Introduction:TIGIT (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITI... more Introduction:TIGIT (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) is an inhibitory immunoreceptor expressed by T and natural killer (NK) cells that is an important regulator of anti-tumor and anti-viral immunity. TIGIT shares its high-affinity ligand PVR (CD155) with the activating receptor CD226 (DNAM-1). We have recently shown that TIGIT blockade, together with PD-L1/PD-1 blockade, provides robust efficacy in syngeneic tumor and chronic viral infection models. Importantly, CD226 blockade abrogates the benefit of TIGIT blockade, suggesting additional benefit of TIGIT blockade through elaboration of CD226-mediated anti-tumor immunity, analogous to CTLA-4/CD28 regulation of T-cell immunity. Whether TIGIT and CD226 are expressed in patients with multiple myeloma (MM) and how TIGIT expression relates to PD-L1/PD-1 expression is unknown. Here we evaluate expression of TIGIT, CD226, PD-1 and PD-L1 in patients with MM to inform novel immunotherapy...
Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogen... more Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD prophylaxis. A diagnosis of VOD was made if either of the following criteria were met:Bilirubin ≥ 2 mg/dl with 2 of the following criteria --hepatomegaly, weight gain ≥ 5%, and ascites; orultrasonographic evidence of VOD. Defibrotide therapy was initiated at 10 mg/kg/day escalated every 24 hours by 10 mg/kg/day to 60 mg/kg/day over 6 days. Doses were administered intravenously at 6-hour intervals. Patients who did not have improvement in VOD at the maximum dose level were further escalated in 10 mg/kg/day increments to a maximum dose of 110 mg/kg/day. We enrolled 21 patients from August 2003 to July 2006.…
734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic c... more 734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.
Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopo... more Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Both disease recurrence and regimen-related toxicities contribute to the high mortality in this population. We designed a reduced intensity conditioning regimen using haploidentical donors in an effort to improve overall survival rates, by both decreasing disease recurrence and transplant-related mortality. From 2003 to 2005, we enrolled 25 patients with refractory hematologic malignancies. The median age was 11.9 years (range 2.8 to 26.5); 15 were male. Diagnoses included ALL (n= 9), AML (n= 10), MDS (n=1), NHL (n=3), CML (n=1), and JMML (n= 1). The majority (n=24) had persistent or refractory disease at the time of HSCT; only one was in remission (n= 1). Nine patients had no prior HSCT, 15 had 1 prior HSCT, and 1 had 3 prior HSCT. Donors were fathers (n=16), mothers (n=6), or siblings (n=3). Donor-recipient pairs matched at 3 (n=18), 4 (n=6), or 5 (n=1) of 6 HLA loci. All grafts were cytokine-mobilized peripheral blood stem cells, using GM-CSF and G-CSF. Grafts were depleted of T-lymphocytes on the CliniMACS device using the OKT3 antibody. Grafts contained a median of 14.89 X106 CD34+/kg (range, 2.23 to 51.20) and 1.4 X105 CD3+/kg (range, 0.1 to 4.5). The conditioning regimen consisted of fludarabine 40 mg/m²/day for 5 days, melphalan 60 mg/m²/day for 2 days, and thiotepa 10 mg/kg/day for 1 day. OKT3 was administered in an escalating and de-escalating fashion from day −9 to day +17. Rituximab was administered on day ) as EBV prophylaxis. MMF was initiated on day −2 for GVHD prophylaxis. The median time to engraftment of neutrophils was day +10 (range, 7–12); the median time to recovery of platelets to 20,000/mm3 and 50,000/mm3 was day +17 (range, 12–36) and day +17 (range, 12–76), respectively. 3 patients did not engraft: recovered with JMML, and were salvaged with grafts from their original HSCT donor. The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 44.0% and 8.0%, respectively; the cumulative incidence of chronic GVHD was 28.0%. No patient developed VOD. 13 patients died of disease recurrence with a median time to relapse of 105 days (range, 26–714). The cumulative incidence of relapse at 2 years post-HSCT was 50%. With only 4 patients dying of non-relapse causes, the cumulative incidence of non-relapse mortality plateaued at 20% at 11 months post-HSCT with 1 patient dying of each of the following: hemorrhage, infection, cardiomyopathy, and chronic GVHD. With a mean follow-up time of 387 days post-HSCT, the overall survival at one year and 2 years post-HSCT was 40% and 35%, respectively. The disease-free survival at one year and 2 years post-HSCT was 36% and 30%, respectively. Eight patients remain alive as outpatients with performance scores ≥90. Haploidentical HSCT with a reduced intensity conditioning regimen is safe and feasible in this high-risk patient population, resulting in prompt engraftment, acceptable GVHD rates, and promising survival rates. Measures to further prevent disease recurrence must be incorporated into future clinical trials to improve outcomes while maintaining low regimen-related toxicity rates.
Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with... more Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with high-risk or recurrent hematologic malignancies. As only 25% of patients have matched siblings and not all have unrelated donors, haploidentical HSCT using mismatched related donors is the only option for many patients. However, historically the risks of GVHD, graft rejection, and prolonged immunocompromise have made this donor option rather limited. More recently, highly purified CD34+ hematopoietic cells have been used with decreased GVHD rates, but at the risk of graft rejection and prolonged immunodsuppression with infectious complications. In an attempt to obtain a PBSC graft with higher T-cell content to maintain acceptable GVHD rates while promoting more rapid immune reconstitution, we initiated a prospective clinical trial for patients with hematologic malignancies who lacked a matched related donor or unrelated donor using a novel method of graft processing. The conditioning regimen consisted of TBI (12 Gy in 8 fractions over 4 days), cyclophosphamide (60 mg/kg/day for 2 days), thiotepa (10 mg/kg/day for 1 day), and rabbit ATG (10 mg/kg/course over 4 days). GVHD prophylaxis consisted of cyclosporine initiated at day -2. G-CSF mobilized PBSC grafts from mismatched related donors were infused after ex vivo T-cell depletion using OKT3 on the CliniMACS device. Patients had weekly peripheral blood analysis for evidence of EBV, CMV, or adenovirus DNA by PCR. If positive, pre-emptive therapy was administered. Twenty patients were enrolled with a median age of 11.9 yrs (range, 2.7–22.1). Diagnoses included ALL (2-CR1, 5-CR2, 3-CR3), AML (2-CR1, 1-CR2, 1-persistent disease), MDS (1-CR1, 2-persistent disease), CML (2- first chronic phase) and NHL (1-CR2). Donors and recipients were matched at 3 (n=11), 4 (n=8) or 5 (n=1) of 6 HLA loci. Of the 19 evaluable patients (one patient died prior to engraftment), the median time to attain ANC > 500/mm3 was 13 days (range, 10–19) and the median time to attain a transfusion-independent platelet count of 50,000/mm3 was 18 days (range, 8–37) post-HSCT. Only 3 patients developed grade 1–2 acute GVHD and none developed grade 3–4 acute GVHD. One patient developed limited chronic GVHD. Complications included post-transplant lymphoproliferative disorder (PT-LPD, n=3), VOD (n=2), BOOP (n=1), CMV retinitis (n=1), and adenovirus reactivation (n=7). No patient died of infectious complications or PT-LPD. 6 patients have died of regimen-related toxicities (n=4), or disease recurrence (n=2) at a median of 160 days (range, 4–208) post-HSCT. Fourteen patients remain alive in remission at a median of 162 days (range, 49–947) post-HSCT. OKT3 depleted PBSC grafts from haploidentical donors depleted of T-celss ex vivo results in favorable outcomes and acceptably low rates of GVHD and infectious complications for children undergoing HSCT from parental donors.
Introduction:Programmed death-ligand 1 (PD-L1) contributes to tumor escape from immune surveillan... more Introduction:Programmed death-ligand 1 (PD-L1) contributes to tumor escape from immune surveillance by binding to programmed death-1 (PD-1), a negative regulator of T-cell responses. PD-L1 is expressed by both tumor cells and immune cells in the tumor microenvironment. In contrast, the role of PD-L2 in tumor immunity is unclear. To better understand the contribution of PD-L1/L2 to immune escape in marrow-based hematologic malignancies, we used multi-color flow cytometry and immunohistochemistry (IHC) to characterize cell-specific PD-L1/PD-L2 expression in patients with multiple myeloma (MM), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Results:PD-L1 was detectable (> 2% positive cells) in 100% of patients, with distinct disease-specific patterns. PD-L1 was expressed most widely in MM, predominantly by malignant plasma cells (median, 95% of plasma cells; n = 5) and lymphocytes (median, 12% of marrow lymphocytes; n = 5). In contrast, in MDS and AML, PD-L1 was more commonly expressed by non-tumor hematopoietic cells: MDS median, 36% of CD34− myeloid precursors and 47% of lymphocytes (n = 13) vs 12% of CD34+ myeloid blasts; AML median, 19% of CD34− myeloid precursors and 26% of lymphocytes (n = 7) vs 16% of CD34+ myeloid blasts were PD-L1+. A higher proportion of CD8+ T cells expressed PD-L1 compared with CD4+ T cells in all 3 malignancies: the CD8:CD4 ratio for PD-L1+ T cells was 3.02 in MM (n = 11), 1.92 in MDS (n = 10), and 1.29 in AML (n = 7). PD-L2 expression was largely absent in AML and MDS (< 2% of CD34+ blasts or lymphocytes expressed PD-L2 (n = 13 MDS and n = 7 AML) but was expressed in a subset of patients with MM on plasma cells (median, 18%; n = 5) but not lymphocytes (< 2%). Across all