scholarly journals Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4816-4816
Author(s):  
Urwat Til Vusqa ◽  
Palash Asawa ◽  
Maitreyee Rai ◽  
Yazan Samhouri ◽  
Prerna Mewawalla ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Intrathecal Chemotherapy ◽  
Intrathecal Methotrexate ◽  
Immune Effector Cell ◽  
Opening Pressure ◽  
Immune Effector ◽  
Car T ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies. However, its use is associated with serious adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can present with aphasia, mutism, somnolence, seizures, signs of increased intracranial pressure and rarely cerebral edema. Corticosteroids (CS) and IL-6 inhibitors are first line treatment for CRS and ICANS. Prolonged CS use has been associated with decreased over-all survival in CAR T-cell treated patients. Data on effective treatments for CART T-cell induced neurotoxicity is limited, especially in steroid-refractory ICANS. Blood-brain barrier (BBB) disruption and infiltration of myeloid and immune effector cells into the central nervous system are implicated in the pathogenesis of ICANS. This likely explains the role of intrathecal chemotherapy, which has been described in literature for treatment of steroid-refractory ICANS. Here, we report the outcomes of two patients with refractory DLBCL who developed severe ICANS after receiving axicabtagene ciloleucel (axi cel) and treated with intrathecal (IT) chemotherapy. Case Presentation Our first case is of a 66 year old male with diagnosis of R/R DLBCL, who was treated with R-CHOP, followed by R-GemOx, with no response then received axi cel. Patient developed grade 2 CRS and grade 1 ICANS (National Cancer Institute Common Terminology Criteria for Adverse Effects v4.03) on day +2 post infusion, treated with tocilizumab and dexamethasone with good response initially. While tapering dexamethasone on day +5, he developed grade 3 CRS and grade 3 ICANS. Brain MRI did not show any intracranial abnormality and EEG showed no seizure activity. Lumbar puncture (LP) was done on day +7 and showed opening pressure of 32 cm H2O, and 12 lymphocytes. He was started on IV solumedrol and tocilizumab was resumed. CRS improved while neurotoxicity progressed to grade 4 prompting intubation and mechanical ventilation on day +8. On day +9, patient received intrathecal methotrexate 12 mg and hydrocortisone 50 mg. On day +12, neurotoxicity improved to grade 1 and patient was extubated on day +13. Steroid taper stopped on +17. Despite disease response, patient remained hospitalized at day +45 for deconditioning and vocal cord paralysis related to a lengthy hospital stay and intubation. He was eventually discharged, however passed away on day +49 from complications of prolonged hospitalization. Our second case is of a 69 year old female with a diagnosis of R/R DLBCL with CNS involvement, treated with RCHOP x6 followed by salvage chemotherapy with refractory disease, She then received axi cel. Patient developed grade 1 CRS on day +4, treated with tocilizumab and dexamethasone, and patient responded well. On day +9, she developed grade 2 CRS and grade 3 ICANS. At that time, dexamethasone was switched to pulse dose solumedrol and tocilizumab was continued. CT head showed no acute intracranial abnormality and EEG did not show any epileptiform activity. LP showed opening pressure of 21, and 84 lymphocytes. On day +11, patient's CRS resolved, however ICANS developed to grade 4 and patient received 12 mg intrathecal methotrexate and hydrocortisone 50 mg for steroid-refractory ICANS. The very next day, patient showed significant neurological improvement. Steroid taper was initiated and patient's ICANS resolved on day +16. MRI brain showed decrease in size of nodular enhancement along periventricular white matter and left occipital area corresponding to treatment response. She was discharged on day +28 and continues to do well one year out of axi cel infusion Conclusion Our abstract adds to the sparse literature about the use IT chemotherapy in cases with severe ICANS. It also highlights its importance as an alternative potential therapy to high doses and prolonged courses of corticosteroids which is associated with increased morbidity and mortality. Steroid-refractory ICANS has limited treatment options and further evaluation of the use of IT chemotherapy in large scale studies is warranted. Disclosures Kahn: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genetech: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Fazal: Agios: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Lister: Oncology Analytics: Other: Academic Board.

