (64%) of ALL pts and only 16 (29%) of CLL/NHL pts (p=0.001). 12 adults with ALL received CTL019; 8/9 evaluable pts achieved CR (MRD negative) at 1 month and 1 pt with extramedullary disease had marked reduction of PET avid disease which is maintained at 1 yr. Severe CRS occurred in 11 of 12 adult ALL pts. CRS was self-limited in 2 pts, rapidly reversed with anti-IL6 directed therapy in 6 pts and was refractory to therapy, contributing to death in 3 pts who were not evaluable for disease response. No baseline attributes differentiate these 3 pts from the 9 adult ALL pts with manageable Gr1-4 CRS. We have shown however that ALL disease burden correlates with CRS severity (in press) and all 3 pts had significant disease burden at baseline. All received lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2 q12h x 6 followed by infusion of CTLO19 cells. These 3 pts each received 6.50E+06, 6.70E+06 and 8.45E+06 CTLO19 cells/kg compared to median CTL019 dose of 3.62E+06 in the 9 adult ALL pts with manageable CRS. Pt 21413-03 developed CRS 12 hrs after infusion and tested positive for influenza B on D3. Despite broad spectrum antimicrobials (including oseltamivir) and anticytokine directed therapy with tocilizumab (4mg/kg x 2) and steroids, he died with refractory hypotension on D5. Pt 21413-06 had extensive disease after 2 prior allogeneic SCTs and developed CRS within 12 hrs of infusion. In addition to broad spectrum antibiotics, she received tocilizumab 8mg/kg (D 3, 6 and 12); intermittent high dose steroids (D 4-15) and etanercept (D14). She died D15 with hypotension, hypoxic respiratory failure and concurrent MDR pseudomonas sepsis and pneumonia. Pt 21413-11 developed CRS within 24 hrs of infusion. He received tocilizumab 8mg/kg (D3&4); siltuximab (D5&15) and intermittent high dose steroids (D 4-15). After an initial response, he developed recurrent fever, pulmonary infiltrates and blood cultures positive for stenotrophomonas. He died D15 with refractory hypoxia and hypotension. All 3 pts’ clinical CRS correlated with marked in vivo CTL019 expansion and progressive serum cytokine elevations (data to be shown). CONCLUSIONS: CRS is the major toxicity of CTL019 therapy and its clinical course varies depending on disease type (more frequent and severe in ALL) and disease burden (in ALL). The 3 refractory CRS cases described here (of 97 total pts treated) have all occurred in adult ALL pts with significant disease burden who received relatively high doses of CTL019 cells. In addition, all 3 had significant infectious complications which potentially fueled underlying CRS and/or were made more virulent due to impairment of immunity with administration of anti-cytokine directed therapies. Future protocol modifications will be made goal of limiting severity of CRS while maintaining high durable remission rates. Further exploration is planned to better correlate timing and choice of anticytokine directed therapy in relation to clinical and investigation parameters of CRS. Disclosures Frey: Novartis: Research Funding. Off Label Use: USe of CART19 cells to treat CLL. Levine:Novartis: Patents & Royalties, Research Funding. Lacey:Novartis: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Schuster:Novartis: Research Funding. Hwang:NVS: Research Funding. Leung:Novartis: Employment. Shen:Novartis: Employment. Ericson:Novartis: Employment. Melenhorst:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding.

Chimeric Antigen Receptor T Cells Directed Against CD19 Induce Durable Responses and Transient Cytokine Release Syndrome in Relapsed, Refractory CLL and ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 717-717 ◽  
Author(s):  
David L Porter ◽  
Stephan A. Grupp ◽  
Michael Kalos ◽  
Alison W. Loren ◽  
Lester Lledo ◽  
...  
Keyword(s):  
T Cells ◽  
Research Funding ◽  
University Of Pennsylvania ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Variable Effect ◽  
To Receive ◽  
Signaling Domains

