Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Jessica Liegel ◽  
Richard M. Stone ◽  
Robert J. Soiffer ◽  
Dina Stroopinsky ◽  
Lina Bisharat ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Vaccine Site

Introduction: We are conducting a clinical trial in which patients with acute myeloid leukemia (AML) who are undergoing allogeneic transplant undergo post-transplant vaccination with DC/AML fusion cells. Allogeneic transplantation is uniquely curative for a subset of patients with AML, however, post-transplant relapse and graft versus host disease remain significant concerns. We have developed a promising leukemia vaccine in which patient derived AML cells are fused with donor-derived dendritic cells (DCs), presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population. We hypothesize that DC/AML vaccination post-transplant would elicit the durable expansion of leukemia specific T cells within the donor T cell repertoire to effectively protect against disease relapse. Methods: Patients undergo collection and cryopreservation of leukemia cells at the time of diagnosis with AML. Patients who undergo an allogeneic transplant in complete remission from a matched related or unrelated donor (cohort A) or a haplo-identical donor (Cohort B) are assessed for eligibility to undergo leukapheresis for dendritic cell generation between day 25-45 post-transplant. In order to proceed with leukapheresis, patients must demonstrate donor hematopoietic recovery in the absence of ongoing grade 2 or higher GVHD. Patients initiate vaccination between day 70-100 post-transplant. 2 vaccines are given at 3 week intervals, in conjunction with GMCSF 100 mcg daily at the vaccine site for 4 days. A booster vaccine may be given 30-60 days following the taper of immune suppression, in the absence of GVHD. Results: To date, 12 participants have undergone vaccine generation. The median age is 62 years (range 23-74). 10 participants were enrolled to cohort A: 7 were transplanted with a matched unrelated donor and 3 were transplanted with a matched sibling donor. 2 participants were enrolled to cohort B following transplant from a haplo-identical donor. The mean yield of leukemia cells was 314 x106 (range 95-to 818-x106)and mean viability was 96%. For DC generation, patients underwent leukapharesis and adherent mononuclear cells were cultured with GM-CSF, IL-4 and TNFa. The mean yield of DCs was 131 x106 and viability 77%. Fusion vaccine was successfully generated in 11/12 patients, with mean fusion efficiency of 51% with viability of 76%. One patient had insufficient DC for vaccine generation. Mean Fusion Vaccine Dose was 4.7 x 106 fusion cells. 3 patients did not meet eligibility to initiate vaccination due to ongoing toxicity following transplant (2 patients) and GVHD (1 patient). 8 participants have initiated vaccine administration and are evaluable for toxicity and response. The most common side effects have been grade 1 vaccine site reactions (n=9 grade 1, n=1 grade 2). 4 patients developed GVHD that was determined to be possibly related to vaccination, at a median time of 16.5 days after vaccination (range 5-21 days). 2 of these patients developed grade 2 acute GVHD of the skin, one patient developed grade 2 gastrointestinal GVHD that subsequently evolved into moderate, chronic GVHD affecting the skin, GI tract, eyes and mouth, and one patient developed mild transaminitis attributed to liver GVHD. An additional 3 patients developed GVHD with a median time of 99 days post vaccination (range 91-123 days), assessed as being unlikely related to vaccine. 7 of the 8 patients remain in a CR at a median time of 15.5 months post-transplant (range 4.8-22.4 months). One patient relapsed 14.8 months post haplo-identical transplant. Immunologic response following vaccination is being assessed, with respect to the presence of leukemia-reactive T cells, T cells targeting previously identified leukemia- associated antigens, T cell clonality, T regulatory cells, and PD-1 expressing T cells. In the absence of treatment associated toxicity, a second cohort is planned, in which vaccine will be given in conjunction with decitabine. Conclusions: Vaccine generation using donor derived DC isolated following engraftment is feasible. Mild to moderate graft versus host disease has been observed in a subset of patients, and 7/8 vaccinated patients remain relapse free. Correlative science studies to assess immune response to vaccination, identify neoantigen targets, and characterize the immune milieu, will be reported. Disclosures Stone: Syros: Consultancy; Syntrix: Consultancy; Syndax: Consultancy; Stemline: Consultancy; Hoffman LaRoche: Consultancy; Macrogenics: Consultancy; Janssen: Consultancy; Gemoab: Consultancy; Elevate: Consultancy; Daiichi-Sankyo: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Biolinerx: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Agios: Consultancy, Research Funding; Actinium: Consultancy; AbbVie: Consultancy, Research Funding. Soiffer:Gilead: Consultancy; Rheos Therapeutics: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Mana Therapeutics: Consultancy; VOR Biopharma: Consultancy; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; alexion: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. Neuberg:Pharmacyclics: Research Funding; Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company.

scholarly journals Human CD83 Targeted Chimeric Antigen Receptor T Cell for the Prevention of Graft Versus Host Disease and Treatment of Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 196-196
Author(s):  
Bishwas Shrestha ◽  
Kelly Walton ◽  
Jordan Reff ◽  
Elizabeth M. Sagatys ◽  
Nhan Tu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Fund Research