scholarly journals EBV Positive DLBCL Is Effectively Treated with Commercial CAR T Cell Therapy but Is Associated with Higher Rates of Severe Immune Effector Cell Associated Neurologic Syndrome (ICANS): A Single Institution Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3862-3862
Author(s):  
Liana Nikolaenko ◽  
Alex F. Herrera ◽  
Elizabeth Budde ◽  
Joo Y. Song ◽  
Geoffrey Shouse
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Introduction: CAR T-cell therapy (CART) has revolutionized the treatment landscape of aggressive B cell lymphoma (aBCL) in the relapsed/refractory (r/r) setting, including high-risk groups such as high grade B cell lymphoma (HGBCL), primary refractory disease, and chemo-resistant relapses. To date, however, there has been no data reported, on the outcomes of patients with Epstein-Barr virus positive (EBV+) DLBCL, NOS. EBV+ DLBCL, NOS is a high-risk group of aBCL characterized by the incorporation of EBV into the malignant cells, with the chronic inflammation associated with EBV infection being thought to contribute to DLBCL pathogenesis. It has been shown to be less responsive to standard chemotherapy with high relapse rates and overall poor prognosis. In the present study, we analyze outcomes and toxicities of patients with EBV+ DLBCL, NOS treated with CD19CART. Methods: We retrospectively analyzed charts of patients treated with commercially available CD19CAR T-cell products for the treatment of aBCL at City of Hope (COH) between April 2018 and March 2021. EBV status was determined by immunohistochemical stains from EBER in situ hybridization on paraffin embedded tissues. Patients were included in the analysis if they had positive or negative EBER staining, referred as EBV+ or EBV-, respectively. The investigation was approved by the COH IRB. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using ASTCT criteria (Lee et al. BBMT 2019). Demographics were analyzed with descriptive statistics. Univariate analysis was performed by Chi Square test. Results: Seventy-three patients had tumor samples that were evaluable for analysis, 92% (n=67) were negative for EBER and 8% (n=6) were positive for EBER. In the entire cohort, the median age was 62 years (range, 21-90), and included 18% (n=13) transformed follicular lymphoma, 73% (n=53) DLBCL, NOS, and 10%(n=7) DH. The median number of prior lines of therapy was 2 (range, 2-6) and 15% (n=11) patients had prior autologous stem cell transplant. Comparing the EBV+ patients to the EBV-, the CR rate was 67% (n=4) vs 58% (n=34), with 16% (n=1) PR vs 27% (n=15) (ORR 83% vs 74%). With a median follow up of 17.0 months (range, 3.6-38.3), 33% (n=2) of EBV+ patients had progressed vs 42% (n=28). In the EBV+ DLBCL, NOS group, 3 CR patients had absence of detectable EBV PCR in the peripheral blood at the time of CART; 1 CR patient did not have clinical indication for EBV viral load (VL) evaluation (EBV PCR not measured); 1 PR and 1 PD patients had detectable viremia. At the time of analysis, 31% (n=21) of EBV- patients died vs 33% (n=2) of EBV+ patients, both with non-CR response to CAR T and persistent EBV VL during therapy. In terms of toxicity, overall CRS rates were similar with 83% (n=5) in the EBV+ patients and 86% (n=58) in EBV- patients. Although overall incidences of ICANS were similar between the two groups (50% [n=3] vs 45% [n=30]), grade 3 ICANS was higher in EBV+ patients (50% [n=3]) than in EBV- patients( 7.5% [n=5]; p = 0.02). EBV VL did not correlate with CRS or neurotoxicity. Conclusion: We present a retrospective analysis of EBV+ DLBCL, NOS patients treated with CART at our institution. Based on our analysis, despite the limited number of cases, the CART is an effective therapy for EBV+ DLBCL,NOS with response rates similar to what has been reported in the literature for other aBCL groups. Responses appear to be improved if EBV VL is undetectable at the time of CART. Interestingly, we demonstrate a statistically significant higher rates of grade 3 ICANS in patients with EBV+ DLBCL,NOS. Our data suggests that close monitoring for ICANS during CART should be considered in EBV+ DLBCL patients with early therapeutic intervention to prevent severe toxicity. Further investigation of a larger cohort of EBV+ DLBCL patients, as well as a deeper analysis of inflammatory markers and EBV viremia in these patients undergoing CART may provide further insight to response and toxicity profile. Disclosures Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Herrera: Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Gilead Sciences: Research Funding. Budde: Mustang Bio, Inc: Research Funding; Gilead: Consultancy; Merck, Inc: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; IGM Biosciences: Research Funding; Roche: Consultancy; BeiGene: Consultancy; Novartis: Consultancy. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria.

