scholarly journals Results from an Expanded Access Program of Anti-CD3/CD7 Immunotoxin Combination (T-Guard®) for the Treatment of Steroid-Refractory Acute Gvhd

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4553-4553 ◽  
Author(s):  
Lenneke F J Groningen ◽  
Christoph Groth ◽  
Manita E J Bremmers ◽  
Eric G Hooren ◽  
Ypke V J M van Oosterhout ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Acute Gvhd ◽  
Expanded Access ◽  
Plasma Citrulline ◽  
Recent Phase ◽  
Grade Ii ◽  
Third Line ◽  
To Receive ◽  
Access Program

Background More effective therapies for treating steroid-refractory acute GVHD (SR-aGVHD) are urgently needed. In our recent phase I/II study, we showed that anti-CD3/anti-CD7 immunotoxin (IT) therapy T-Guard was both safe and well tolerated, and yielded both a high rate of CR and high 6-month OS in high-risk patients (Groth et al. BBMT 2019). Following this study, patients with SR-aGVHD were offered T-Guard via an expanded access treatment program (EAP). Objectives We evaluated patients' outcome after receiving T-Guard for SR-aGVHD. In addition, we examined the relationship between plasma citrulline levels (a biomarker of enterocyte mass) and the response to T-Guard in a subset of patients with SR-aGVHD of the gut, combining 16 patients from the phase I/II trial and 9 patients in the EAP group. Methods An EAP was started after completion of the phase I/II trial. This program was approved by the local ethics committee and the Health and Youth Care Inspectorate of the Dutch government. Adult patients with grade II-IV SR-aGVHD were eligible to receive T-Guard as their second- or third-line treatment for aGVHD. Patients with an uncontrolled infection, signs of moderate-severe chronic GVHD, and/or severe renal impairment were not eligible to receive T-Guard. Eligible patients received four 4-hour i.v. infusions of 4 mg/m2 T-Guard delivered at 48-hour intervals. In addition, plasma citrulline levels were measured at baseline and every 7 days after the start of T-Guard therapy using HPLC with mass spectrometry. A plasma citrulline level <10 µmol/L was considered to indicate severe GI-GVHD. Results From Jan. 2017 through Dec. 2018, 12 patients (8 male, 4 female; median age: 54 yr, range: 20-70 yr) who had received an allogeneic stem cell transplantation for myeloid or lymphoid malignancy were treated with T-Guard. T-Guard was given as the second-line therapy to 10 patients; the remaining 2 patients received T-Guard as the third-line therapy after receiving ruxolitinib (N=1) or cyclosporin-UVB (N=1). The median time between aGVHD onset and the start of T-Guard therapy was 7 days (range: 3-55 days). SR-aGVHD was classified as grade II, III, or IV in 1, 7, and 4 patients, respectively. Nine patients (75%) had GI involvement, and the skin and liver were involved in 6 and 2 cases, respectively. All 12 patients were classified as high-risk in accordance with MacMillan et al. (BJH 2012), and the median albumin level at baseline was 23 g/L (range: 13-32 g/L). By treatment day 28, 9 patients (75%) had achieved a clinical response, with 5 achieving complete remission. After a median follow-up of 16 months, 7 patients were alive; the 6-month and 1-year OS rate was 75% and 58%, respectively, which was significantly higher than historical controls; Figure 1. The cause of death in the other five patients was refractory aGVHD (N=3), relapse AML (N=1), and GVHD after undergoing a second stem cell transplantation for relapse AML (N=1). No significant infusion-related reactions were recorded. As expected, the overall rate of infection was high, but was comparable to other cohorts; 1 and 2 patients developed an EBV or CMV infection, respectively, but these were manageable. The most common potentially treatment-related adverse events were transient worsening of hypoalbuminemia and thrombocytopenia. One patient developed grade 2 vascular leak syndrome, but this was easily managed. One patient developed severe thrombotic microangiopathy with renal insufficiency, but several contributing factors other than the use of T-Guard were present in this patient, including calcineurin toxicity, severe GI-GVHD, and CMV disease. Our preliminary analysis of citrulline levels in 16 patients with GI-GVHD showed that mean baseline levels were extremely low (4.3 µmol/L; range: 2.9-17.9 µmol/L); 28 days after the start of T-guard, citrulline levels had increased significantly in the 9 patients who achieved complete remission; Figure 2. Conclusion Consistent with our recent phase I/II trial, our expanded access program in which 12 patients with high-risk SR-aGVHD received T-guard confirms that this treatment is safe and significantly improves patient outcome. A multicenter phase III study is planned to start in 2019 (BMT-CTN 1802). Disclosures Hooren: Xenikos BV: Employment. van Oosterhout:Xenikos BV: Employment.