indications on both tumor cells and lymphocytes, PD-L1 was expressed by a larger fraction of cells than PD-L2 (AML: CD34+ blasts, P < .01 and lymphocytes, P = .005 [n = 7]; MDS: CD34+ blasts, P < .01 and lymphocytes, P = .0001 [n = 13]; MM: plasma cells, P = .03 and lymphocytes, P = .04 [n = 5]). These results were confirmed in a distinct set of 16 cases of primary AML analyzed independently, with detectable PD-L1 expression on myeloid blasts in 14 of 16 cases (88%) without co-expression of PD-L2 (0 of 16 cases). Comparisons of flow cytometry and IHC revealed that some IHC methods may underestimate the prevalence of PD-L1/PD-L2 in marrow-based hematologic malignancies, and results comparing different methods for detecting PD-L1/PD-L2 in the bone marrow will be presented. Conclusions:PD-L1 is highly prevalent in MM, MDS and AML, with significant expression by non-tumor hematopoietic cells, particularly CD8+ T cells. PD-L2 expression was largely absent in myeloid diseases but detectable in MM. Interestingly, PD-L1 expression was most common on tumor cells in MM and on non-tumor hematopoietic cells in MDS, whereas expression on non-tumor and tumor cells in AML was comparable. These data support clinical development of anti-PD-L1/PD-1 therapies in MM, MDS and AML. Future analyses will determine whether different patterns of PD-L1 expression are associated with clinical efficacy. Authors M Dail, L Yang, S Rodig, and J Venstrom contributed equally to this work. Disclosures Dail: Genentech, Inc.: Employment. Green:Genentech, Inc.: Employment. Ma:Genentech, Inc.: Employment. Robert:Genentech, Inc.: Employment. Kadel:Genentech, Inc.: Employment. Koeppen:Roche: Employment, Equity Ownership. Adamkewicz:Genentech, Inc.: Employment. Byon:Genentech, Inc.: Employment. Woodard:Genentech, Inc.: Employment. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Venstrom:Genentech: Employment.
Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of sy... more Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of symptomatic children with sickle cell disease who have undergone the procedure. Despite these encouraging results, only 15% of children with symptoms that might merit consideration for transplantation have an available, unaffected HLA-matched sibling donor, severely limiting this therapeutic option. To address this problem, we developed a protocol for children with SCD and stroke using reduced-intensity conditioning and CD34-selected peripheral blood stem cells from haploidentical parental donors. We now report our preliminary experience using this approach in three children with SCD and stroke. After a chemotherapy-only conditioning regimen of fludarabine 150–200 mg/m2, thiotepa 10 mg/kg, i.v. busulfan targeted to a steady state concentration of 900 ng/ml, and OKT3, patients received an average of 27.2 x 106 CD34+cells/kg and 1.1 x 104 CD3+ cells/kg. Two patients required additional immun...
We investigated whether a novel chemotherapy-alone conditioning regimen would permit durable engr... more We investigated whether a novel chemotherapy-alone conditioning regimen would permit durable engraftment of standard doses of CD34 ؉ purified stem cell grafts from full-haplotype mismatched related donors. We also examined the role of infusing limited doses of donor leukocytes for prevention of leukemia relapse. Our conditioning regimen consisted of thiotepa, fludarabine, rabbit antithymocyte globulin, melphalan, cyclosporin, and prednisolone. Since October 1998, 14 patients with high-risk leukemia were treated; 13 donorpatient pairs shared 3 of 6 HLA antigens, and 1 pair shared 5 of 6 HLA antigens. A median of 5.4 ؋ 10 6 CD34 ؉ cells per kilogram, 1.62 ؋ 10 4 CD3 ؉ cells per kilogram, and 9.32 ؋ 10 4 CD19 ؉ cells per kilogram were infused. T-cell depletion was the only graft-versus-host disease (GVHD) prophylaxis. All patients had prompt engraftment, and no late graft rejections were observed. All surviving patients received at least 1 infusion of donor whole blood containing 5, 7, 10, 25, or 50 ؋ 10 3 CD3 ؉ cells per kilogram between days 25 and 95 after transplantation, after which 8 developed acute GVHD (3 grade I, 2 grade II, 2 grade III, and 1 grade IV) and 2 developed a bronchiolitis obliterans-like syndrome. After attaining complete remission, 5 patients relapsed and died with active leukemia. The estimated relapse-related mortality at 4 years is 38.1%. As of June 15, 2003, 6 of 14 patients have survived a median of 43.5 months after transplantation with 100% donor cells. All 6 surviving patients developed acute GVHD and had a natural killer cell mismatch with their donors in the direction of graft versus host. The estimated overall survival and event-free survival for the 14 patients at 4 years is 41.7% ؎ 13.5%.
Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopo... more Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Both disease recurrence and regimen-related toxicities contribute to the high mortality in this population. We designed a reduced intensity conditioning regimen using haploidentical donors in an effort to improve overall survival rates, by both decreasing disease recurrence and transplant-related mortality. From 2003 to 2005, we enrolled 25 patients with refractory hematologic malignancies. The median age was 11.9 years (range 2.8 to 26.5); 15 were male. Diagnoses included ALL (n= 9), AML (n= 10), MDS (n=1), NHL (n=3), CML (n=1), and JMML (n= 1). The majority (n=24) had persistent or refractory disease at the time of HSCT; only one was in remission (n= 1). Nine patients had no prior HSCT, 15 had 1 prior HSCT, and 1 had 3 prior HSCT. Donors were fathers (n=16), mothers (n=6), or siblings (n=3). Donor-recipient pairs matched a...
Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogen... more Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD proph...
Allogeneic HSCT is the only curative intervention for patients with persistent disease or who rec... more Allogeneic HSCT is the only curative intervention for patients with persistent disease or who recur after transplantation; however, these patients are often not considered for HSCT because of their persistent disease or high risk for regimen-related toxicity. We conducted a prospective study for patients who had hematologic malignancies with refractory disease or who relapsed after allogeneic HSCT using mismatched family member donors and a reduced intensity conditioning regimen in an effort to allow GVHD to occur to reduce disease recurrence in this high risk patient population. The conditioning regimen consisted of fludarabine (40 mg/m2/day for 5 days), melphalan (60 mg/m2/day for 2 days), and thiotepa (10 mg/kg/day for one day). One dose of melphalan was omitted in 6 patients who were aplastic at the time of transplantation. OKT3 was administered from day −9 to +17 for prevention of graft rejection. GVHD prophylaxis consisted of MMF initiated on day −2. Rituximab 375 mg/m2 was ad...
Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP... more Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. Data from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 × 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.
Lubin and Eliane Gluckman Christiane Vermylen, Nunzia Tannoia, Federico Garnier, Irina Ionescu, M... more Lubin and Eliane Gluckman Christiane Vermylen, Nunzia Tannoia, Federico Garnier, Irina Ionescu, Mark C. Walters, Bertram H. Roberto Miniero, Patrick Lutz, Thirumalairaj Raja, Irene Roberts, Andrew M. Will, Isaac Yaniv, Brochstein, Diane J. Nugent, Julie Blatt, Paul Woodard, Joanne Kurtzberg, Charles M. Rubin, Grafakos, Benedicte Brichard, Xiaxin Li, Arnon Nagler, Giovanna Giorgiani, Paul R. Haut, Joel A. Franco Locatelli, Vanderson Rocha, William Reed, Françoise Bernaudin, Mehmet Ertem, Stelios thalassemia and sickle cell disease Related umbilical cord blood transplantation in patients with
LILRB4, also known as ILT3, is an immune inhibitory transmembrane protein found on monocytes and ... more LILRB4, also known as ILT3, is an immune inhibitory transmembrane protein found on monocytes and antigen presenting cells, including dendritic cells (DCs). LILRB4 upregulation in DCs induces a tolerogenic phenotype that facilitates the generation of antigen-specific T regulatory cells. LILRB4 is also expressed on acute myeloid leukemia (AML) with monocytic differentiation, in which it promotes T cell suppression and tumor infiltration. IO-202 is a first-in-class LILRB4 antagonist antibody that is being evaluated in a Phase I trial (NCT04372433) for the treatment of AML and chronic myelomonocytic leukemia (CMML). RNA-seq data from TCGA database indicates that LILRB4 expression is upregulated in many solid tumor types. Therefore, the therapeutic potential of IO-202 in solid tumors was investigated in this study. Using computational biology approaches, we found that high LILRB4 expression in solid tumors from TCGA database is associated with macrophage infiltration in the tumor microen...
Patients with myelomonocytic and monocytic AML are often resistant to current standards of care. ... more Patients with myelomonocytic and monocytic AML are often resistant to current standards of care. LILRB4, an immunosuppressive myeloid checkpoint, is expressed in myelomonocytic and monocytic AML and CMML. Preclinical evaluation of a novel anti-LILRB4 IgG1 monoclonal antibody, IO-202, demonstrated 3 mechanisms of action: 1) activation of effector T-cells; 2) prevention of leukemic blast infiltration; and 3) killing of LILRB4-high blasts via ADCC and ADCP. IO-202 exhibits high affinity binding to human LILRB4, blocking APOE binding and activation of LILRB4. Inhibiting this pathway activates T-cell cytotoxicity against leukemic cells, reversing T-cell suppression mediated by AML cells in vitro. In a syngeneic mouse AML model, IO-202 increases CD8+ T cells, resulting in tumor growth inhibition. In mouse xenograft models, IO-202 inhibits AML tumor growth, prolongs survival, and blocks tissue infiltration of leukemia cells. IO-202 depletes leukemic cells expressing high levels of LILRB4 i...