scholarly journals Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

2022 ◽  
Vol 10 (1) ◽  
pp. e003847
Author(s):  
Marc Wehrli ◽  
Kathleen Gallagher ◽  
Yi-Bin Chen ◽  
Mark B Leick ◽  
Steven L McAfee ◽  
...  
Keyword(s):  
T Cell ◽  
Effector Cell ◽  
Standard Treatment ◽  
Treatment Guidelines ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell ◽  
Car T ◽  
Steroid Refractory

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

IL-1 receptor antagonist for prevention of severe immune effector cell-associated neurotoxicity syndrome.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7566-7566
Author(s):  
Caspian Oliai ◽  
Anna Crosetti ◽  
Sven De Vos ◽  
Herbert Eradat ◽  
Monica Diane Mead ◽  
...  
Keyword(s):  
T Cell ◽  
Receptor Antagonist ◽  
Effector Cell ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

7566 Background: Progress in chimeric antigen receptor (CAR) T-cell therapy has included reduction in life-threatening toxicity. Rates of severe cytokine release syndrome (CRS) have declined from 50% in early trials to 7% in the most recent real-world experience. However, rates of severe immune effector cell-associated neurotoxicity (ICANS) associated with axicabtagene ciloleucel (Axicel) remain unchanged. IL-1 is a major driver of ICANS pathophysiology that is produced upstream of IL-6. The IL-1 receptor antagonist, Anakinra, can prevent neurotoxicity in animal models when given at fever onset. We present our early experience of the first 13 participants enrolled into a phase II trial evaluating Anakinra to prevent severe ICANS (NCT4205838). Methods: This investigator-sponsored trial included adults eligible for standard-of-care Axicel for large B-cell lymphoma after ≥2 lines of intensive chemoimmunotherapy. Participants received Anakinra 100 mg SQ q6h x 12-36 doses until ICANS returned to grade ≤1. The trigger to initiate Anakinra was any grade ICANS or grade ≥3 CRS in the absence of ICANS. A protocol modification, made after the first 3 participants were treated, changed the trigger for Anakinra to grade ≥2 CRS. In addition to Anakinra, all participants received standard-of-care interventions for CRS and ICANS. The primary objective is to estimate the efficacy of Anakinra in preventing severe ICANS (grade ≥3) according to ASTCT 2018 consensus grading. Results: To date, 13 participants have been enrolled, and 7 met criteria to initiate Anakinra and received the first dose prior to severe ICANS. Median age was 56 years (range, 23-84 years). Of the 7 participants whom received Anakinra prior to severe ICANS, only 1 of 7 (14%) developed grade 3 ICANS. The most common adverse event was injection site reaction, which peaked at grade 2. There were no unexpected toxicities. Once the protocol was amended to initiate Anakinra for grade ≥2 CRS (N = 4), no participant developed severe ICANS, and only one participant met the institutional standard to receive corticosteroids (Table). Conclusions: Anakinra is feasible to initiate in the non-prophylactic setting in patients at increased risk for severe ICANS. These early results demonstrate potential to reduce severe ICANS associated with Axicel to a rate similar to other CAR T-cell products, and to reduce corticosteroid use. Further enrollment to the pre-planned sample size of N=36 is required to demonstrate statistical efficacy. Serum IL-1 analysis is also ongoing. Clinical trial information: NCT4205838. [Table: see text]

scholarly journals Incidence and Causes of Prolonged Hematologic Toxicity after Chimeric Antigen Receptor T Cell Therapy: A City of Hope (COH) Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Geoffrey Shouse ◽  
Thai Cao ◽  
Jianying Zhang ◽  
Matthew Mei ◽  
Alex F. Herrera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
T Cell Therapy ◽  
Car T ◽  
Grade 3