Abstract Abstract 717 Background: Chimeric antigen receptors (CARs) combine the antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein. CD19 is an ideal target for CARs since expression is restricted to normal and malignant B cells. Inclusion of the CD137 (4-1BB) signaling domain results in potent antitumor activity and in vivo persistence of anti-CD19 CARs in mice. We reported anti-tumor activity of CAR-modified autologous T cells targeted to CD19 (CART19 cells) in 3 patients (pts) with CLL with relatively short follow up (Porter, et al NEJM 2011; Kalos et al Sci Trans Med 2011). We now report on outcomes and longer follow up from 10 pts treated with CART19 cells. Methods: Autologous T cells collected by leukapheresis were transduced with a lentivirus encoding anti-CD19 scFv linked to 4-1BB and CD3-z signaling domains. Gene-modified T cells were expanded and activated ex-vivo by exposure to anti-CD3/CD28 beads. Pts had CLL or ALL with persistent disease after at least 2 previous treatments. Results: 10 pts have received CART19 cells; 9 adults median age 65 yrs (range 51–78) were treated for relapsed, refractory CLL and one 7 yr old was treated for relapsed refractory ALL. CLL pts had received a median of 5 prior regimens (range 2–10) and all had active disease at the time of infusion. 3/9 CLL patients had deletion of the p53 gene. The ALL pt had chemorefractory relapse, having received chemotherapy 6 weeks prior to infusion. All CLL pts received lymphodepleting chemotherapy 4–6 days before infusions (FC, PC or bendamustine, while the ALL pt had an ALC <10 after prior chemotherapy and did not require further lymphodepletion). A median of 7.5 × 108 total cells (range 1.7–50) corresponding to 1.45 × 108 (range 0.14–5.9) genetically modified cells were infused on day 0. Median follow-up as of 8/12/2012 was 5.6 mo (range 1–24 mo). 9 pts are evaluable for response (<30d follow up in 1 pt). No pt has died. There were no infusional toxicities >grade 2. CART19 homed to the marrow in the CLL pts and marrow and CSF for the ALL patient with detectable CART19 cells in the CSF (21 lymphs/uL, 78% CAR+) day 23 after infusion. 4/9 evaluable pts achieved CR. (3 CLL, 1 ALL). 2 CLL pts had a PR lasting 3 and 5 months, and 3 pts did not respond. In the 4 pts who achieved CR, maximal expanded cells in the blood were detected at an average of 27 fold higher than the infused dose (range 21–40-fold) with maximal in-vivo expansion between day 10 and 31 post infusion. No patient with CR has relapsed. All pts who responded developed a cytokine release syndrome (CRS) manifested by fever, and variable degrees of nausea, anorexia, and transient hypotension and hypoxia. In responding CLL pts the maximal fold elevation from baseline for IFN-γ was 89–298x, IL-6 6–40x, and IL2R 5– 25x, while no significant elevation in systemic levels of TNFα or IL2 were observed. For the ALL pt, maximal elevations from baseline were: IFNγ: 6040x; IL-6: 988x; IL2R: 56x, while significant elevations in TNFα (17x) and IL2 (163x) were also observed. The timing for maximum cytokine elevation differed but in all cases correlated with peak T cell expansion in the PBMC. 5 pts with CRS required treatment; patient 03 was treated with high dose steroids with resolution of symptoms but only achieved a PR. While steroid treatment had a variable effect on the CRS, we noted that these symptoms were temporally associated with significant elevations in serum IL-6. Accordingly, 4 of these pts were treated with the IL6-receptor antagonist tocilizumab on day 3–10 with prompt resolution of fevers, hypotension and hypoxia. 3 of these patients are evaluable for response and 2 achieved a CR. For the pts in CR, CART19 expression in the blood was documented by flow cytometry at the most recent follow up for each patient: 24 mo (pt 01), 22 mo (pt 02), 3 mo (pt 100), and 2 mo (pt 09). Conclusions: Autologous T cells genetically engineered to express an anti-CD19 scFv coupled to 4-1BB/CD3-z signaling domains can undergo robust in-vivo expansion, persist for at least up to 2 yrs, and can be associated with a significant CRS that responds to anti-cytokine therapy. CART19 cells can induce potent and sustained responses (6/9 responses, 4 CR) for patients with advanced, refractory and high risk CLL and relapsed refractory ALL. Disclosures: Porter: Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Off Label Use: The use of CART19 cells to treat CD19+ malignancy and the use of tocilizumab to treat cytokine activation syndrome related to CART19 cells. Kalos:University of Pennsylvania: Employment, Patents & Royalties. Levine:TxCell: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Pennsylvania: financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight Patents & Royalties. June:Novartis: Research Funding, entitled to receive royalties from patents licensed to Novartis, entitled to receive royalties from patents licensed to Novartis Patents & Royalties.

scholarly journals In vivo generation of human CD 19‐ CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

2018 ◽  
Vol 10 (11) ◽  
Author(s):  
Anett Pfeiffer ◽  
Frederic B Thalheimer ◽  
Sylvia Hartmann ◽  
Annika M Frank ◽  
Ruben R Bender ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