Distinct from pharmacologic immunosuppression, we designed a programmed cytolytic effector T cell that prevents graft versus host disease (GVHD). CD83 is expressed on allo-activated conventional T cells (Tconv) and pro-inflammatory dendritic cells (DCs), which are implicated in GVHD pathogenesis. Therefore we developed a novel human CD83 targeted chimeric antigen receptor (CAR) T cell for GVHD prophylaxis. Here we demonstrate that human CD83 CAR T cells eradicate cell mediators of GVHD, significantly increase the ratio of regulatory T cells (Treg) to allo-activated Tconv, and provide lasting protection from xenogeneic GVHD. Further, we show human, acute myeloid leukemia (AML) expresses CD83 and can be targeted by CD83 CAR T cells. A 2nd generation CD83 CAR was generated with CD3ζ and 41BB costimulatory domain that was retrovirally transduced in human T cells to generate CD83 CAR T cells. The CD83 CAR construct exhibited a high degree of transduction efficiency of about 60%. The CD83 CAR T cells demonstrated robust IFN-γ and IL-2 production, killing, and proliferation when cultured with CD83+ target cells. To test whether human CD83 CAR T cells reduce alloreactivity in vitro, we investigated their suppressive function in allogeneic mixed leukocyte reactions (alloMLR). CD83 CAR T cells were added to 5-day alloMLRs consisting of autologous T cells and allogeneic monocyte-derived DCs at ratios ranging from 3:1 to 1:10. The CD83 CAR T cells potently reduced alloreactive T cell proliferation compared to mock transduced and CD19 CAR T cells. We identified that CD83 is differentially expressed on alloreactive Tconv, compared to Tregs. Moreover, the CD83 CAR T cell efficiently depletes CD83+ Tconv and proinflammatory DCs with 48 hours of engagement. To test the efficacy of human CD83 CAR T cells in vivo, we used an established xenogeneic GVHD model, where mice were inoculated with human PBMCs (25x106) and autologous CD83 CAR (1-10x106) or mock transduced T cells. The CD83 CAR T cells were well tolerated by the mice, and significantly improved survival compared to mock transduced T cells (Figure 1A). Mice treated with CD83 CAR T cells exhibited negligible GVHD target organ damage at day +21 (Figure 1B). Mice inoculated with CD83 CAR T cells demonstrated significantly fewer CD1c+, CD83+ DCs (1.7x106 v 6.2x105, P=0.002), CD4+, CD83+ T cells (4.8x103 v 5.8x102, P=0.005), and pathogenic Th1 cells (3.1x105 v 1.1x102, P=0.005) at day +21, compared to mice treated with mock transduced T cells. Moreover, the ratio of Treg to alloreactive Tconv (CD25+ non-Treg) was significantly increased among mice treated with CD83 CAR T cells (78 v 346, P=0.02), compared to mice injected with mock transduced T cells. Further, CD83 appears to be a promising candidate to target myeloid malignancies. We observed CD83 expression on malignant myeloid K562, Thp-1, U937, and MOLM-13 cells. Moreover, the CD83 CAR T cells effectively killed AML cell lines. Many AML antigens are expressed on progenitor stem cells. Thus, we evaluated for stem cell killing in human colony forming unit (CFU) assays, which demonstrated negligible on-target, off-tumor toxicity. Therefore, the human CD83 CAR T cell is an innovative cell-based approach to prevent GVHD, while providing direct anti-tumor activity against myeloid malignancies. Figure Disclosures Blazar: Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; Alpine Immune Sciences, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Fate Therapeutics, Inc.: Research Funding; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Davila:Atara: Research Funding; Celgene: Research Funding; Precision Biosciences: Consultancy; Bellicum: Consultancy; GlaxoSmithKline: Consultancy; Adaptive: Consultancy; Anixa: Consultancy; Novartis: Research Funding.

scholarly journals Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA-Haploidentical HSCT (haplo-HSCT) in Children with Malignant or Non-Malignant Disorders