Introduction The most common toxicities after chimeric antigen receptor (CAR) T cell therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and hematologic toxicity. The reported grade 3 and higher neutropenia, anemia and thrombocytopenia lasting longer than 30 days occurred in 15%, 3% and 18% of patients treated with Axicabtagene ciloleucel (Axi-Cel) (Yescarta package insert). Early hematologic toxicity after lymphodepleting chemotherapy (LDP) prior to infusion of CAR T cells is expected. However, prolonged cytopenias lasting longer than 28 days cannot be explained by the toxicity of LDP alone. Here, we described the incidence and potential causes for prolonged cytopenias in patients (pts) treated with Axi-cel for r/r aggressive B cell lymphoma. Methods We retrospectively analyzed 78 consecutive pts receiving Axi-cel at our institution between November 1, 2017 and April 1, 2020. This study was conducted with approval from the COH Institutional Review Board. All patients received standard LDP regimen with cyclophosphamide and fludarabine followed by infusion of Axi-cel at day 0. Clinical response was determined between day 28-35. Neutropenia, anemia and thrombocytopenia were defined as meeting the NCI CTCAE v5.0 criteria and were considered prolonged if lasting >28 days. CRS and ICANS severity were graded using the ASTCT criteria. Results A total of 78 pts were included with the median age of 61 years (range, 22-77), 33% > 65 years old, 68% male. Seventeen (22%) pts had transformed follicular lymphoma (tFL), 55 had diffuse large (DLBCL), and 6 (8%) had primary mediastinal (PMBCL). Median lines of prior treatment were 3 (range 2-6) with 18 (23%) having prior autologous stem cell transplant (ASCT). Responses were seen in 71 pts (91%), with 25 (32%) partial responses (PR) and 46 (59%) complete responses (CR) at the first assessment. Forty-eight pts (62%) remained progression free with a median follow up of 252 days (range, 56-785). CRS was noted in 67 pts (86%), with 6 (8%) grade 3 (G3), while 35 (45%) developed ICANS, with 8 (10%) G3. No grade 4 or higher CRS or ICANS were seen. All pts developed ≥ G3 neutropenia and lymphopenia that lasted a median of 51 days (range 7-456), and 39 days (range 6-737) respectively. G3 and higher anemia and/or thrombocytopenia were seen in 49% of pts. Prolonged ≥ G3 cytopenias were seen in 72% of pts with 47%, 23%, and 29% showing prolonged neutropenia, anemia and thrombocytopenia respectively. Importantly, CRS was associated with a statistically significant increase (79% vs 27%) in risk of developing prolonged cytopenias (p=0.001). In addition, a biphasic pattern of hematologic toxicity in which late cytopenias recurred after a period of recovery, was noted in 8% of pts. These delayed cytopenias were associated with lymphocyte recovery after CAR T cell administration. Finally, 7% of pts with prolonged ≥ G3 cytopenias developed therapy related MDS: the median age in this group was 60 (range 50-74), with a median of 3 prior lines of therapy (range 2-4), and 75% having prior ASCT. Overall, infections were seen in 14 pts (18%) and 9 were after day 28. In pts with prolonged ≥ G3 neutropenia, rates of infection beyond day 28 (9%) were similar to those without prolonged neutropenia (8%). Use of GCSF did not correlate with increased CRS, ICANS or prolonged cytopenias. Conclusion Our real-world experience reported high response rates and favorable incidences of CRS, and ICANS with no grade 4 noted in comparison to that described in clinical trials and by others. We identified CRS as a significant risk factor associated with development of prolonged hematologic toxicity and this may indicate an underlying bone marrow suppressive effect of the inflammation associated with CRS. Like others, we also observed a biphasic hematologic toxicity associated with recovery from B cell aplasia. Due to significant rates of therapy related MDS, bone marrow evaluation before and after CAR T therapy should be considered, especially in patients with prior transplant. Last, despite the high rates of prolonged hematologic toxicity, infection rates were not higher in patients with prolonged neutropenia, underscoring the importance of supportive medical management. Disclosures Shouse: Kite Pharma: Honoraria, Speakers Bureau. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Herrera:AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Karyopharm: Consultancy. Zain:Seattle Genetics: Research Funding; Mundi Pharma: Research Funding; Kyowa Kirin: Research Funding. Siddiqi:BeiGene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Speakers Bureau; TG Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Oncternal: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Budde:Amgen: Research Funding; Merck: Research Funding; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Roche: Consultancy; Gilead Sciences: Consultancy; Kite, a Gilead Company: Consultancy.