scholarly journals B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1147-1147 ◽  
Author(s):  
Adam D. Cohen ◽  
Alfred L. Garfall ◽  
Edward A Stadtmauer ◽  
Simon Francis Lacey ◽  
Eric Lancaster ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Depth Of Response ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Background : BCMA is expressed on MM cells, and CAR T cells targeting BCMA have pre-clinical anti-MM activity. CART-BCMA is an autologous T cell product engineered by lentiviral transduction to express a fully human BCMA-specific CAR with CD3ζ and 4-1BB signaling domains, and then expanded ex vivo using CD3/CD28 beads. Methods: In this ongoing, 3+3 dose-escalation study, relapsed/refractory MM patients (pts) receive CART-BCMA cells as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2). Three cohorts are planned: 1) 1-5 x 108 CART cells alone; 2) cyclophosphamide (CTX) 1.5 g/m2 + 1-5 x 107 CART cells; and 3) CTX 1.5 g/m2 + 1-5 x 108 CART cells. Pts need serum creatinine (Cr) <2.5 mg/dL or Cr clearance≥30 ml/min, and adequate hepatic, cardiac, and pulmonary function. BCMA expression on MM cells is analyzed by flow cytometry, though no pre-specified level is required for eligibility. CART-BCMA frequency and activation status are assessed in blood and marrow by flow cytometry. Levels of CAR-transduced cells are also measured by qPCR using a transgene-specific primer/probe pair. Soluble BCMA, BAFF and APRIL levels in serum are assessed by ELISA. Bioactivity of the infusion product and CART-related cytokine release syndrome are analyzed by Luminex. Responses are assessed by IMWG criteria. Results: To date, 11 pts have been screened, and 6 treated in cohort 1. Reasons for not receiving treatment were screen fail (n=2), rapid MM progression/renal failure (n=2), and pt/MD choice (n=1). The 6 treated pts were all IMID/PI-refractory with high risk cytogenetics and median 9 lines of therapy (Table). All expressed BCMA on MM cells, and achieved the minimum target dose of 1x108 CART-BCMA cells. All but 2 received 100% of planned dose, with 2 (pts 01and 03) receiving 40% (3rd infusions held for fever). Cytokine release syndrome (CRS) occurred in 5 patients: 2 grade 3 requiring tocilizumab (pts 01 and 03), 1 grade 2, and 2 grade 1. High-grade CRS was associated with elevated levels of IL-6, IFNg, MCP1, MIG, IL2Ra, and IL-10, as seen in our acute lymphoblastic leukemia CTL019 trial (Teachey et al, 2016). There was 1 DLT: grade 4 PRES (posterior reversible encephalopathy syndrome) in pt 03, with severe delirium, recurrent seizures, obtundation, and cerebral edema on MRI. This resolved after anti-epileptics, high-dose methylprednisolone and cyclophosphamide, without long-term neurologic sequelae. Other grade 3/4 toxicities to date include hypophosphatemia (n=3 pts), hypocalcemia (n=2), and anemia, neutropenia, lymphopenia, thrombocytopenia, hypofibrinogenemia, fatigue, pneumonia, UTI, elevated Alk phos and AST, hypokalemia, hypertension, and pleural effusion (n=1 each). CART-BCMA cells were detected in blood and marrow by CAR-specific PCR in all 6 pts, and in 4/6 by flow cytometry, with 2 pts, 01 and 03, having massive CART expansion peaking at 90% and 76% of peripheral CD3+ T cells, respectively. CART-BCMA cells during peak expansion were predominantly CD8+ and highly activated. Pt 01 has ongoing CART-BCMA persistence, with ongoing stringent CR at 7 months and MRD-negative bone marrow by flow cytometry. Pt 03, who had pleural and possible dural MM involvement, had CART-BCMA cells found in pleural fluid and CSF, and achieved VGPR (IF+ only) with resolution of extramedullary disease on PET/CT scan. She progressed at 5 months, associated with significant reduction of CART-BCMA cells and loss of BCMA expression on her MM cells by flow cytometry, suggestive of antigen escape. Two pts (02, 11) had modest CART-BCMA expansion, with 1 minimal response (MR) lasting 2 months, and 1 ongoing MR 1 month post-infusion. Two pts (09, 10) had minimal expansion and no response. Soluble BCMA levels, which were elevated in all pts at baseline, declined in parallel with CART-BCMA expansion and correlated with depth of response, with an accompanying increase in previously suppressed BAFF and APRIL levels in serum. Conclusions: CART-BCMA cells can be manufactured from heavily-pretreated MM pts, and demonstrate promising in vivo expansion and clinical activity, even without lymphodepleting conditioning. Depth of response correlates with degree of CART-BCMA expansion and CRS. Toxicities to date include CRS and in 1 pt, severe reversible neurotoxicity, as described in other CAR T cell studies. Expanded accrual in cohort 1, as well as in cohorts with CTX conditioning, is ongoing, with updated data to be presented at the meeting. Table Table. Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Garfall:Bioinvent: Research Funding; Novartis: Consultancy, Research Funding; Medimmune: Consultancy. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Teva: Consultancy; Janssen: Consultancy. Lacey:Novartis: Research Funding. Lancaster:Janssen: Consultancy; Medimmune, Inc.: Consultancy; Grifols, Inc.: Other: Teaching courses. Vogl:Millennium: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Teva: Consultancy; Acetylon: Research Funding; Glaxo Smith Kline: Research Funding; Calithera: Research Funding; Constellation: Research Funding. Ambrose:Novartis: Research Funding. Plesa:Novartis: Patents & Royalties, Research Funding. Kulikovskaya:Novartis: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations. Richardson:Novartis: Employment, Patents & Royalties, Research Funding. Isaacs:Novartis: Employment. Melenhorst:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria. Milone:Novartis: Patents & Royalties, Research Funding.

Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Relapsed/Refractory (R/R) CLL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1983-1983 ◽  
Author(s):  
David L. Porter ◽  
Simon F. Lacey ◽  
Wei-Ting Hwang ◽  
Pamela Shaw ◽  
Noelle V. Frey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Grading System ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Life Threatening ◽  
Guide Intervention

Abstract CTL019 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain with the CD3z and 4-1BB signaling domains, and mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL, ALL and NHL. CRS is the most serious toxicity of CTL019 therapy; symptoms can include fevers, nausea, myalgias, capillary leak, hypoxia, and hypotension. Standard CRS grading criteria are not applicable to CAR T cell therapies. To better capture clinical manifestations of CRS and guide intervention after CTL019, we devised a novel CRS grading scale. that was applied to 40 pts treated with CTL019 for R/R CLL; 14 pts on an initial pilot and 26 pts on an ongoing dose-optimization trial (reported separately). Our new CRS grading system is shown below. Pts were 80% male, a median age of 65 (range 51-78) and received a median of 4 prior therapies (range 1-10). 41% had known mutation at p53. 83% of 24 pts tested had unmutated IgVH. Response rate to CTL019 (CR+PR) was 42%. CRS was the major toxicity and occurred in 57% (23/40) of pts. CRS was gr 1 in 10%, gr 2 in 17%, gr 3 in 15% and gr 4 in 15%. Development of CRS correlated with response; 13/23 (57%) pts with CRS responded versus 4/17 (24%) pts without CRS responded (p=0.05). CRS was associated with elevations in IL-6, IFN-g, and other cytokines; details for 33 pts will be presented. Peak fold-increase over baseline for IL-6 was a median of 10.6x (range 0.28–649) and for IFN- g a median of 32.9x (1–7243x). For pts with CRS, this increase in IL-6 was a median of 23.5x compared to 1.86x in pts without CRS (p=0.001); and in IFN- g was a median of 97.2xin pts with CRS compared to 24.2x without (p=0.018). Increasing CRS severity was associated with peak fold change in IL-6 (p< 0.0001) and IFN- g (p=0.015). Notably, unlike cytokine changes associated with sepsis, TNF-a did not markedly increase during CRS. CRS occurred with a consistent and often dramatic increase in ferritin, C reactive protein (CRP), and hemophagocytosis, suggesting concurrent macrophage activation syndrome (MAS). Increasing CRS severity was associated with an increasing trend for peak ferritin (log scale, p<0.001) and peak CRP (p<0.001). The median peak ferritin was 13,463 ng/ml in pts with CRS compared to 378 in pts without (p<0.001). Median peak CRP was 16 mg/dl in pts with CRS compared to 3.86 in pts without (p=0.002). CRS required intervention in 8 pts. 1 pt was successfully treated with corticosteroids. Given marked increases in IL-6, 7 patients received the IL6-receptor antagonist tocilizumab with or without corticosteroids with resolution of CRS. Tocilizumab was given to 1/7 pts with gr 2 CRS, 1/6 pts with gr 3 and 5/6 pts with gr 4. Several pts also received corticosteroids and/or etanercept. All pts had resolution of CRS signs with no TRM from CRS. CRS is the most significant complication of CTL019 and can be life threatening. A novel CRS grading system was needed to identify CRS severity more accurately guide intervention timing. CTL019-related CRS is associated with a unique cytokine profile and has been manageable with anti-cytokine therapy in pts with R/R CLL. CRS appears to correlate with response of CLL to CTL019. Further study is needed to develop reliable methods to predict severity and minimize CRS toxicity without inhibiting anti-leukemia activity of CTL019. New CRS Grading System for CTL019 Abstract 1983. Table Grade 1 Grade 2 Grade 3 Grade 4 Mild: Treated with supportive care such as anti-pyretics, anti-emetics Moderate: Requiring IV therapies or parenteral nutrition; some signs of organ dysfunction (i.e. gr 2 Cr or gr 3 LFTs) related to CRS and not attributable to any other condition. Hospitalization for management of CRS related symptoms including fevers with associated neutropenia. More severe: Hospitalization required for management of symptoms related to organ dysfunction including gr 4 LFTs or gr 3 Cr related to CRS and not attributable to any other conditions; this excludes management of fever or myalgias. Includes hypotension treated with IV fluids or low-dose pressors, coagulopathy requiring FFP or cryoprecipitate, and hypoxia requiring supplemental O2 (nasal cannula oxygen, high flow 02, CPAP or BiPAP). Pts admitted for management of suspected infection due to fevers and/or neutropenia may have gr 2 CRS. Life-threatening complications such as hypotension requiring “high dose pressors”, hypoxia requiring mechanical ventilation. Disclosures Porter: Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Off Label Use: Use of genetically modified T cells (CTL019) to treat CLL and use of tocilizumab to treat cytokine release syndrome.. Lacey:Novartis: Research Funding. Hwang:NVS: Research Funding. Frey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Chen:Novartis: Research Funding. Kalos:Novartis: Patents & Royalties, Research Funding. Gonzalez:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Litchman:Novartis: Employment. Shen:Novartis: Employment. Quintas-Cardamas:Novartis: Employment. Wood:Novartis Pharma: Employment. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding.

Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 681-681 ◽  
Author(s):  
Stephan A. Grupp ◽  
Shannon L Maude ◽  
Pamela A Shaw ◽  
Richard Aplenc ◽  
David M. Barrett ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Young Adults ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Disease Burden ◽  
Children And Young Adults

BACKGROUND CARs combine a targeting antibody (scFv) domain with intracellular signaling domains. We have previously reported on CTL019 cells expressing an anti-CD19 CAR, which have resulted in up to 100,000x in vivo proliferation, durable anti-tumor activity, and prolonged persistence in pts with B cell tumors, including sustained CRs in adults and children with ALL (Grupp et al., NEJM 2013, Maude et al., NEJM 2014). We now report on outcomes and longer follow up of the first 53 pts with relapsed/refractory (r/r) ALL treated on our pilot trial in pediatric ALL. METHODS T cells were lentivirally transduced with a CAR composed of anti-CD19 scFv/4-1BB/CD3ζ, activated/expanded ex-vivo with anti-CD3/anti-CD28 beads, and then infused into children with r/r CD19+ ALL. 48/53 pts received lymphodepleting chemotherapy the week prior to CTL019 infusion. The targeted T cell dose range was 107 to 108 cells/kg with a transduction efficiency of 3.6-45%. T cells for manufacturing were collected from the pt regardless of prior SCT status, and not their allo donors. RESULTS We treated 53 children and young adults with CD19+ ALL, median age 11y, (4-24y). To assess disease burden after lymphodepleting chemotherapy, pts had BM aspirations performed 1D prior to 1st CTL019 infusion: 41/53 pts had detectable ALL while 12 were MRD(-). A median of 4.3x106 CTL019 cells/kg (1-17.4x106/kg) were infused over 1-2D (1 pt got cells over 3D). There were no infusional toxicities >gr2, although pts who developed fevers within 24h of infusion did not receive a planned 2nd infusion of CTL019 cells. 50 pts (94%) achieved a CR, including a patient with CD19+ T ALL, 3 did not respond. MRD measured by clinical flow cytometry was <0.01% at D28 in 45 responding pts and positive at 0.024%-1.1% in 5 pts, with 2 patients becoming negative by 3 mo with no further therapy. With median follow up 10.6 mo (1-39 mo), 29 pts have ongoing CR, with only 6 receiving subsequent treatment such as donor lymphocyte infusion or SCT, EFS is 70% at 6 mo (95% CI, 58-85%) and 45% at 12 mo (95% CI, 31-66%), RFS is 72% at 6 mo (95% CI, 59-87%) and 44% at 12 mo (95% CI, 30-65%), and OS is 78% at 12 mo (95% CI, 67-91%). CTL019 was detected by qPCR in the CSF of 46/47 pts and 4 pts with CNS2a ALL experienced a CR in CSF. 20 pts with a CR at 1 mo have subsequently relapsed, with 3 relapses occurring after subsequent therapy (i.e. SCT) and 13 with CD19(-) blasts. 4/5 pts previously refractory to CD19-directed blinatumomab went into CR with CTL019, 3 subsequently relapsed with CD19(-) disease. All but 5 (90%) of pts developed grade 1-4 cytokine release syndrome (CRS) at peak T cell expansion. Detailed cytokine analysis showed marked increases of IL6 and IFNγ (both up to 1000x), and IL2R. Treatment for CRS was required for hemodynamic or respiratory instability in 28% of patients and was reversed in all cases with the IL6-receptor antagonist tocilizumab, together with short courses of corticosteroids in 9 pts. Although T cells collected from the 35 pts who had relapsed after allo SCT were median 100% donor origin, no GVHD has been seen. Grade 4 CRS was associated with high disease burden prior to infusion and with elevations in IL-6, ferritin (suggesting macrophage activation syndrome) and C reactive protein after infusion. Persistence of CTL019 cells can be detected by flow cytometry and/or QPCR, and results in the pharmacodynamic marker of CTL019 function, B cell aplasia, which continued for 3-39 months after infusion in pts with ongoing responses. B cell aplasia has been treated with IVIg without significant infectious complications. CONCLUSIONS: CTL019 cells can undergo robust in vivo expansion and can persist for 3 years or longer in children and young adults with r/r ALL, allowing for the possibility of long-term disease control without subsequent therapy such as SCT. This approach also has promise as salvage therapy for patients who relapse after allo SCT with a low risk of GVHD. CTL019 therapy is associated with a significant CRS that responds rapidly to IL-6-targeted anti-cytokine treatment. CTL019 cells can induce potent and durable responses for patients with r/r ALL; however, recurrence with cells that have lost CD19 is an important mechanism of CTL019 resistance. Rapid loss of CTL019 cells (prior to 3 months) is associated with a high risk of CD19+ relapse. CTL019 therapy has received Breakthrough Therapy designation from the FDA in pediatric and adult ALL, and phase 2 multicenter registration trials are well underway. Disclosures Grupp: Novartis: Consultancy, Research Funding. Maude:Novartis: Consultancy, Research Funding. Shaw:Novartis: Research Funding. Aplenc:Sigma Tau: Consultancy. Lacey:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. Rheingold:Novartis: Consultancy; Endo: Other: Husband's employer, has equity interest. Teachey:Novartis: Research Funding. Wood:Novartis Pharmaceuticals Corporation: Employment. Porter:Novartis: Other: IP interest, Research Funding; Genentech: Other: Spouse employment. June:University of Pennsylvania: Patents & Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding.