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2171-2171
Author(s):  
Mattia Algeri ◽  
Pietro Merli ◽  
Waseem Qasim ◽  
Mary Slatter ◽  
Melissa Kuhn ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Life Threatening ◽  
Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for children with leukemia or life-threatening non-malignant disorders. Approximately 25% of patients have a HLA-matched sibling and ~50% have a suitable matched unrelated donor, leaving ~25% of patients who require an alternative donor. HLA-partially matched (haploidentical, haplo) donors represent a suitable alternative for these children; extensive T-cell depletion of the graft is largely employed to minimize the risk of graft-versus-host disease (GvHD). BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of CD3+ CD19+ T-cells following transplant. The polyclonal nature of the BPX-501 T cells provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid. Aims To evaluate the safety and efficacy of BPX-501 T cells administered after a T-cell receptor αβ and B-cell-depleted haplo-HSCT in pediatric patients with malignant or non-malignant disorders. The primary endpoint is event-free survival at 180 days (events include TRM (or NRM for malignant patients), severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life-threatening infections (Grade 4). Methods This multicenter EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 (BPX-501). BPX-501 cells were planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of dimerizing rimiducid activating iC9. The efficacy evaluable population (EEP) was defined as any patient who received HSCT, BPX-501 infusion and at least one follow-up assessment. Results At the time of clinical cut-off (June 30, 2018) 166 patients met the EEP definition. All patients were from EU sites. Key baseline and transplant characteristics are shown in Table 1. In patients who obtained sustained engraftment of donor cells, the median time for neutrophil and platelet engraftment was 16 (15-17) and 11 (11-12) days, respectively. No patients experienced graft failure. Thirty-one patients developed Grade I-IV aGvHD (18.7% [95% CI;12.8 - 24.7%]). Three patients developed Grade III-IV aGvHD (1.8% [95% CI; 5.2 - 14.1%]). Of 132 evaluable patients, 9 developed cGvHD (7.2% [95% CI; 2.6 - 11.7%]) with only 2 patients experiencing moderate - severe cGvHD (95% CI: 0.0 - 3.1). Rimiducid was administered to 11 patients. Ten patients had ≥ 1 response assessment following administration of rimiducid. The best overall response rate (CR/PR) was 100% with 9 patients (90%) achieving complete response. At the time of clinical cut off, EFS at 180 days was 92.7% (95% CI: 88.7 - 96.7%). An interim analysis with approximately 100 patients from a concurrent Matched Unrelated Donor (MUD) HSCT comparator trial and previously published data is planned for the time of the congress. At a median follow-up of 17.6 mos (1.5 - 43.7 mos) 5 patients experienced transplant related mortality (TRM) (3.3% [95% CI: 0.4 - 6.2%]). DFS was 89.4% (95% CI: 84.7 - 94.2%). Overall survival (OS) was 94.2% (95% CI: 90.5 - 97.9%). CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by day 100. IgA and IgM levels achieved normal values by day 180. The percentage of circulating and median absolute BPX-501 T-cells at Day 100 were 9.06% ± 10.52% (0 - 54.9%) and 109.49 ± 213.99 cells/ml (0 - 1001 cells/ml), respectively. Conclusion Preliminary evaluation of the primary endpoint and additional time-dependent efficacy outcomes, shows that the adoptive transfer of BPX-501 T cells following αβ-T and B-cell depleted haplo-HSCT followed by infusion of BPX-501 represents a novel and highly effective transplantation strategy for pediatric patients with malignant or non-malignant disorders. Despite the addition of BPX-501, overall rates of GvHD were low with few cases of high-grade aGvHD or cGvHD. Rimiducid was shown to be an effective treatment for patients who developed steroid-refractory GvHD. Disclosures Qasim: Bellicum: Research Funding; Autolus: Equity Ownership; Servier: Research Funding; Orchard: Equity Ownership. Slatter:Medac: Other: Travel assistance. Locatelli:bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The Novel Combination of Sirolimus and Bortezomib Prevents Graft-Versus-Host Disease but Mantains the Graft-Versus-Leukemia Effect After Allogeneic Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3738-3738
Author(s):  
Teresa Caballero-Velazquez ◽  
Luis Ignacio Sanchez-Abarca ◽  
Belen Blanco ◽  
Carmen Herrero ◽  
Silvia Gutierrez-cosio ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effect ◽  
Board Of Directors ◽  
Graft Versus Host Disease ◽  
Allogeneic Transplantation ◽  
Advisory Committees ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract Abstract 3738 Graft-versus-host disease (GVHD) represents a major challenge and the main cause of morbidity and mortality after allogeneic transplantation. Using the standard GVHD prophylaxis based on a calcineurin inhibitor plus methotrexate (MTX). The incidence of acute GVHD is in the range of 30–60%, so that new strategies are required in order to decrease GVHD without hampering GVL. Sirolimus, an mTOR inhibitor, allows to decrease the risk of GVHD and increases the number of Treg after transplantation. Unfortunately, its use may increase the risk of microangiopathy and, moreover, its combination with calcineurin inhibitors blocks the development of Treg. Bortezomib is a proteosome inhibitor and blocks the nuclear translocation and activation of NF-kB. It induces depletion of alloreactive T and allows the expansion of T-cells with suppressive properties. Accordingly, both drugs could favour the development of a tolerogeneic immune response after transplantation. In the current study we have analyzed the synergistic effect of sirolimus together with bortezomib. Bortezomib 100 nM plus sirolimus 5nM synergistically inhibited T-cell activation as assessed by the expression of CD25, production of IFNg and expression of CD40L as well as proliferation assessed as expression of PKH. Remain vibility, these effects could not be attributed to a decreased viability of T-cells, as assessed by 7-AAD, at the concentrations evaluated. As compared to each drug alone, the combination significantly decreased the production of Th1 cytokines (IFNg, IL-2 and TNF) while regarding TH2 cytokines, only IL-6 significantly decreased upon combining both drugs. Concerning the mechanisms involved in this synergistic effect, the combination of both drugs resulted in an inhibition of the Akt and Erk ½ phophorylation, thus indicating that sirolimus inhibit pathways which could allow T-cells to escape from the effect of bortezomib at the doses used in the current experiment. In order to confirm in vivo the synergistic effect of sirolimus and bortezomib, a GVHD mouse model (C57/BL6-Balb/c) was carried out. Mice receiving both drugs (Bortezomib 1μg/day intravenous on days 0, +1, +2 postransplantat and sirolimus 0.25mg/Kg intra-peritoneal on days 0 to 12) has a significantly lower incidence of GVHD and longer survival as compared to each drug alone. We also wanted to evaluate whether the immunosuppressive effect of the combination was unspecific or, by contrast, it allowed induce specific immune tolerance against host but maintaining the immune response against other antigens. For this purpose a haematopoietic cells of Balb/c mice which were C57/BL6 complete chimeras were infused to NOD-SCID mice. While none of the donors had developed GVHD after transplantation plus sirolimus and bortezomib postransplant, the NOD-SCID mice succumbed due to GVHD. Furthermore, we infused WEHI cells to BALB/c after total body irradiation and we observed that, while all BALB/c mice receiving WEHI plus C57BL/6 donor BM cells died due to leukemic infiltration, none of those receiving WEHI cells plus C57BL/6 donor BM cells plus splenocytes (and GVHD prophylaxis with sirolimus and bortezomib) did develop leukemic infiltration, thus confirming that, using this approach, we were able to separate GVHD and GVL effect. In conclusion, the current study shows a potent synergistic effect between sirolimus and bortezomib in vitro and in vivo which prevent GVHD while maintaining GVL. Disclosures: Cañizo: CELGENE: Membership on an entity's Board of Directors or advisory committees. San Miguel:JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; MILLENNIUM: Membership on an entity's Board of Directors or advisory committees. Off Label Use: sirolimus and bortezomib are not approved for use in prophylaxis of graft versus host disease.