scholarly journals A Phase II Trial of Anakinra for the Prevention of CAR-T Cell Mediated Neurotoxicity

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2814-2814
Author(s):  
Matthew J. Frigault ◽  
Kathleen M.E. Gallagher ◽  
Marc Wehrli ◽  
Betsy Valles ◽  
Keagan Casey ◽  
...  
Keyword(s):  
T Cell ◽  
Stock Options ◽  
Research Funding ◽  
Leadership Role ◽  
Publicly Traded ◽  
Car T Cell ◽  
Car T ◽  
Post Infusion ◽  
Grade 3 ◽  
Privately Held

Abstract Introduction: Chimeric antigen receptor (CAR)-T cell therapy is limited in most cases to inpatient use due to risk of severe treatment-related toxicities. The two primary toxicities observed with CAR-T therapy, cytokine release syndrome (CRS) and neurotoxicity, are associated with increased circulating inflammatory cytokines such as IL-6 and IL-1. Targeting IL-6 with tocilizumab is effective for treating CRS but not neurotoxicity. Anakinra is an FDA-approved recombinant IL-1 receptor antagonist that competitively inhibits IL-1 receptor signaling and therefore blocks downstream production of inflammatory cytokines including IL-6. Leveraging support from Kite Pharma, we opened an investigator-initiated clinical trial (NCT04150913) with the hypothesis that anakinra could be administered prophylactically to prevent severe CRS and neurologic events (NE) in patients receiving axicabtagene ciloleucel (axi-cel). Here we report preliminary outcomes of this study. Study Design and Methods: This is a phase II single center, open-label study for patients ≥18 years old with relapsed or refractory large cell lymphoma. Patients must have progressed after ≥2 lines of systemic therapy but could not have CNS disease or have been previously treated with CAR-T therapy. Following leukapheresis and manufacturing, patients received 3 days of lymphodepleting chemotherapy (LDC, cyclophosphamide 500mg/m 2 and fludarabine 30 mg/m 2) and 200 mg of subcutaneously administered anakinra starting 4 hours prior to axi-cel infusion and daily thereafter for a total of 7 days. CRS and NE were graded based on the Lee 2013 criteria and the CTCAE 4.03 criteria, respectively, to enable direct comparison to the pivotal Zuma-1 cohorts. The primary endpoint is the rate and severity of NE within the first 30 days of infusion; secondary endpoints include the incidence and severity of CRS and disease response. CAR-T cell expansion, serum cytokines, and circulating biomarkers of toxicity were measured at baseline, day 3, 7, 14, 21, and 28 post CAR-T cell infusion. Results: Interim analysis of the first 6 patients demonstrated a median age of 68 (range 59-72). Patients included a diverse group of histologies including double-hit lymphoma (n=2), transformed indolent NHL (n=3), and DLBCL NOS (n=1). Two patients were considered primary refractory at time of enrollment. Pre-LDC baseline characteristics included a median SPD of 2819 mm 2 (range 1063-5802), median LDH of 415 (range 147-497) which were comparable to the pivotal ZUMA-1 cohorts. Baseline ferritin, CRP, SAA and IL-15 were similar to the pivotal ZUMA-1 cohorts. While low-grade CRS was observed in 5/6 patients, no patients experienced severe CRS and median onset occurred on day +8 (range 1-8). Four patients did not experience any NE, while two patients experienced grade 3 NE on days +6 till +9 (somnolence) and +12 (global aphasia only, for one day) respectively. With a median follow-up of 4 months, the day +28 overall response rate was 100% (4 CRs, 2 PRs), with 4/6 patients having an ongoing complete response at last disease assessment. One patient was re-infused at progression and remains in a CR 3 months from re-infusion. Responses were seen despite varying CAR-T peak level with most patients demonstrating expansion in the lower quartile of the historic ZUMA-1 cohort. Median post-infusion peak of CRP, ferritin, IL-2, GM-CSF, IFNγ, IL-10, IL-6 and SAA were lower than that observed in the pivotal ZUMA-1 cohorts. All patients remain alive at time of data analysis. Conclusions: With a limited number of patients analyzed thus far, anakinra appears to provide benefit to the toxicity profile of axi-cel, presenting reduced and/or delayed CRS and NE and a decrease in post-infusion inflammatory analytes, when compared to ZUMA-1 pivotal cohorts. No severe CRS was observed in this initial analysis and 2/6 patients experienced grade 3 NE (somnolence and global aphasia) after day 6. Despite CAR-T expansion in the lower quartile of that of ZUMA-1, we observed a 100% ORR with 4 patients remaining in CR at a median follow-up of 4 months. Additional subjects will be assessed to investigate the role of prophylactic anakinra in the management of CRS and NE, which has potential for making axi-cel treatment an outpatient therapy. Disclosures Frigault: BMS: Consultancy; Editas: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Takeda: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Wehrli: CSL Behring: Patents & Royalties; Nestle: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Chou: Kite Pharma: Current Employment. Shen: Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Filosto: Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership ; Tusk Therapeutics: Patents & Royalties: or other intellecular property. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Maus: Agenus: Consultancy; Arcellx: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Atara: Consultancy; Bayer: Consultancy; BMS: Consultancy; Cabaletta Bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; In8bio (SAB): Consultancy; Intellia: Consultancy; GSK: Consultancy; Kite Pharma: Consultancy, Research Funding; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company.