ACTR087, Autologous T Lymphocytes Expressing Antibody Coupled T-Cell Receptors (ACTR), Induces Complete Responses in Patients with Relapsed or Refractory CD20-Positive B-Cell Lymphoma, in Combination with Rituximab

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 580-580 ◽  
Author(s):  
Luke Paul Akard ◽  
Samantha Jaglowski ◽  
Steven M. Devine ◽  
Matthew S. McKinney ◽  
Michael Vasconcelles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Prior Therapy

Abstract Background: Autologous T cells engineered to express the universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res. 2014]. Preclinical findings with ACTR+ T cells, which bind immunoglobulin Fc via CD16V158 and signal via CD3ζ and 4-1BB (ACTR087), demonstrate markedly enhanced target- and antibody-specific tumor cell cytotoxicity, as evidenced by CD20+ B cell lymphoma killing in combination with rituximab, compared with rituximab alone. Preclinical data also demonstrate rituximab dose-dependent effects in combination with ACTR087, suggesting that the therapeutic index of ACTR087 in combination with rituximab may be affected by rituximab dose or schedule and present an advantage over chimeric antigen receptor (CAR) T cell therapies [Huet H, Blood 2016]. Study UT-201501 (ATTCK-20-2) is the first clinical trial of ACTR087 in combination with rituximab in patients with relapsed or refractory CD20+ B cell lymphoma previously treated with rituximab (NCT02776813). We report data from the 7 patients treated with ACTR087 in the first dose level of the ATTCK-20-2 study. Methods: This is a multicenter Phase 1 dose escalation study. The primary objective is to evaluate the safety of the combination of ACTR087 and rituximab, and the key secondary objective is to evaluate antitumor efficacy. Exploratory objectives include measurement of ACTR T cell persistence, cytokines, and rituximab pharmacokinetics. Eligible patients must have histologically confirmed relapsed/refractory aggressive CD20+ B cell lymphoma of DLBCL, MCL, PBMCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb in combination with anthracycline-containing chemotherapy. In the first dose level, patients received lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR087 (0.5x106 ACTR+ T cells/kg). Up to 7 additional doses of rituximab are then administered, one dose every 3 weeks in the absence of disease progression. Results: Seven patients received ACTR087 in combination with rituximab at the first dose level. Median age was 64 years (range: 36-71), 57.1% were male, all had ECOG PS 1, 86% were treated with ≥ 3 lines of prior therapy, and 86% were refractory to the immediate prior therapy. ACTR087 was successfully manufactured for all subjects. ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. One patient had a dose-limiting toxicity of grade 4 thrombocytopenia for > 14 days that later resolved. At the first dose level, there were no SAEs or deaths related to ACTR087 and no AEs of special interest, including cytokine-release syndrome, neurotoxicity, or autoimmune events. Cytopenias were the most common ≥ grade 3 AEs (neutropenia n=7, leukopenia n=5). Rituximab pharmacokinetics were not affected by ACTR087 administration. Independently-confirmed objective responses were observed in patients evaluable for response (n=6), including 2 ongoing complete responses (CR) and 1 partial response (PR). One of the CRs continues 6+ months after a single dose of ACTR087. Conclusions:In the first dose level studied in patients with relapsed/refractory aggressive CD20+ B cell lymphoma, ACTR087 in combination with rituximab induced complete responses with no serious AEs, AEs leading to treatment discontinuation, cytokine-release syndrome, or neurotoxicity. ACTR+ T cells were detectable in all patients and ACTR+ T cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR087 in combination with rituximab; dose level 2 enrollment is ongoing and updated data, including correlative biomarkers, will be presented. Disclosures Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. McKinney: Kite Pharma: Other: advisory comittee. Vasconcelles: Unum Therapeutics Inc: Employment. Huet: Unum Therapeutics Inc: Employment. Ettenberg: Unum Therapeutics Inc.: Employment. Ranger: Unum Therapeutics Inc: Employment. Abramson: Seattle Genetics: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Kite Pharma: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; LAM Therapeutics: Research Funding; Novartis: Consultancy.

scholarly journals Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?