CD133 is a unique antigen found on hematopoietic precursor cells, with a limited expression on no... more CD133 is a unique antigen found on hematopoietic precursor cells, with a limited expression on non-hematopoietic cells. These features make it an attractive marker for obtaining tumor-free hematopoietic grafts. We conducted a prospective clinical trial for patients with solid tumors and lymphomas who required autologous HSCT. 11 children (6 male, 5 female) had CD133+ peripheral blood stem cells (PBSC) collected for subsequent autologous HSCT. The median age was 12.4 yrs (range, 2.2–26). Diagnosis included Hodgkin lymphoma (1 stable disease, 2 PR), neuroblastoma (2 PR), NHL (2PR), Ewing sarcoma (1 stable disease), CNS PNET (1 PR), and desmoplastic small round cell tumor (1 PR). All had received priming chemotherapy with growth factor support. PBSC were collected in 1 or 2 procedures when the absolute CD34+ count was ≥ 40/ul. A stem cell product was cryopreserved as a backup. The PBSC product was processed on the CliniMACS device with positive selection methodology using the CD133 ant...
Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapse... more Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has ...
Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sick... more Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m2, and OKT3/methylprednisolone and infusion of CD34+ HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34+ cells and CD3+ cells with a fixed T-cell addback of 1.0–1.5 x 105 CD3+ cel...
Adenovirus (ADV) infections are increasingly recognized as significant cause of morbidity and mor... more Adenovirus (ADV) infections are increasingly recognized as significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Early diagnosis and prompt initiation of effective treatment are important in preventing often fatal disseminated ADV disease. We report our experience with using cidofovir (CDV) for the treatment of adenovirus infection in 57 HSCT patients, median age 8 years (range 0.5–26). Fifty-four patients received allogeneic HSCT, 35 of whom were T-cell depleted with 3 patients receiving autologous marrow. Blood was tested weekly for ADV by quantitative real-time PCR, with viral culture performed on urine, stool and throat swabs. Antiviral therapy was initiated immediately upon detection of ADV by PCR, culture or tissue histopathology. Cidofovir was given at 5mg/kg once weekly for 2 weeks, then every 2 weeks untill 3 negative PCR or cultures were documented. ADV was first detected at a median of 53 days (range 6–319 days) after HSCT. The...
Introduction:TIGIT (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITI... more Introduction:TIGIT (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) is an inhibitory immunoreceptor expressed by T and natural killer (NK) cells that is an important regulator of anti-tumor and anti-viral immunity. TIGIT shares its high-affinity ligand PVR (CD155) with the activating receptor CD226 (DNAM-1). We have recently shown that TIGIT blockade, together with PD-L1/PD-1 blockade, provides robust efficacy in syngeneic tumor and chronic viral infection models. Importantly, CD226 blockade abrogates the benefit of TIGIT blockade, suggesting additional benefit of TIGIT blockade through elaboration of CD226-mediated anti-tumor immunity, analogous to CTLA-4/CD28 regulation of T-cell immunity. Whether TIGIT and CD226 are expressed in patients with multiple myeloma (MM) and how TIGIT expression relates to PD-L1/PD-1 expression is unknown. Here we evaluate expression of TIGIT, CD226, PD-1 and PD-L1 in patients with MM to inform novel immunotherapy...
Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogen... more Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD prophylaxis. A diagnosis of VOD was made if either of the following criteria were met:Bilirubin ≥ 2 mg/dl with 2 of the following criteria --hepatomegaly, weight gain ≥ 5%, and ascites; orultrasonographic evidence of VOD. Defibrotide therapy was initiated at 10 mg/kg/day escalated every 24 hours by 10 mg/kg/day to 60 mg/kg/day over 6 days. Doses were administered intravenously at 6-hour intervals. Patients who did not have improvement in VOD at the maximum dose level were further escalated in 10 mg/kg/day increments to a maximum dose of 110 mg/kg/day. We enrolled 21 patients from August 2003 to July 2006.…
734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic c... more 734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.
Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopo... more Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Both disease recurrence and regimen-related toxicities contribute to the high mortality in this population. We designed a reduced intensity conditioning regimen using haploidentical donors in an effort to improve overall survival rates, by both decreasing disease recurrence and transplant-related mortality. From 2003 to 2005, we enrolled 25 patients with refractory hematologic malignancies. The median age was 11.9 years (range 2.8 to 26.5); 15 were male. Diagnoses included ALL (n= 9), AML (n= 10), MDS (n=1), NHL (n=3), CML (n=1), and JMML (n= 1). The majority (n=24) had persistent or refractory disease at the time of HSCT; only one was in remission (n= 1). Nine patients had no prior HSCT, 15 had 1 prior HSCT, and 1 had 3 prior HSCT. Donors were fathers (n=16), mothers (n=6), or siblings (n=3). Donor-recipient pairs matched at 3 (n=18), 4 (n=6), or 5 (n=1) of 6 HLA loci. All grafts were cytokine-mobilized peripheral blood stem cells, using GM-CSF and G-CSF. Grafts were depleted of T-lymphocytes on the CliniMACS device using the OKT3 antibody. Grafts contained a median of 14.89 X106 CD34+/kg (range, 2.23 to 51.20) and 1.4 X105 CD3+/kg (range, 0.1 to 4.5). The conditioning regimen consisted of fludarabine 40 mg/m²/day for 5 days, melphalan 60 mg/m²/day for 2 days, and thiotepa 10 mg/kg/day for 1 day. OKT3 was administered in an escalating and de-escalating fashion from day −9 to day +17. Rituximab was administered on day ) as EBV prophylaxis. MMF was initiated on day −2 for GVHD prophylaxis. The median time to engraftment of neutrophils was day +10 (range, 7–12); the median time to recovery of platelets to 20,000/mm3 and 50,000/mm3 was day +17 (range, 12–36) and day +17 (range, 12–76), respectively. 3 patients did not engraft: recovered with JMML, and were salvaged with grafts from their original HSCT donor. The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 44.0% and 8.0%, respectively; the cumulative incidence of chronic GVHD was 28.0%. No patient developed VOD. 13 patients died of disease recurrence with a median time to relapse of 105 days (range, 26–714). The cumulative incidence of relapse at 2 years post-HSCT was 50%. With only 4 patients dying of non-relapse causes, the cumulative incidence of non-relapse mortality plateaued at 20% at 11 months post-HSCT with 1 patient dying of each of the following: hemorrhage, infection, cardiomyopathy, and chronic GVHD. With a mean follow-up time of 387 days post-HSCT, the overall survival at one year and 2 years post-HSCT was 40% and 35%, respectively. The disease-free survival at one year and 2 years post-HSCT was 36% and 30%, respectively. Eight patients remain alive as outpatients with performance scores ≥90. Haploidentical HSCT with a reduced intensity conditioning regimen is safe and feasible in this high-risk patient population, resulting in prompt engraftment, acceptable GVHD rates, and promising survival rates. Measures to further prevent disease recurrence must be incorporated into future clinical trials to improve outcomes while maintaining low regimen-related toxicity rates.
Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with... more Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with high-risk or recurrent hematologic malignancies. As only 25% of patients have matched siblings and not all have unrelated donors, haploidentical HSCT using mismatched related donors is the only option for many patients. However, historically the risks of GVHD, graft rejection, and prolonged immunocompromise have made this donor option rather limited. More recently, highly purified CD34+ hematopoietic cells have been used with decreased GVHD rates, but at the risk of graft rejection and prolonged immunodsuppression with infectious complications. In an attempt to obtain a PBSC graft with higher T-cell content to maintain acceptable GVHD rates while promoting more rapid immune reconstitution, we initiated a prospective clinical trial for patients with hematologic malignancies who lacked a matched related donor or unrelated donor using a novel method of graft processing. The conditioning regimen consisted of TBI (12 Gy in 8 fractions over 4 days), cyclophosphamide (60 mg/kg/day for 2 days), thiotepa (10 mg/kg/day for 1 day), and rabbit ATG (10 mg/kg/course over 4 days). GVHD prophylaxis consisted of cyclosporine initiated at day -2. G-CSF mobilized PBSC grafts from mismatched related donors were infused after ex vivo T-cell depletion using OKT3 on the CliniMACS device. Patients had weekly peripheral blood analysis for evidence of EBV, CMV, or adenovirus DNA by PCR. If positive, pre-emptive therapy was administered. Twenty patients were enrolled with a median age of 11.9 yrs (range, 2.7–22.1). Diagnoses included ALL (2-CR1, 5-CR2, 3-CR3), AML (2-CR1, 1-CR2, 1-persistent disease), MDS (1-CR1, 2-persistent disease), CML (2- first chronic phase) and NHL (1-CR2). Donors and recipients were matched at 3 (n=11), 4 (n=8) or 5 (n=1) of 6 HLA loci. Of the 19 evaluable patients (one patient died prior to engraftment), the median time to attain ANC > 500/mm3 was 13 days (range, 10–19) and the median time to attain a transfusion-independent platelet count of 50,000/mm3 was 18 days (range, 8–37) post-HSCT. Only 3 patients developed grade 1–2 acute GVHD and none developed grade 3–4 acute GVHD. One patient developed limited chronic GVHD. Complications included post-transplant lymphoproliferative disorder (PT-LPD, n=3), VOD (n=2), BOOP (n=1), CMV retinitis (n=1), and adenovirus reactivation (n=7). No patient died of infectious complications or PT-LPD. 6 patients have died of regimen-related toxicities (n=4), or disease recurrence (n=2) at a median of 160 days (range, 4–208) post-HSCT. Fourteen patients remain alive in remission at a median of 162 days (range, 49–947) post-HSCT. OKT3 depleted PBSC grafts from haploidentical donors depleted of T-celss ex vivo results in favorable outcomes and acceptably low rates of GVHD and infectious complications for children undergoing HSCT from parental donors.