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.

scholarly journals Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1612-1612 ◽  
Author(s):  
Hamza Hashmi ◽  
Alicia Darwin ◽  
Christina A Bachmeier ◽  
Julio Chavez ◽  
Bijal Shah ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.

scholarly journals Easix Predicts Severe Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neuro-Toxicity Syndrome (ICANS) in Patients Receiving CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3861-3861
Author(s):  
Felix Korell ◽  
Olaf Penack ◽  
Michael Schmitt ◽  
Carsten Müller-Tidow ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Validation Cohort ◽  
T Cell Therapy ◽  
Training Cohort ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Background: Endothelial dysfunction underlies the two main complications of chimeric antigen receptor T (CAR-T) cell therapy, i.e. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The purpose of this retrospective analysis was to evaluate and validate the Endothelial Activation and Stress Index (EASIX)) as predictor for CRS and ICANS in patients receiving CD19-directed CAR-T cells. Methods: In this retrospective study, the training cohort recruited 107 patients treated with CAR-T cells at the University Hospital Heidelberg (n=83) and Charité University Medicine Berlin (n=24) from Oct 1, 2018, to March 31, 2021. Patients from the validation cohort (n=93) received CAR-T cells within the ZUMA-1 trial (ClinicalTrials.gov number: NCT02348216). The training cohort included 37 and 34 patients with relapsed / refractory (r/r) large B-cell lymphoma (LBCL) treated with Axi-cel and Tisa-cel, respectively, 1 patient with acute lymphoblastic leukemia (ALL) treated with Tisa-cel, 2 patients with mantle cell lymphoma (MCL) treated with KTE-X19 on an early access program; and 5 patients with LBCL, 5 patients with MCL, 5 patients with chronic lymphocytic leukemia, 4 patients with follicular lymphoma, and 14 patients with ALL treated with the 3 rd generation CAR-T HD-CAR-1. Median age was 57 (20-81) years, 72% were male. The 93 patients of the validation cohort all had r/r LBCL and received Axi-Cel. EASIX and serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin and interleukin-8) were measured before start of lymphodepletion (EASIX-pre), and on days 0, 3, and 7 after CAR-T infusion. Primary endpoints were severe CRS and/or ICANS (grades 3-4). Results: Of the 107 patients of the training cohort, 61 patients (58%) developed CRS grades 1-4 and 24 patients (22%) developed ICANS grades 1-4. Higher grade CRS (grade ≥ 3) was seen in 6 patients (6%) with a median onset of 4 (0-14) days, while grade ≥ 3 ICANS occurred in 11 patients (11%; median onset 8 (4-17) days). EASIX values increased continuously from lymphodepletion to day 7 after CAR-T cell application (EASIX-pre 2.0 (0.5-76.6, interquartile range (IQR) 