scholarly journals A Phase II Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy of Cmvpepvax for Preventing CMV Reactivation/Disease after Matched Related/Unrelated Donor Hematopoietic Cell Transplant

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2887-2887
Author(s):  
Ryotaro Nakamura ◽  
Corinna La Rosa ◽  
Dongyun Yang ◽  
Joshua A. Hill ◽  
Armin Rashidi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Double Blind ◽  
Cmv Reactivation

Abstract Cytomegalovirus (CMV) infection remains a major cause of morbidity/mortality after allogeneic hematopoietic cell transplantation (HCT). Preemptive antiviral therapy is associated with drug-induced toxicities, and prophylactic therapy with letermovir is associated with late reactivations and delayed antiviral immune reconstitution. Therefore, substituting antivirals with a vaccine that harnesses the native immune response to CMV may improve outcomes for HCT recipients. Our group has developed a peptide vaccine, CMVPepvax, composed of an HLA-A*0201 restricted pp65 495-503 CD8 T cell epitope, covalently linked to a universal tetanus T helper epitope and co-administered with PF-03512676 adjuvant. CMV PepVax was safe and immunogenic in a healthy volunteer study (La Rosa et al. PMID: 22402037;) and a phase Ib HCT recipient trial (Nakamura, et al. PMID: 26853648) with the latter demonstrating a promising sign of efficacy in reducing CMV viremia. In this double blind, placebo-controlled, randomized phase 2 trial (NCT02396134), HCT recipients were enrolled at four USA transplant centers. Eligible patients were CMV seropositive, HLA A*0201-positive, 18-75 years, receiving HCT from a matched related/unrelated donor. T-cell depleting agents (i.e. ATG) or recipients of ex-vivo T-cell-depleted grafts were excluded. Prophylactic antiviral therapy was not allowed. Patients were enrolled prior to day 0 of HCT and reassessed on day +28 for eligibility and randomization to the vaccine (VA) or placebo arm (PA), stratified by donor CMV serostatus. PepVax was administered subcutaneously on days +28 and +56 post-HCT. The primary endpoint of the trial was CMV viremia ≥1250 IU/m or CMV disease through 100 days post-HCT. A total of 96 patients were planned to be randomized at 1:1 ratio, providing 90% power to detect a reduction of viremia from 40% to 15%. CMVpp65-specific immune reconstitution was monitored by measuring levels of CD8 T cells binding to MHC class I pp65 495-503 and HIVgag 77-85 (as control) multimers (Immudex Dextramers), as well as CD28 and CD45 memory markers (BD Biosciences). The intensity of the fluorescent labels was measured using a Gallios flow cytometer with Kaluza software (Beckman Coulter). Enrollment started in June 2015 but was stopped in November 2017 when a planned interim analysis suggested futility for the primary efficacy endpoint. By that time, 76 subjects had been consented, of whom 61 met the day 28 eligibility criteria and were randomized to the VA (n=32) or PA (n=29). The unblinded data were released when the planned one-year follow up was completed for these 61 subjects. The two groups were overall balanced in their demographics and HCT characteristics. There was no difference in the primary endpoint of CMV reactivation/disease between VA (25.1%) and PA (13.8%, p=0.15). The incidence of preemptive therapy was similar between the two arms. PepVax was well tolerated with no increase in adverse events. Transplant outcomes were also similar between the two groups with regards to 1-year overall survival, relapse-free survival, non-relapse mortality, relapse, and acute GVHD. In subjects in VA who reached the primary endpoint (n=8), CMV viremia occurred at a median of 20 days (interquartile range: 15-23 days; range, 0-48) after the first vaccine, suggesting that there was insufficient time for the vaccine-induced T cell expansion. Significantly higher levels of long lasting pp65-specific T cells with effector memory phenotype were measured in non viremic participants in the VA compared to those in the PA; this effect was driven by differences observed late after vaccination (p = 0.004 by GEE analysis; Figure, panel A). In patients who controlled viremia, robust expansion of functional pp65-specific CD8 T cells was observed following PepVax injections (Figure, panels B-C). Our results confirm safety and immunogenicity of PepVax in CMV seropositive HCT recipients. However, the trial failed to demonstrate a clinical efficacy of PepVax in reducing CMV viremia/disease despite favorable CD8 T cell responses. Early CMV reactivation/disease detected before receipt of the second vaccine may have reduced the ability of PepVax to elicit a protective T cell response. Transfer of vaccine-induced immunity through donor CMV immunization combined with recipient booster immunization may overcome this issue and lead to faster immune reconstitution post-HCT. Figure 1 Figure 1. Disclosures Hill: Amplyx: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allogene therapeutics: Consultancy; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; CLS Behring: Consultancy; Karius: Research Funding. Al Malki: Hansa Biopharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Rigel Pharma: Consultancy; CareDx: Consultancy. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Devine: Tmunity: Current Employment, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Verneris: Novartis: Other: advisory board; jazz: Other: advisory board; Fate Therapeutics: Consultancy. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Diamond: Pfizer Inc: Other; Helocyte Inc: Membership on an entity's Board of Directors or advisory committees, Other, Patents & Royalties.