Introduction:Programmed death-ligand 1 (PD-L1) contributes to tumor escape from immune surveillan... more Introduction:Programmed death-ligand 1 (PD-L1) contributes to tumor escape from immune surveillance by binding to programmed death-1 (PD-1), a negative regulator of T-cell responses. PD-L1 is expressed by both tumor cells and immune cells in the tumor microenvironment. In contrast, the role of PD-L2 in tumor immunity is unclear. To better understand the contribution of PD-L1/L2 to immune escape in marrow-based hematologic malignancies, we used multi-color flow cytometry and immunohistochemistry (IHC) to characterize cell-specific PD-L1/PD-L2 expression in patients with multiple myeloma (MM), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Results:PD-L1 was detectable (> 2% positive cells) in 100% of patients, with distinct disease-specific patterns. PD-L1 was expressed most widely in MM, predominantly by malignant plasma cells (median, 95% of plasma cells; n = 5) and lymphocytes (median, 12% of marrow lymphocytes; n = 5). In contrast, in MDS and AML, PD-L1 was more commonly expressed by non-tumor hematopoietic cells: MDS median, 36% of CD34− myeloid precursors and 47% of lymphocytes (n = 13) vs 12% of CD34+ myeloid blasts; AML median, 19% of CD34− myeloid precursors and 26% of lymphocytes (n = 7) vs 16% of CD34+ myeloid blasts were PD-L1+. A higher proportion of CD8+ T cells expressed PD-L1 compared with CD4+ T cells in all 3 malignancies: the CD8:CD4 ratio for PD-L1+ T cells was 3.02 in MM (n = 11), 1.92 in MDS (n = 10), and 1.29 in AML (n = 7). PD-L2 expression was largely absent in AML and MDS (< 2% of CD34+ blasts or lymphocytes expressed PD-L2 (n = 13 MDS and n = 7 AML) but was expressed in a subset of patients with MM on plasma cells (median, 18%; n = 5) but not lymphocytes (< 2%). Across all indications on both tumor cells and lymphocytes, PD-L1 was expressed by a larger fraction of cells than PD-L2 (AML: CD34+ blasts, P < .01 and lymphocytes, P = .005 [n = 7]; MDS: CD34+ blasts, P < .01 and lymphocytes, P = .0001 [n = 13]; MM: plasma cells, P = .03 and lymphocytes, P = .04 [n = 5]). These results were confirmed in a distinct set of 16 cases of primary AML analyzed independently, with detectable PD-L1 expression on myeloid blasts in 14 of 16 cases (88%) without co-expression of PD-L2 (0 of 16 cases). Comparisons of flow cytometry and IHC revealed that some IHC methods may underestimate the prevalence of PD-L1/PD-L2 in marrow-based hematologic malignancies, and results comparing different methods for detecting PD-L1/PD-L2 in the bone marrow will be presented. Conclusions:PD-L1 is highly prevalent in MM, MDS and AML, with significant expression by non-tumor hematopoietic cells, particularly CD8+ T cells. PD-L2 expression was largely absent in myeloid diseases but detectable in MM. Interestingly, PD-L1 expression was most common on tumor cells in MM and on non-tumor hematopoietic cells in MDS, whereas expression on non-tumor and tumor cells in AML was comparable. These data support clinical development of anti-PD-L1/PD-1 therapies in MM, MDS and AML. Future analyses will determine whether different patterns of PD-L1 expression are associated with clinical efficacy. Authors M Dail, L Yang, S Rodig, and J Venstrom contributed equally to this work. Disclosures Dail: Genentech, Inc.: Employment. Green:Genentech, Inc.: Employment. Ma:Genentech, Inc.: Employment. Robert:Genentech, Inc.: Employment. Kadel:Genentech, Inc.: Employment. Koeppen:Roche: Employment, Equity Ownership. Adamkewicz:Genentech, Inc.: Employment. Byon:Genentech, Inc.: Employment. Woodard:Genentech, Inc.: Employment. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Venstrom:Genentech: Employment.
Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of sy... more Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of symptomatic children with sickle cell disease who have undergone the procedure. Despite these encouraging results, only 15% of children with symptoms that might merit consideration for transplantation have an available, unaffected HLA-matched sibling donor, severely limiting this therapeutic option. To address this problem, we developed a protocol for children with SCD and stroke using reduced-intensity conditioning and CD34-selected peripheral blood stem cells from haploidentical parental donors. We now report our preliminary experience using this approach in three children with SCD and stroke. After a chemotherapy-only conditioning regimen of fludarabine 150–200 mg/m2, thiotepa 10 mg/kg, i.v. busulfan targeted to a steady state concentration of 900 ng/ml, and OKT3, patients received an average of 27.2 x 106 CD34+cells/kg and 1.1 x 104 CD3+ cells/kg. Two patients required additional immun...