1.2/4.1); EASIX-d0 2.0 (0.3-91.5, IQR 1.2/4.2); EASIX-d3 2.4 (0.3-69.1, IQR 1.3/4.9) and EASIX-d7 2.7 (0.4-94.0, IQR 1.4/7.5)). In the validation cohort, Grade ≥ 3 CRS was observed in 10 patients (11%) and grade ≥ 3 ICANS in 28 patients (30%). Similar to the training cohort, EASIX values rose from lymphodepletion to day 3 after CAR-T cell application (EASIX-pre 1.8 (0.3-106.1, IQR 1.0/4.7); EASIX-d0 2.0 (0.3-120.4, IQR 1.1/4.1) and EASIX-d3 2.7 (0.3-57.9, IQR 1.7/6.2). In both cohorts, all EASIX values (pre, d0, d3, d7) were significantly higher in patients who developed either grade 3-4 CRS, ICANS or both (see Figure 1 for the training cohort). EASIX predicted grade 3-4 CRS and ICANS before lymphodepleting therapy (-pre), on day 0 and on day 3 in both cohorts: AUC EASIX-pre, training cohort 0.73 (0.62-0.85, p=0.002), validation cohort 0.76 (0.66-0.87, p&lt;0.001). An optimized cut-off for EASIX-pre (1.86) identified in the training cohort associated with an odds ratio (OR) of 5.07 (1.82-14.10), p=0.002 in the validation cohort in multivariable binary logistic regression analysis including age, gender, diagnosis and disease stage. Serum endothelial stress markers did not predict the two complications when assessed before CAR-T infusion, but diagnostic markers were strongly associated with CRS and ICANS grade 3-4 on day+7. Conclusions: EASIX-pre is a validated predictor of severe complications after CAR-T therapy and may help to tailor safety monitoring measures according to the individual patient's needs. Data on patients from the ZUMA-1 trial were provided by Kite/Gilead. Figure 1 Figure 1. Disclosures Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Takeda: Research Funding; Incyte: Research Funding; Priothera: Consultancy; Shionogi: Consultancy; Omeros: Consultancy. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding. Müller-Tidow: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Bioline: Research Funding. Bullinger: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Honoraria; Menarini: Consultancy; Sanofi: Honoraria; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Hexal: Consultancy; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Dreger: Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

Next-Generation Implementation of Chimeric Antigen Receptor T-Cell Therapy Using Digital Health

2021 ◽  
pp. 668-678
Author(s):  
Rahul Banerjee ◽  
Nina Shah ◽  
Adam P. Dicker
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Effector Cell ◽  
Antigen Receptor ◽  
Machine Learning Algorithms ◽  
Immune Effector Cell ◽  
Next Generation ◽  
Immune Effector ◽  
Patient Reported ◽  
Car T

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell–associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments–based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T–related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.