2013 ◽  
Vol 191 (9) ◽  
pp. 4589-4598 ◽  
Author(s):  
Sjoukje J. C. van der Stegen ◽  
David M. Davies ◽  
Scott Wilkie ◽  
Julie Foster ◽  
Jane K. Sosabowski ◽  
...  
Keyword(s):  
T Cells ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Human T Cells ◽  
Therapeutic Opportunity

scholarly journals Suppressed Fibrinolytic Activity Demonstrated By Simultaneous Thrombin and Plasmin Generation Assay during Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4807-4807
Author(s):  
Takashi Ishihara ◽  
Yasuyuki Arai ◽  
Makiko Morita ◽  
Tomoko Onishi ◽  
Hanako Shimo ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Time Points ◽  
Car T ◽  
D Dimer ◽  
Coagulation And Fibrinolysis

Abstract Introduction: Infusion T cells engineering to express CD19-specific chimeric antigen receptor T cells (CAR-T) following lymphodepleting chemotherapy has shown promising efficacy in patients with relapsed and/or refractory CD19-positive B-cell malignancies including B-cell acute lymphoblastic leukemia (B-ALL), and diffuse large B-cell lymphoma (DLBCL). CAR-T therapy can often be associated with cytokine release syndrome (CRS), which has been reported to present severe coagulopathy. Conventional coagulation and fibrinolysis parameters have been reported to worsen in correlation with CRS grading [Hay KA et al. Blood 2017]. In the present study, we hypothesized that the change of balance between coagulation and fibrinolysis due to coagulopathy is associated with CRS after CAR-T therapy. To clarify our hypothesis, we investigated the global coagulation and fibrinolytic function of patients receiving CD19 CAR-T therapy using simultaneous thrombin and plasmin generation assay (T/P-GA). Patients: We enrolled 13 consecutive patients aged 23-69 years (8 males and 5 females, DLBCL; n = 11, B-ALL; n = 2) receiving CD19 CAR-T therapy from May 2020 to December 2020 at a single center in Japan. Due to a history of internal jugular venous thrombosis, one patient received edoxaban, an anticoagulant. Methods: We evaluated the global functions of coagulation and fibrinolysis using T/P-GA [Matsumoto et al. TH 2013]. This clotting was initiated by the mixture of recombinant human tissue factor (Innovin ®, f.c. 1 pM), phospholipid vesicles (f.c. 4 μM), and tissue-type plasminogen activator (f.c. 3.2 nM). We simultaneously monitored thrombin and plasmin generation using thrombin- and plasmin-specific fluorogenic substrate (Z-Gly-Gly-Arg-AMC and BOC-Glu-Lys-Lys-MAC, respectively) in separate microtiter wells. The first derivatives (velocity) of thrombin and plasmin generation were utilized to derive the parameters, lag time (LT), endogenous potential (EP), peak levels (Peak), and time to peak (ttPeak). In this study, EP of thrombin generation (T-EP) and plasmin-peak (P-Peak) were selected as parameters for evaluation. We calculated the ratio of T-EP and P-Peak of patients' plasmas to those of control normal plasma. A ratio &gt; 1.0 was defined as high coagulation or fibrinolytic potential relative to normal. Using fibrinogen (Fbg), D-dimer, and antithrombin (AT), we also monitored the conventional laboratory markers of hemostasis. Soluble IL-2 receptor (sIL-2R) was also measured as a marker of inflammatory cytokines. Day 0 was defined as the day of CAR-T infusion. Plasmas were collected at T0; pre-lymphodepleting chemotherapy, T1; Days -2-0, T2; Days 1-3, T3; Days 4-6, T4; Days 7-9, T5; Days 10-12, T6; Days 13-18, and T7; Days 19-23. Results: All patients had Grade ≤ 2 CRS. Two cases developed CRS-associated coagulopathy, one of whom required fresh frozen plasma transfusion and cryoprecipitate for low Fbg level, and the other required tranexamic acid for hemorrhagic cystitis. The median values of AT remained within the reference value (RV). The median Fbg values were 229-525 mg/dL, and which were significantly greater at T0-T3 than at T5-T7 (p &lt; 0.05). The median D-dimer values were 0.45-3.9 µg/mL, which were within or above the RV with no significant change between time points. The median values of sIL-2R were 819-3,953 U/mL, and which were significantly increased at T3-T4 than at T0-T1 (p &lt; 0.05). T-EP/P-Peak revealed a median of 1,877/21.9, 1,659/18.6, 1,731/19.8, 1,856/15.0, 1,931/16.3, 1,758/18.5, 1,600/19.1, 1,634/20.3, and 1,594/17.4 nM for T0-T7 and control plasma, respectively, indicating the reduced P-Peak ratios (Fig. 1). T-EP ratios showed consistently maintaining &gt; 1 with no significant difference between time points, while P-Peak ratios were significantly lower at T3 and T4 than at T0 (p &lt; 0.01) (median ratios of T-EP/P-peak; T0; 1.23/1.22, T1; 1.08/1.05, T2; 1.12/1.09, T3; 1.23/0.81, T4; 1.27/0.91, T5; 1.19/1.11, T6; 1.07/1.12, and T7; 1.20/1.15, respectively). Conclusion: The results of T/P-GA showed that hemostatic kinetics in patients with Grade ≤ 2 CRS were likely to shift to hypercoagulable states throughout the entire period and that they were likely to experience hypofibrinolytic activity during the CRS phase. These results suggest that the imbalance of coagulation and fibrinolysis might cause organ disorder due to thrombotic tendency associated with CRS after CAR-T therapy. Figure 1 Figure 1. Disclosures Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding.