Outcome and Prognostic Factors after Unrelated Donor Umbilical Cord Blood Transplantation in Adult Patients with Hematologic Malignancies Transplanted in Early Disease Stages.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2149-2149 ◽  
Author(s):  
Guillermo Sanz ◽  
Ignacio Lorenzo ◽  
Federico Moscardo ◽  
Dolores Planelles ◽  
Luis Larrea ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Early Disease ◽  
Blood Transplantation ◽  
Cd34 Cells ◽  
Grade Ii ◽  
Disease Stages

Abstract Stage of the disease at transplant is critical for outcome after unrelated donor umbilical cord blood transplantation (UD-UCBT). The results of UD-UCBT in adults transplanted early in the course of their disease are unclear. Thus, UD-UCBT remains as the last resort for most patients. The major aim of this report was to study the outcome of a series of adult patients with hematologic malignancies undergoing UD-UCBT early in the course of their disease in a single institution. From May 1997 to May 2004, 40 patients in early disease stages underwent UD-UCBT. All patients received thiotepa, busulfan (orally in 29, intravenously in 11), cyclophosphamide, and antithymocyte globulin (Lymphoglobulin in 24 and Thymoglobulin in 16) as conditioning, cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis, and filgrastim to fasten engraftment. Diagnosis were chronic myeloid leukemia in chronic phase in 14 cases, high-risk acute lymphoblastic leukemia in 14 (12 in CR1, 1 in CR2, and 1 in CR3), high-risk acute myeloblastic leukemia in 8 (7 in CR1 and 1 in CR2), and high-risk myelodysplastic syndrome in 4 (3 untreated and 1 in CR1). Median age was 27 years (range, 16–46). The degree of HLA match (HLA-A and -B by serology and -DRB1 by high-resolution DNA typing) was 6/6 in 2 (5%), 5/6 in 18 (45%), and 4/6 in 20 cases (50%). The median number of nucleated and CD34+ cells infused was 1.8 x 107/kg (range, 0.9–4) and 0.8 x 105/kg (range, 0.1–5.7) respectively. Median time to PMN above 0.5 x 109/L and to platelets above 20 x 109/L was 22 days (range, 13–44) and 69 days (range, 32–188), and the cumulative incidence of myeloid and platelet engraftment was 90% (95% CI, 81–99%) and 70% (95% CI, 57–86%), respectively. Time to myeloid engraftment showed a direct relationship with the number of CFU-GM and CD34 cells cryopreserved (P = .02 and .01 respectively) and infused (P = .0001 and .0004 respectively). Platelet engraftment was faster in patients receiving grafts with a higher number of CFU-GM (P = .005) and CD34+ cells (P = .04), in those receiving Thymoglobulin (P = .02) and in those not developing acute GVHD above grade II (P = .04). Eight patients (20%) developed acute GVHD above grade II, and 9 of 25 patients at risk had extensive chronic GVHD. Patients receiving Thymoglobulin had a lower risk of acute GVHD (P = .0003). With a median follow-up of 33 months (range, 3–87), the probability of disease-free survival (DFS) at 3 years was 48% (95% CI, 30–66%) and was related directly to age (P = .004) and inversely to the development of acute GVHD above grade II (P = .004). The probability of DFS at 3 years was 66 % for patients younger than 31 years and 54% for those not developing acute GVHD above grade II. Cell dose, degree of HLA mismatch, and diagnosis did not clearly influence DFS. These results compare to those obtained after matched unrelated donor bone marrow transplantation, and suggest that UD-UCBT is a reasonable first-line option for adults with hematologic malignancies requiring transplantation and lacking a HLA-matched sibling donor.