Phase I Clinical Trial Evaluating Abatacept in Patient with Steroid-Refractory Chronic Graft Versus Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 387-387 ◽  
Author(s):  
Myrna R. Nahas ◽  
Robert J. Soiffer ◽  
Edwin P. Alyea ◽  
Jon Arnason ◽  
Robin Joyce ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Graft Versus Host ◽  
Circulating T Cells ◽  
Grade 3 ◽  
Nih Consensus Criteria ◽  
Cell Expression ◽  
Steroid Refractory

Abstract Introduction: Chronic graft versus host disease (cGVHD) remains a major source of morbidity and mortality following allogeneic transplantation. While corticosteroids remain first line therapy for cGVHD, they are associated with significant toxicity, and a substantial proportion of patients fail to completely respond. Treatments for steroid-refractory cGVHD are limited. While the pathophysiology of chronic GVHD is complex, activated T cells play a critical role, driven by allo-antigen stimulation. As such, inhibition of T cell activation via blockade of co-stimulation has potential as a therapeutic target in cGVHD. Abatacept is a recombinant fusion protein consisting of the extracellular domain of human CTLA-4 and a fragment of the Fc domain of human IgG1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is the first drug in a class of agents termed "selective co-stimulation modulators." The CTLA-4 moiety of Abatacept binds specifically to CD80 and CD86 and down-modulates the CD28-mediated co-stimulation of T cells. We conducted a phase I clinical trial was conducted to evaluate the safety, clinical and immune effects of Abatacept in patients with steroid-refractory cGVHD. Methods: The study followed a 3+3 design with two escalating doses of Abatacept to determine the maximum tolerated dose (MTD): 3 mg/kg and 10 mg/kg. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 toxicities judged to be probably or definitely related to Abatacept. Infection was not considered a DLT. Abatacept was administered for a total of 6 doses. Doses 1-3 were administered at two-week intervals. One month following Dose 3, Abatacept was given at four-week intervals for three doses (Doses 4-6). Inclusion criteria included recipients of allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning, with cGVHD defined by NIH consensus criteria. Patients must have had treatment with ≥ 0.5 mg/kg/day of prednisone for at least 4 weeks. Patients with active malignant disease relapse or other active malignancy and patients with uncontrolled infection were excluded. Peripheral blood was drawn prior to each dose of Abatacept and following completion of therapy to assess the effect of treatment on circulating T cells. PD-1 expression on circulating T cells, and T cell expression of interferon gamma versus IL-10 was assessed by multichannel FACS analysis. Results: 17 subjects were treated. Three patients were treated at a dose of 3 mg/kg without DLT. Three evaluable patients completed treatment on cohort 2, at a dose of 10mg/kg without DLT. A forth participant withdrew consent following one dose of treatment and therefore is not evaluable. Ten patients were treated on an expansion cohort at a dose of 10mg/kg. We observed one grade 4 pulmonary infection, and three grade 3 pulmonary infections which resolved. Other Abatacept related adverse events included grade 2 gastritis (n=1), grade 2 pain (n=1), and grade 1 diarrhea (n=2), fatigue (n=2), rash (n=1), and skin pain (n=1). Of the 16 evaluable patients, 7 (44%) achieved a clinical partial response as defined by improvement of two disease systems based on the 2011 NIH consensus criteria. Abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders with a mean baseline dose of 27mg compared to a mean dose of 14mg 1 month following the 6th dose of Abatacept (p = 0.01). PD-1 expression on circulating CD4+ and CD8+ T cells increased from a mean of 3.4% and 2.7% respectively at baseline to a mean of 8.9% and 7.6% respectively at one month following the 6thdose of Abatacept in clinical responders (n=3; p<0.05). In contrast, no change in T cell expression of PD-1 was observed in non-responders. A shift from Th1 to Th2 cytokine secretion was observed in clinical responders, with a mean 2.8 fold decrease in interferon gamma and a mean 2.5 fold increase in IL-10 secretion by circulating T cell populations (n=4). Conclusion: Abatacept is well-tolerated in the treatment of steroid-refractory cGVHD. Abatacept resulted in the improvement in NIH cGVHD scores in 44% of patients with steroid-refractory GVHD with a significant decrease in prednisone dose. An increase in PD-1 expression and a skewing toward Th2 cytokines was observed in clinical responders. Based on this promising data, a phase II trial is being initiated. Disclosures Soiffer: GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Arnason:Gilead: Consultancy. Avigan:Astex: Research Funding; DCPrime: Research Funding. Rosenblatt:Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding.

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