scholarly journals Effective Immunomodulation with Pomalidomide Beginning at Early Lymphocyte Recovery during Induction Timed Sequential Therapy (TST) for Acute Myeloid Leukemia (AML) and High-Risk Myelodysplasia (HR-MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 335-335
Author(s):  
Joshua F Zeidner ◽  
Hanna Knaus ◽  
Amer M. Zeidan ◽  
Amanda Blackford ◽  
Raul Montiel-Esparza ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Median Time ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Research Funding ◽  
Disease Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3

Abstract Introduction: Adults with AML have immune aberrations leading to immune suppression, exhaustion, evasion, and senescence. Early lymphocyte recovery (ELR) after induction TST is dominated by an expansion of oligoclonal peripherally derived regulatory T cells (Tregs). Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), leads to the selective ubiquitination of Aiolos and Ikaros by cereblon; this ubiquitination increases IL-2 production, inhibits Tregs, and inhibits angiogenesis. We hypothesize that Pom administration after induction TST may enhance anti-leukemic activity through immune modulation. Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom administration after induction TST in newly diagnosed AML and HR-MDS patients 18-65 years. Favorable-risk cytogenetics were excluded. All patients received induction TST with AcDVP16: Cytarabine 667 mg/m2/day continuous IV days 1-3, daunorubicin 45 mg/m2 IV days 1-3 (or idarubicin 8-12 mg/m2 IV days 1-3 in daunorubicin shortage), etoposide 400 mg/m2 IV days 8-10, followed by Pom administration at ELR (after day 14 and within 3 days of the total white blood cell (WBC) reaching ≥0.2x109/L above nadir, but no later than day 30). Pom dose escalation occurred in 2 cohorts: 10 days versus 21 days of administration, in a traditional 3+3 design. Results: A total of 51 patients were enrolled and 43 (AML: n=39, HR-MDS: n=4) received Pom across 3 institutions (Table 1). Eight patients did not receive Pom due to no ELR by day 30 (n=3), sepsis (n=3), noncompliance with treatment (n=1), and death prior to ELR due to acute respiratory distress syndrome (n=1). Median time for Pom initiation after AcDVP16 induction was day 21 (range: 15-30 days). Pom maximal tolerated dose (MTD) was 4 mg for 21 consecutive days at ELR. The most common non-hematologic grade ≥3 toxicities related to Pom were febrile neutropenia (30%), maculopapular rash (14%), and aminotransferase elevation (5%). Dose-limiting toxicities (DLTs) of Pom at 8 mg for 21 days were grade 3 ALT/AST elevation and grade 4 respiratory failure, respectively. Pom was discontinued early (median duration = 7 days; range: 3-20 days) in 14 (33%) patients due to disease progression (n=4), grade 3 rash (n=3), DLT (n=2), patient decision (n=2), progressive cytopenias (n=1), and grade 4 acute kidney injury (n=1). Overall, 32/43 (74%) achieved CRc (CR: n= 30, CRi: n=2). Among the 4 HR-MDS patients, 2 (50%) achieved CRc, whereas 77% (30/39) of AML patients achieved CRc. Of the 32 CRc patients, 19 (59%) had no evidence of minimal residual disease (MRD) by standard testing (flow cytometry, FISH, cytogenetics, and/or molecular PCR). Encouraging CR rates were seen in poor-risk subsets: Age ≥60 years: 75% CRc (9/12); Secondary AML: 71% CRc (10/14); Adverse-risk cytogenetics: 82% CRc (14/17). Thirty- and 60-day mortality were 0 and 2%, respectively. Median time to neutrophil (≥1.0x109/L) and platelet (≥100x109/L) recovery was 38 (range: 28-86) and 33 days (range: 24-75), respectively. With a median follow-up of 23.9 months, median overall survival, disease-free survival and event-free survival were 33.8 months, 20.3 months, and 8.7 months, respectively. Pharmacodynamic biomarker studies revealed a significant decrease in the expression of Aiolos in peripheral blood CD4+ and CD8+ T cells when compared with AML controls who received AcDVP16 induction but did not receive pomalidomide (p <0.05; Figure 1). Moreover, these findings were corroborated in the bone marrow where Aiolos expression in CD4+ and CD8+ T cells substantially decreased after pomalidomide initiation. Conclusions: Pom can be added at the time of ELR after induction TST without increased toxicity and CR rates that compare favorably with historical controls of TST and other standard induction therapies. Despite administration at the time of profound cytopenias, Pom was well tolerated and did not significantly prolong hematologic recovery. Correlates suggest that Aiolos expression may be a pharmacodynamic biomarker of activity. Identification of immune biomarkers to predict for response and duration of response are ongoing. Further exploration of Pom both at the time of induction TST and during CR are warranted. Disclosures Zeidner: Rafael Pharmaceuticals: Other: Travel Fees; Merck: Research Funding; Asystbio Laboratories: Consultancy; Takeda: Other: Travel fees, Research Funding; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Zeidan:Agios: Consultancy; Incyte: Employment; Novartis: Consultancy; Celgene: Consultancy; Ariad: Consultancy, Speakers Bureau; Gilead: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy. Pratz:Astellas: Consultancy, Research Funding; Agios: Research Funding; Boston Scientific: Consultancy; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding. Foster:Shire: Honoraria; Pfizer: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding. Coombs:H3 Biomedicine: Honoraria; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; Incyte: Other: Travel fees. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merck inc: Research Funding; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3980-3980
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Effect of Demethylating Agents (5-Azacytidine/5-AzaC) On the Immune Response