The Addition Of Interleukin-6 Inhibition To Standard Gvhd Prophylaxis Prevents Acute Gvhd: Interim Results Of a Phase I/II Clinical Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 908-908 ◽  
Author(s):  
Glen A Kennedy ◽  
Antiopi Varelias ◽  
Slavica Vuckovic ◽  
Ping Zhang ◽  
Kelli PA MacDonald ◽  
...  
Keyword(s):  
Phase I ◽  
Interleukin 6 ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Off Label Use ◽  
Control Cohort ◽  
Off Label ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Grade Ii

Abstract We and others have demonstrated the dysregulation of interleukin-6 (IL-6) early after experimental bone marrow transplantation (BMT) and protection from acute GVHD following the administration of an anti-IL-6 receptor (IL-6R) antibody. In these models, where GVHD prophylaxis is not administered, systemic IL-6, IFNγ and TNF levels peak 7 days after BMT before returning to baseline by the third week. We have determined cytokine dysregulation in a large clinical cohort of allogeneic stem cell transplant (SCT) recipients conditioned with myeloablative Cy/TBI (12 Gy, n = 25) or reduced intensity Flu/Mel (120mg/m2, n = 25) receiving standard GVHD prophylaxis with cyclosporine and MTX (d 1 at 15mg/m2, d 3, 6, 11 at 10mg/m2). IL-6 levels rose from pre-transplant levels of 6.4 ± 0.7 pg/ml to a peak of 58.8 ± 8.8 pg/ml at day 7 (P < 0.0001) with a fall at day 14 to 39.0 ± 12.5 pg/ml (P < 0.0001) and return to baseline by day 30 (6.2 ± 0.9 pg/ml), consistent with the preclinical data. IL-6 dysregulation was not different in recipients of matched sibling or unrelated donor grafts but was proportional to the intensity of conditioning (day 7 levels after Cy/TBI vs. Flu/Mel: 83.3 ± 12.2 pg/ml vs. 31.0 ± 10.1 pg/ml, P< 0.0001). In contrast to preclinical mouse data, no systemic increases were seen in any other cytokine including IFNγ, TNF, IL-17, IL-4, IL-13 and IL-10. We thus initiated a phase I/II study whereby a human neutralizing monoclonal antibody (mAb) against the IL-6R was administered on day -1 to patients receiving Cy/TBI or Flu/Mel conditioned allogeneic SCT from HLA (10/10)–matched sibling or unrelated donors with standard cyclosporine/MTX GVHD prophylaxis. There was no T cell depletion. The primary endpoint was the incidence of grade II-IV acute GVHD and the study has achieved its planned enrollment (n = 48). There was no toxicity attributable to IL-6R antibody administration. Pharmacokinetic analysis confirmed high levels of IL-6R Ab at day 3 (mean 64.7 ug/ml) which persisted in all patients 3 weeks after BMT (mean = 9.8 ug/ml) and remained above the level of detection (0.1ug/ml) in 75% of patients at day 30 (mean = 1.9 ug/ml). IL-6 levels were dramatically increased (relative to baseline) in patients receiving antibody due to the inability to excrete the inactive IL-6 – soluble IL-6R antibody complex (peak IL-6 levels at day 7 = 773.6 ± 207.9 pg/ml; P < 0.0001) and remained increased at day 30 (60.9 ± 24.4 pg/ml; P < 0.0001), returning to baseline by day 60 (9.5 ± 1.7 pg/ml), consistent with antibody clearance. Soluble IL-6R levels also rose over the first month of SCT and levels at day 30 correlated with residual antibody levels (r2 = 0.72, P = 0.02). Neutrophil (> 0.5x109/L) and platelet (> 20x109/L) recovery was normal relative to a matched untreated control cohort at a median of 16 and 18 days respectively. Donor chimerism and immune reconstitution (conventional T, regulatory T and B cells) was equivalent at day 30 in recipients of IL-6R inhibition versus the control cohort. In contrast, changes in innate immunity were seen in patients receiving IL-6R inhibition with increases in plasmacytoid DC (P = 0.002), CD1c+ conventional DC (P = 0.04) NKT cells (P =0.03) and marked reductions in inflammatory (CD14+CD16+) monocytes (P < 0.0001). Transcriptional profiling of T cell subsets is underway. With 36 patients evaluable (beyond day 100, median follow up of 297 days), the incidence of grade II-IV GVHD is 11.1% in recipients of IL-6R inhibition versus 39.6% in the matched (n = 53) control cohort (P = 0.004). The incidence of grade III/IV acute GVHD is 5.6% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.045). Protection from grade II-IV acute GVHD was noted in patients receiving both Cy/TBI (7.7% vs. 40.7%, P=0.045) and Flu/Mel conditioning (13.0% vs. 38.5%, P = 0.044). Rates of CMV reactivation were very low in the IL-6R neutralized patients (16.7% vs. 35.8% in controls, P = 0.04), likely due to the prevention of acute GVHD and its’ consequent therapy. At one year, the relapse incidence and disease free survival in patients receiving IL-6R inhibition versus the control cohort is 21.2% vs. 30.0% (P = 0.28) and 73.1% vs. 62.4% (P = 0.14) respectively. IL-6 is thus the principal inflammatory cytokine dysregulated after clinical allogeneic SCT and its inhibition appears to offer profound protection from acute GVHD despite robust immune reconstitution, without compromise of the GVL effect. Disclosures: Off Label Use: The use of Tocilizumab to prevent GVHD is experimental and an off label use.