CAR-T Therapy for Lymphoma with Prophylactic Tocilizumab: Decreased Rates of Severe Cytokine Release Syndrome without Excessive Neurologic Toxicity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31 ◽  
Author(s):  
Paolo F Caimi ◽  
Ashish Sharma ◽  
Patricio Rojas ◽  
Seema Patel ◽  
Jane Reese ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Advisory Board ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Significant Difference ◽  
Car T

INTRODUCTION: Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and CAR-T related encephalopathy syndrome (CRES/ICANS) are well-known complications of CAR-T cell therapy. Tocilizumab, a humanized monoclonal antibody targeting the interleukin 6 (IL-6) receptor, is approved for treatment of CRS. Our institutional standard was modified to administer prophylactic tocilizumab before infusion CAR-T cell products. We present the outcomes of subjects treated with locally manufactured antiCD19 CAR-T cells (TNFRSF19 transmembrane domain, CD3Zeta/4-1BB costimulatory signaling) with and without prophylactic tocilizumab. METHODS: Relapsed / refractory (r/r) lymphoma patients (pts) treated with anti-CD19 CAR-T cells at our institution were included. Baseline demographic and clinical characteristics, as well as laboratory results were obtained from our Hematologic Malignancies and Stem Cell Therapy Database. Prior to institution of prophylactic tocilizumab, pts received this agent only if they presented evidence of CRS grade 2 or higher. In May 2019, our institutional practice changed to provide tocilizumab 8mg/kg, 1 hour prior to infusion of CAR-T cell product. CRS was measured according to the ASTCT Consensus Grading, whereas CRES was measured using the CARTOX-10 criteria. Comparisons between groups were done with the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables. RESULTS: Twenty-three relapsed / refractory lymphoma pts were treated with antiCD19 CAR-T cells; 15 pts received prophylactic tocilizumab. Median follow up was 312 days (range 64 - 679) days. Baseline characteristics are listed in table 1. Both groups were similar: There were no statistically differences in the rate of bulky, refractory disease, prior ASCT or number or prior lines of therapy. Baseline lymphocyte counts, C - reactive protein (CRP) and were also comparable between groups (Table 2). We did not observe immune adverse reactions to tocilizumab infusion. There were no differences in the incidence of cytopenias or infectious complications between groups. CRS of any grade was observed in 6/8 (75%) of pts without prophylactic tocilizumab vs. 6/15 (40%) in pts treated with prophylactic tocilizumab (p = 0.23), whereas CRS grade &gt;1 was observed in 5 pts (62.5%) without prophylactic tocilizumab and in 3 pts (20%) treated with prophylactic tocilizumab (p = 0.02). There was no significant difference in the incidence of all grade CRES (no prophylaxis, 3/8 [38%] pts; prophylaxis 5/15 [30%] pts, p = 0.2969). There was a statistically significant difference in the peak CRP and peak ferritin without difference in the peak lymphocyte count after CAR-T infusion (Table 2, Figure 1). Patients given prophylactic tocilizumab had higher IL-6 plasma concentrations on day 2 after infusion (Figure 2). Complete response was observed in 4/8 (50%) pts without prophylactic tocilizumab vs. 12/15 (80%) pts with prophylactic tocilizumab (p = 0.18). All pts had detectable Anti-CD19 CAR-T cells on day 30, both groups had peak CAR-T expansion on day 14, with no statistically significant differences in expansion rates between groups. All evaluable subjects have had CAR-T persistence on days 60, 90, 180, and 365. CONCLUSIONS: Use of prophylactic tocilizumab prior to infusion of antiCD19 CAR-T cells is associated with reduced incidence of severe CRS and decreased levels of clinical laboratory markers of inflammation, despite increases in plasma concentration of IL-6. This decreased rate of grade ≥2 CRS is not associated with impaired disease control and did not result in increased rates of neurologic toxicity. Prophylactic tocilizumab does not appear to affect CAR-T cell expansion or persistence. Figure 1 Disclosures Caimi: ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board. Worden:Lentigen, a Miltenyi biotec company: Current Employment. Kadan:Lentigen, a Miltenyi biotec company: Current Employment. Orentas:Lentigen Technology, a Miltenyi Biotec Company: Research Funding. Dropulic:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. de Lima:Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. OffLabel Disclosure: Use of tocilizumab as prophylaxis for CRS is not approved, whereas use for treatment is approved and on label.

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