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2771-2771
Author(s):  
Silvia Gutiérrez Cosío ◽  
Esteban Ballestar ◽  
Carlos Santamaría ◽  
Belén Blanco ◽  
Luis Ignacio Sánchez Abarca ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Board Of Directors ◽  
Methylation Status ◽  
Allogeneic Transplantation ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Expression Of Genes ◽  
Before And After ◽  
First Time

Abstract Abstract 2771 Introduction: We have previously shown that 5-azaC inhibits T-cells proliferation and favours the development of Tregs which decreases the risk of GVHD after allogeneic transplantation. This is at least in part due to the effect of the drug on the expression of genes such as FOXP3. Nevertheless, considering the unspecific effect of 5-azaC, it could also favour the overexpression of other genes related to the regulation of the immune response such as TBET, GATA3, IFNg or IL-2, which in turn would favour the development of a Th1, Th2 or Th17 polarization instead of a Treg expansion. In the current study we have evaluated the effect of 5-azaC on these genes in order to know the mechanisms involved in the effect of the drug on the immune response. Methods: We analyzed TBET, GATA3, FOXP3, IFNg and IL-2 mRNA expression of T lymphocytes by RT-PCR after exposure to 1mM 5-azaC during eleven days of culture. These T cells were cultured in medium alone or stimulated with plate-bound anti-CD3 (5 mg/ml) plus soluble anti-CD28 (2.5 mg/ml). Furthermore, we analyzed the methylation status of the promoters of these genes before and after 5-azaC treatment. Results: The expression of TBET, GATA3 and RORγ is not significantly affected by the exposure to the drug whereas the expression of FOXP3 significantly increases along the culture. Regarding IFNg and IL-2 expression no increased expression was observed after exposure to the drug at different time-points along the 11 days of culture. Upon analyzing the mathylation status of the promoter of these genes, we observed that in steady state the promoter of TBET and GATA is demethylated, which is in contrast to FOXP3 promoter. For this reason, the exposure to the drug decreases the methylation status of the promoter of FOXP3 while there is no effect on the promoters of TBET or RORg, thus justifying the absence of effect on the expression of these genes. By contrat, the promoter of both IFNg and IL-2 is methylated prior to the exposure to 5-azaC and it is demethylated after exposure to the drug, which is in contrast to the absence of increased expression of these genes. Accordingly, other mechanisms in addition to the epigenetic regulation of the promoter of IFNg and IL-2 are responsible for their expression in this model. Conclusions: In the current study we show by the first time the effect of 5-azaC on the promoters of genes which regulate the immune response. While no effect was observed for TBET, and GATA3 5-azaC induces a strong demethylation in the promoter of IFN or IL-2. In spite of this effect there is no increase in their expression which could be due to the overexpression of FOXP3 or to additional mechanisms involved in their regulation which are currently being evaluated. Disclosures: Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jangssen-cilag: Membership on an entity's Board of Directors or advisory committees; millennium: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The drug used in this study is the demethylating agent 5-azacytidine (5-azaC) and the purpose is the inhibition of graft versus host disease.

scholarly journals Haplo-Cord Transplantation Vs Unrelated Donor Stem Cell Transplantation in Patients with AML/MDS Older Than 50

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1235-1235 ◽  
Author(s):  
Joanna Rhodes ◽  
Koen van Besien ◽  
Hongtao Liu ◽  
Usama Gergis ◽  
Stephanie B. Tsai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant

Abstract Haplo-cord Transplantation Vs Unrelated Donor Stem Cell Transplantation In Patients with AML/MDS older than 50 Between 2007 and 2013, 109 patients with AML/MDS who were 50 years and older and had no HLA- matched related donor underwent allogeneic hematopoietic stem cell transplant. 64 had an HLA identical unrelated donor and received fludarabine/melphalan/alemtuzumab conditioning and post transplant tacrolimus for graft vs host disease (GVHD) prophylaxis. 45 underwent haplo-cord (HC) SCT with fludarabine/melphalan/ thymoglobulin; post-transplant tacrolimus and MMF. We compared patient characteristics and transplant outcomes between both groups. (Table 1) Age distribution and ASBMT risk category were similar. There were more patient's with AML in the HC group. (P=0.01) Time to neutrophil recovery, treatment related mortality (TRM), relapse rate, progression free survival (PFS) and overall survival (OS) were nearly identical between the two groups. Time to platelet recovery was on average 5 days longer after HC (p=0.05) The incidences of acute and chronic GVHD were very low in both groups, in part due to the use of in-vivo T cell depletion. HC transplant with reduced intensity conditioning is a curative treatment for older patients with AML/MDS who lack HLA identical unrelated donors. Despite inclusion of many patients with high risk features, nearly two thirds were estimated to be alive one year after transplant and very few had chronic GVHD. Haplo-cord grafts are more readily available, a potential advantage over MUD grafts in situations where transplant is needed urgently. TableMatched Unrelated DonorHaplo Cord PN6445Age (range)62 (50-73)62 (50-74)AML/MDS45/2041/5 0.01ASBMTLow/Int /High21/6/3015/10/200.7KPS 9090Time to ANC >50010110.1Time to Plt >2018230.05PFS@ 1 Y (95% CI)46 (34-58)41 (26-56)0.6OS@ 1 Y (95% CI)57 (44-70)64 (49-79)0.8Cum Inc TRM @100 d (95% CI)9 (2-16)9 (0-18)0.2Cum Inc TRM @ 1 Y(95% CI)25 (14-36)29 (15-44)0.2Cum Inc Relapse @ 1Y (95% CI)30 (18-42)26 (12-40)0.5Cum Inc AGVHD @ 100 D (95% CI)25 (14-36)29 (13-43)0.7Cum Inc CGVHD @ 1 Y (95% CI)6 (0-12)7 (0-15)0.9 Disclosures van Besien: Miltenyi: Research Funding. Mark:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Artz:Miltenyi: Research Funding.