A Phase I/II Trial Evaluating the Use of a Histone Deacetylase Inhibitor Panobinostat (LBH589) in Addition to Glucocorticoids in Patients with Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1167-1167 ◽  
Author(s):  
Lia Perez ◽  
Teresa Field ◽  
Marcie L Riches ◽  
Hugo F Fernandez ◽  
Frederick L Locke ◽  
...  
Keyword(s):  
Phase I ◽  
Graft Versus Host Disease ◽  
Histone Deacetylase Inhibitor ◽  
Acute Gvhd ◽  
Response Rate ◽  
Liver Stage ◽  
Graft Versus Host ◽  
Deacetylase Inhibitor ◽  
Grade Ii ◽  
Stage 1

Abstract Graft-versus-host disease (GVHD) remains the principal obstacle to successful outcomes in allogeneic hematopoietic stem cell transplant (HCT). Glucocorticoids are the current standard initial treatment for acute GVHD with variable complete responses rates (30% to 60%). New immunosuppressive strategies are required to improve survival and to decrease immunosuppressive toxicities. Vorinostast, a histone deacetylase inhibitor (HDACi), have shown efficacy for acute GVHD prevention in MRD HCT. Panobinostat is a potent inhibitor of deacetylases and HSP90 belonging to a structurally novel class of the cinnamic hydroxamic acid class and is one of most potent pan-HDACi. This protocol tested the safety and efficacy of Panobinostat (LBH589) as initial adjunct treatment for acute GVHD, administered within 72 hours of the first high dose glucocorticoid (methylprednisolone 0.8 mg/Kg/day IV or equivalent PO for 14 days and then taper per MD discretion). We have enrolled 19 subjects, median age 53 years (range, 34-76), male (n=12)/female (n=7), white(n=14)/hispanic(n=5); with diagnosis of CLL (n=2), MDS (n=2), Myeloma (n=1), Follicular NHL (n=1), CML(n=1), Myelofibrois (n=3), AML (n=5), MDS/CMML (n=3) or ALL(n=1). Conditioning regimens included Busulfan(BU)/fludarabine(FLU) AUC 5300 (n=10) or AUC 3500 (n=3), FLU/Melphalan (n=4) or Pentostatin/BU (n=2); and GVHD prophylaxis for MUD 8/8 (n=11) or MRD (n=5) HCT with TAC/MTX (n=6), TAC/rapamycin(n=7), TAC/MMF(n=3) and for mismatched transplants with either TAC/RAPA/ATG (n=2) or TAC/MTX/ATG (n=1). Median day of acute GVHD (n=16) onset was day + 37 post HCT (26 -109 days) with overall grade GVHD II (n=13) or III (n=6); and median day of acute symptoms in overlap GVHD patients (n=3) was day + 712 (528-981). All Patients were treated with voriconazole (n=15) or micafungin (n=4) for fungal prophylaxis. For the first four patients Panobinostat was administered intravenously (IV) weekly x 4 at 2.5MG/M2 (n=3) or 5MG/M2 IV (n=1) with all 4 achieving either CR (n=3) or PR (n=1) GVHD responses by day +15 of Panobinostat. Due