Dendritic Cell Tumor Fusion Vaccination in Conjunction with Autologous Transplantation for Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 783-783
Author(s):  
Jacalyn Rosenblatt ◽  
Irit Avivi ◽  
Baldev Vasir ◽  
Tami Katz ◽  
Lynne Uhl ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Cd8 Cells ◽  
Post Transplant

Abstract Abstract 783 Autologous stem cell transplantation (ASCT) for multiple myeloma (MM) offers a unique setting to explore the role of immunotherapeutic strategies in eradicating malignancy. Patients achieve tumor cytoreduction following ASCT, however ultimately experience disease relapse from a persistent reservoir of chemotherapy resistant disease. Cancer vaccines that educate host immunity to target myeloma cells can be used to eradicate residual disease following ASCT. Our group has developed a cancer vaccine whereby dendritic cells (DCs) are fused with autologous tumor cells. DC/MM fusion cells present a broad array of tumor antigens in the context of DC derived costimulatory molecules. We are conducting a clinical trial in which patients with MM undergo ASCT followed by post-transplant vaccination with 3 doses of DC/MM fusions (cohort 1). A second cohort of patients receive an additional vaccination prior to stem cell collection in order to induce the expansion of tumor specific lymphocytes that are collected in the stem cell product (cohort 2). The infusion of educated lymphocytes provides a platform for subsequent post-transplant vaccination. To date, 26 patients have been enrolled in cohort 1 and 9 patient have been enrolled in cohort 2. Adherent mononuclear cells were isolated from leukapheresis collections and cultured with GM-CSF and IL-4 for 5-7 days, then exposed to TNFα for 48-72 hours to generate mature DCs. DCs expressed co-stimulatory (mean CD86 70%) and maturation markers (mean CD83 55%). MM cells were isolated from bone marrow and were identified by their expression of CD38 or CD138. DC and MM cells were co-cultured with PEG and fusion cells were quantified by determining the percentage of cells that co-express unique DC and myeloma antigens. Mean yield of the DC and myeloma preparations was 1.72 × 108 and 6.6 × 107 cells, respectively. Mean fusion efficiency was 38% and the mean cell dose generated was 3.6 × 106 fusion cells. Mean viability of the DC, myeloma, and fusion preparations was 87%, 87%, and 78%, respectively. As a measure of their potency as antigen presenting cells, fusion cells potently stimulated allogeneic T cell proliferation in vitro. Mean stimulation indexes were 13, 60, and 32 for T cells stimulated by myeloma cells, DCs, and fusion cells at an APC: T cell ratio of 1:10. Adverse events judged to be potentially vaccine related were mild, and included injection site reactions, pruritis, myalgias, fever, chills, and tachycardia. ASCT was associated with suppression of measures of cellular immunity. Circulating CD4 cells were depressed in the post-transplant period and CD4:CD8 ratios remained inverted for greater than 10 months. Similarly, 65% of patients had a positive DTH response to candida antigen prior to transplant while only 21% demonstrated a positive response in the early post-transplant period. T cell response to PHA mitogen was transiently depressed post-transplant with mean stimulation indexes of 79, 10, 26, 36, and 63 prior to transplant, 1, 2, 3, and 6 months post-transplant, respectively. Consistent with these findings, in vitro T cell responses to tetanus toxoid were blunted in the post-transplant period. In contrast, a significant increase in circulating tumor reactive lymphocytes was noted, as determined by T cell expression of IFN by CD4 and CD8 cells following ex vivo coculture with autologous myeloma cell lysate (Mean percentage of tumor reactive CD8 cells was 1 and 7.7 pre and post-transplant, respectively; mean percentage of CD4 cells was 0.9 and 3.2). A further amplification of tumor reactive lymphocytes was seen with vaccination in a subset of patients (mean percentage of CD4 and CD8 tumor reactive T cells was 6.4 and 13.4, respectively). In the post-transplant period, regulatory T cells fell to minimal levels. To date, 23 patients have completed follow up and were evaluable for clinical response. 3 patients achieved CR at 1 month following ASCT. Of note, an additional 7 patients obtained a CR following completion of vaccinations, suggesting a role for post-transplant immunotherapy in mediating elimination of disease. In summary, fusion cell vaccination in conjunction with ASCT was well tolerated, stimulated anti-tumor immunity and was associated with the induction of post-transplant complete response. Disclosures: Richardson: Millenium (Research Funding and Advisory Board), Celgene, Keryx, BMS, Merck, Johnson and Johnson (All Advisory Board): Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Millenium (Research Funding and Advisory Board: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Keryx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Comparative Analysis of Alpha-Beta T-Cell and B-Cell Depleted (abTCD) HLA-Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT) Versus Abtcd Haplo-HSCT with T-Cell Add-Back of Rivogenlecleucel Cell [Donor T Cells Transduced with the Inducible Caspase 9 (iC9) Gene Safety Switch] in Children with High-Risk Acute Leukemia (AL) in Remission