to manufacturer discontinuation of IV formulation, the protocol was amended to use PO Panobinostat. Using 10mg PO TIW 3 doses q week x 4 weeks, we treated 2 subjects which were both discontinued from study drug due to presumed GHVD progression within 7 days of Panobinostat (after 3-4 doses). First subject had grade II GVHD (skin stage 3, gut stage 1 and liver stage 0) that progress in gut and skin; second subject with grade II GVHD (skin stage 3, gut stage 1, liver stage 1) with LFTs worsening ultimately evolving into VOD. Due to safety concerns next subjects were treated with 5 mg PO TIW 3 doses q week x 4 weeks, dose that was determined to be the maximal tolerated dose (MTD) after 6 patients completed therapy in phase I. Currently we are enrolling in phase II portion (n=7). GVHD response rate among MTD treated was complete in 85% (n=11), partial in 7.6% (n=1) or progressive in 7.6% (n=1) by day +36 after Panobinostat with majority achieving responses by day +21. Chronic GVHD at day +365 in evaluable patients (n=6) was none (n=3) or mild (n=3) and steroid was discontinued at a median of 3 months (3-6). Hematological toxicities in evaluable patients (n=13) were mild with worsening of prior thrombocytopenia (n=7/10), anemia (n=3/10) and leukopenia (n=3/10) and returned to baseline within 1-2 weeks; LFTs deterioration (n=1) within 1 week of Panobinostat in a GVHD stages 3 liver/3 skin patient; pericarditis/cardiogenic shock CTCAE 5 of unclear etiology (n=1); worsening thyroid function (n=1) and hypercholesterolemia (n=1). Preliminary correlative studies in MTD treated patients showed that CD4 and CD8 numbers remained stable during treatment. T regulatory cells numbers decreased at day +8 after Panobinostat and recovered by days +15 and +29 of treatment. Level of T regs inducing cytokines (TGFB and IL-10) increased, possibly contributing to an immune-modulatory environment. There is evidence of an increased in acetylation of histone 3 in CD4, CD8 and monocytes subsets over time. We are encouraged with tolerability of level -1 Panobinostat dose and the high GVHD response rate of 85% which may compare favorably to the historical GVHD response rate. These results suggest a potential role for Panobinostat as a tool to improve success of glucocorticoids for acute GVHD treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expanded Access Program: Evaluating Safety of Erythrocytes Encapsulating L-Asparaginase in Combination with Polychemotherapy in Patients Under 55 Years Old with Acute Lymphoblastic Leukaemia (ALL) at Risk to Receive Other Formulations of Asparaginase