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 145-145 ◽  
Author(s):  
Annalisa Ruggeri ◽  
Pietro Merli ◽  
Mattia Algeri ◽  
Marco Zecca ◽  
Franca Fagioli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Median Time ◽  
Advisory Committees ◽  
Post Transplant ◽  
Cd34 Cells ◽  
Donor T Cells ◽  
Alpha Beta ◽  
Cmv Reactivation

Background: For children with AL candidate to receive an allograft and lacking a suitable HLA-matched donor, HLA-haplo-HSCT after abTCD may represent a valid alternative. Due to delayed recovery of adaptive T-cell immunity with abTCD-haplo-HSCT alone, we conducted a phase I/II trial testing the safety and efficacy of post-transplant infusion of a titrated number of donor-derived T cells transduced with the iC9 gene (rivogenlecleucel; ClinicalTrials.gov id: NCT02065869) in children with malignant and non-malignant diseases. Here, we report on the cohort of 70 patients with AL treated in Italy with abTCD-haplo-HSCT+rivogenlecleucel, comparing the results with those of 88 patients given abTCD-haplo-HSCT alone and previously published by our group (Blood 2018; 132:2594-2607). Patients and methods: Patients (age &lt; 18 years) were transplanted between 2010 and 2018. Patient and disease characteristics are shown in Table 1. Median age at HSCT was 6 years (range 0.3-18), and median follow-up was 71 and 31 months for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. Compared to the control group, abTCD-haplo-HSCT+rivogenlecleucel recipients were transplanted more recently and from a younger donor, and received a higher number of CD34+ cells (Table 1). Diagnosis did not differ between the 2 groups, acute lymphoblastic leukemia (ALL) being the most frequent diagnosis. All patients were transplanted in morphological complete remission (CR1 and CR2) and received myeloablative preparation. Graft composition is reported in Table 1; notably all patients received &gt;10x106 CD34+cells/Kg and &lt;1x105 alpha-beta+ T-cells/Kg. Patients did not receive any pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis. Results: Graft failure occurred in 2% of patients in each group. Median time to neutrophil and platelet engraftment was 14 (6-23) and 11 (5-56) days, with no differences between groups (p=0.28). Rivogenlecleucel were infused at a median time of 21 days (range 11-59). Treatment was well tolerated; no infusion-related side effects were recorded. Cumulative incidence (CI) of 100-day grade II-IV acute GvHD was 18.9% vs 15.9% (p=0.77) and CI of 1-year chronic GvHD was 6.9% vs 5.7% (p=0.56) in abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. The 4-year non-relapse-mortality (NRM) was significantly lower in abTCD-haplo-HSCT+rivogenlecleucel (1.4% vs 8%, p=0.05) (Figure 1). There was no statistically significant difference in the 4-year CI of relapse (RI) (17% vs. 25%, p=0.30), respectively. Disease recurrence was the most common causes of death in both groups, viral and fungal infections being the most frequent non-relapse fatalities. The 4-year overall survival (OS) and leukemia-free survival (LFS) was 70% vs 87%, p=0.01 (Figure 2) and 67% vs 82%, p=0.05, for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. There was no difference in 4-year CI of CMV reactivation between the 2 groups (p=0.68), median time to CMV reactivation being 29 and 30 days (p=0.29), respectively. Once infused, rivogenlecleucel expanded (mainly in the CD8+ subset), reaching a peak at 9 months after infusion. At 6-months, median CD3+, CD3/CD4, CD3/CD8, CD3-/CD56 and CD20/CD19 count/microL were 820, 265, 225, 141, 171, for abTCD-haplo-HSCT and 898, 294, 288, 214, and 161 for abTCD-haplo-HSCT+rivogenlecleucel, (p=ns, p=ns, p=0.02, p=0.03, p=ns), respectively. The advantage in the recovery of CD3/CD8 and CD3-/CD56 after abTCD-haplo-HSCT+rivogenlecleucel persisted at 1 year (p=0.01, p=0.03, respectively). In multivariable analysis, abTCD-haplo-HSCT+rivogenlecleucel was associated with better OS (HR 0.27, p=0.003) and LFS (HR 0.40, p=0.001); there was also a trend for lower relapse risk (HR 0.50, p=0.098). Age below the median value at HSCT (HR 2.62, p=0.01), CR1 at HSCT (HR 0.35, p=0.03) and use of irradiation in the conditioning regimen (HR 0.32, p=0.02) were other factors correlating with OS and LFS. Conclusions: These data confirm that the infusion of donor-derived rivogenlecleucel is safe and well tolerated. Rivogenlecleucel cells infusion contributed to enhance recovery of cytotoxic T and NK cells, improving patients NRM and OS/LFS. Rivogenlecleucel (with the possibility of inducing apoptosis of donor T cells) may facilitate the cellular therapy approaches aimed at optimizing immune recovery after HSCT. Disclosures Merli: Amgen: Honoraria; Bellicum: Consultancy; Novartis: Honoraria; Sobi: Consultancy. Algeri:Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Woodard:Bellicum Pharmaceuticals, Inc: Employment, Other: Stock, Stock options. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy.

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