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1214-1214
Author(s):  
Yves Bertrand ◽  
Nicolas Boissel ◽  
Claudine Schmitt ◽  
Alban Villate ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
At Risk ◽  
Board Of Directors ◽  
Whole Blood ◽  
Research Funding ◽  
Advisory Committees ◽  
E Coli ◽  
Expanded Access ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Introduction Asparaginase is an important part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity is found in 16.8% of patients treated with pegylated asparaginase (PEG-asp). Hypersensitivity is the most common cause of truncated asparaginase therapy which has been associated with decreased event free survival. Asparaginase (ASNase) encapsulated in erythrocytes (eryaspase) is an alternative formulation of ASNase aiming to prolong the half-life of ASNase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane protects asparaginase against elimination and prevents activation of the immune system. In the NOR-GRASPALL 2016 trial eryaspase consistently demonstrated prolonged ASNase activity in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated when combined with multiagent chemotherapy. The objective of this expanded access program was to explore the tolerability of eryaspase (150 U/Kg) combined with polychemotherapy in patients under 55 years of age with ALL, unable or at risk to receive any other available ASNase formulation. Patients in this study had developed hypersensitivities to prior E-Coli- and Erwinia-derived asparaginase therapies. Methods This was a non-randomized, multicentre, open label, Phase 1 study to assess the limiting toxicities, global safety and biological efficacy of eryaspase in combination with chemotherapy regimens. Patients were under 55 years of age with ALL de novo or in relapse or refractory; eligible for a chemotherapy treatment including ASNase; known contraindication and/or at risk of toxicity from other ASNase formulations. Eryaspase (150 U/Kg) was given as a replacement therapy for the remaining intended courses of asparaginase therapy. The number of courses was not defined and depended on therapeutic treatment chosen by the Investigator and the patient's response and tolerance. The primary endpoint was the exploration of the toxicity of eryaspase defined as the number and percent of patients presenting at least one limiting toxicity (LT) of eryaspase in combination with chemotherapy. Major secondary endpoints included: adverse events (AEs), pharmacokinetics (PK), pharmacodynamics (PD) and complete remission (CR) status at end of induction and survival status up to 12 months after inclusion. Results Eighteen patients enrolled of which seven (38.8%) patients experienced a total of 24 AE limiting toxicities, which were primarily bone marrow failure, and were indicative of the underlying ALL disease process and of the concomitant chemotherapy-related myelosuppression. All patients experienced at least one AE and Treatment Emergent (TEAE) and most (11 [61.1%] patients) experienced at least one SAE. A total of 17 (94.4%) patients experienced a TEAE of Grade 3 or above. No TEAEs led to withdrawal or dose reduction of eryaspase. Sparse whole blood ASNase concentrations following 150 U/Kg were within the range of concentrations expected for this dose level. At 14 days following the first infusion, the range of whole blood ASNase was 111 to 1160 U/Kg, which would be equivalent to the trough (nadir) for infusions every 2 weeks. Mean and median plasma asparagine (ASN) concentrations over time demonstrated a reduction by approximately 50% at 3 days post eryaspase infusion, followed by a slow return toward baseline before the next infusion of eryaspase. Seventeen (94.4%) patients achieved CR at least once overall. Fourteen (77.8%) patients were alive at the end of the study. Survival rate was 88.9% at 6 months and 77.8% at 12 and 18 months. Conclusion The AE profile of eryaspase was consistent with other studies and was as expected for this cohort of patients. Serious AEs were generally consistent with those that would be expected in this study population. A total of 17 patients in the study achieved a CR at least once overall and 14 were still alive at the end of the study. This study evaluated additional asparaginase therapy in double (and even triple) allergic patient population, who have received prior E-Coli- or Erwinia-derived asparaginase therapy. All patients achieved target asparaginase activity. Therefore, eryaspase provides an additional option for patients for whom further ASNase treatment is contraindicated due to toxicity and/or immunization. Disclosures Boissel: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; CELGENE: Honoraria. Recher: Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Incyte: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. El-Hariry: Erytech: Current Employment, Current holder of stock options in a privately-held company.

Infusions of T Cells Armed with Anti-CD3 x Anti-Her2/neu Bispecific Antibody Modulate In Vivo Patient Immune Responses in Phase I Clinical Trials for Breast and Hormone Refractory Prostate Cancers.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1349-1349 ◽  
Author(s):  
Pamela A. Davol ◽  
Jonathan M. Gall ◽  
Ryan C. Grabert ◽  
Wendy B. Young ◽  
Francis J. Cummings ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Immune Responses ◽  
Phase I ◽  
Phase I Clinical Trials ◽  
Phase Ii Trials ◽  
Specific Lysis ◽  
Grade Ii ◽  
Hormone Refractory

Abstract Phase I dose escalation trials using ex vivo expanded, anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-Her2/neu (Her2Bi) to evaluate toxicity and immune responses were conducted in 8 Stage IV breast cancer (BrCa), 5 high-risk Stage II BrCa, and 3 hormone refractory prostate cancer (HRPC) patients. Patients received 8 infusions (Inf) twice per week for 4 weeks totaling 40 billion (11/16 patients) or 80 billion (5/16 patients) HER2Bi-armed ATC. Phenotyping the expansion product showed 90.0±10.1% (mean±SD)CD3, 47.5±22.2 CD4, and 41.9±19.9 CD8. Specific lysis of SK-BR-3 targets by patients’ armed ATC (n= 16 patients) at E:T of 10, 5, and 2.5 averaged 54.1±17, 39.5±14, and 25.9±11, respectively. These results were comparable to 63.4±17 (p = 0.23), 57.7±20 (p = 0.09), and 33.9±16 (p = 0.38) specific lysis mediated by armed ATC from 6 normal donors at the respective E:T confirming the function of Her2Bi-armed ATC at the time of Inf. By ELISA, 4/8 (50%) of the patients developed anti-mouse antibody responses (HAMA) to OKT3, which peaked (median: 35.4 ng/ml; range: 4–64 ng/ml) between Inf#5 and Inf#8 (14–27 days post-Inf #1). There were no AEs associated with elevated HAMA titers. Th1/Th2 panels were obtained from patient sera using the Bio-Plex Protein Array System and analyzed as a function of number of Infs. The in vivo T cell response, calculated as the mean Th1[IL-2+IFN-g]/Th2[IL-4+IL-5] ratio of cytokines, showed a polarized Th1 response as a function of armed ATC Inf that increased from 89.1(Inf#1) to 538.6 (Inf #8). Levels of IL-12 also increased by Inf#5 and were constant from Inf#5 through Inf#8 (mean±SD = 34.0±17.2 pg/ml). These findings were consistent with increased CTL responses observed in ELISPOTs of patient post-Inf PBMC exposed to Her2+ tumor targets. Overall immune response, calculated as the average ratio of Th1[IL-2+IFN-g] /Th2 [IL-4+IL-5+IL-10+IL-13], remained Th1 polarized throughout treatment though the ratio decreased as a function of Inf#: going from 9.46 (Inf#1) to 1.42 (Inf #8). TNF-alpha levels were contant from Inf #1–8 (mean±SD = 9.5 ± 4.9 pg/ml), and GM-CSF peaked between Inf #5–8 (92.2 ± 36.4 pg/ml). Detection of MIgG2a+ (anti-CD3 coated) cells in the PBL from 8 patients was highest post-Inf#1 (18.4% ± 16.1) and decreased by Inf #5–8 (4.1% ± 6.1). In 2 patients, MIgG2a+ armed T cells could still be detected 1 week and 3 weeks after Inf#8. All patients received their targeted doses of armed ATC: no dose-limiting toxicities were observed in any patients, and with the exception of a few patients with grade II–III chills/grade II fever, infusions of Her2Bi-armed ATC were well-tolerated. These observations provide evidence that the endogenous immune system is being modulated by the infusion of armed ATC and further support the rationale for performing phase II trials using armed ATC in Her2+ advanced/high risk BrCa and HRPC patients.

scholarly journals Treatment of Steroid Resistant Grade II to IV Acute GVHD by Infusion of Mesenchymal Stroma Cells Expanded with Platelet Lysate - a Phase I/II Study

2013 ◽  
Vol 19 (2) ◽  
pp. S144
Author(s):  
Liane te Boome ◽  
Cristina Mansilla ◽  
Caroline Lindemans ◽  
Lotte van der Wagen ◽  
Marloes Cuijpers ◽  
...  
Keyword(s):  
Phase I ◽  
Acute Gvhd ◽  
Platelet Lysate ◽  
Steroid Resistant ◽  
Grade Ii ◽  
Mesenchymal Stroma ◽  
Mesenchymal Stroma Cells
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