We investigated whether a novel chemotherapy-alone conditioning regimen would permit durable engr... more We investigated whether a novel chemotherapy-alone conditioning regimen would permit durable engraftment of standard doses of CD34 ؉ purified stem cell grafts from full-haplotype mismatched related donors. We also examined the role of infusing limited doses of donor leukocytes for prevention of leukemia relapse. Our conditioning regimen consisted of thiotepa, fludarabine, rabbit antithymocyte globulin, melphalan, cyclosporin, and prednisolone. Since October 1998, 14 patients with high-risk leukemia were treated; 13 donorpatient pairs shared 3 of 6 HLA antigens, and 1 pair shared 5 of 6 HLA antigens. A median of 5.4 ؋ 10 6 CD34 ؉ cells per kilogram, 1.62 ؋ 10 4 CD3 ؉ cells per kilogram, and 9.32 ؋ 10 4 CD19 ؉ cells per kilogram were infused. T-cell depletion was the only graft-versus-host disease (GVHD) prophylaxis. All patients had prompt engraftment, and no late graft rejections were observed. All surviving patients received at least 1 infusion of donor whole blood containing 5, 7, 10, 25, or 50 ؋ 10 3 CD3 ؉ cells per kilogram between days 25 and 95 after transplantation, after which 8 developed acute GVHD (3 grade I, 2 grade II, 2 grade III, and 1 grade IV) and 2 developed a bronchiolitis obliterans-like syndrome. After attaining complete remission, 5 patients relapsed and died with active leukemia. The estimated relapse-related mortality at 4 years is 38.1%. As of June 15, 2003, 6 of 14 patients have survived a median of 43.5 months after transplantation with 100% donor cells. All 6 surviving patients developed acute GVHD and had a natural killer cell mismatch with their donors in the direction of graft versus host. The estimated overall survival and event-free survival for the 14 patients at 4 years is 41.7% ؎ 13.5%.
Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopo... more Patients with refractory hematologic malignancies and those who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Both disease recurrence and regimen-related toxicities contribute to the high mortality in this population. We designed a reduced intensity conditioning regimen using haploidentical donors in an effort to improve overall survival rates, by both decreasing disease recurrence and transplant-related mortality. From 2003 to 2005, we enrolled 25 patients with refractory hematologic malignancies. The median age was 11.9 years (range 2.8 to 26.5); 15 were male. Diagnoses included ALL (n= 9), AML (n= 10), MDS (n=1), NHL (n=3), CML (n=1), and JMML (n= 1). The majority (n=24) had persistent or refractory disease at the time of HSCT; only one was in remission (n= 1). Nine patients had no prior HSCT, 15 had 1 prior HSCT, and 1 had 3 prior HSCT. Donors were fathers (n=16), mothers (n=6), or siblings (n=3). Donor-recipient pairs matched a...
Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogen... more Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD proph...
Allogeneic HSCT is the only curative intervention for patients with persistent disease or who rec... more Allogeneic HSCT is the only curative intervention for patients with persistent disease or who recur after transplantation; however, these patients are often not considered for HSCT because of their persistent disease or high risk for regimen-related toxicity. We conducted a prospective study for patients who had hematologic malignancies with refractory disease or who relapsed after allogeneic HSCT using mismatched family member donors and a reduced intensity conditioning regimen in an effort to allow GVHD to occur to reduce disease recurrence in this high risk patient population. The conditioning regimen consisted of fludarabine (40 mg/m2/day for 5 days), melphalan (60 mg/m2/day for 2 days), and thiotepa (10 mg/kg/day for one day). One dose of melphalan was omitted in 6 patients who were aplastic at the time of transplantation. OKT3 was administered from day −9 to +17 for prevention of graft rejection. GVHD prophylaxis consisted of MMF initiated on day −2. Rituximab 375 mg/m2 was ad...
Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP... more Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. Data from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 × 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.
Lubin and Eliane Gluckman Christiane Vermylen, Nunzia Tannoia, Federico Garnier, Irina Ionescu, M... more Lubin and Eliane Gluckman Christiane Vermylen, Nunzia Tannoia, Federico Garnier, Irina Ionescu, Mark C. Walters, Bertram H. Roberto Miniero, Patrick Lutz, Thirumalairaj Raja, Irene Roberts, Andrew M. Will, Isaac Yaniv, Brochstein, Diane J. Nugent, Julie Blatt, Paul Woodard, Joanne Kurtzberg, Charles M. Rubin, Grafakos, Benedicte Brichard, Xiaxin Li, Arnon Nagler, Giovanna Giorgiani, Paul R. Haut, Joel A. Franco Locatelli, Vanderson Rocha, William Reed, Françoise Bernaudin, Mehmet Ertem, Stelios thalassemia and sickle cell disease Related umbilical cord blood transplantation in patients with
LILRB4, also known as ILT3, is an immune inhibitory transmembrane protein found on monocytes and ... more LILRB4, also known as ILT3, is an immune inhibitory transmembrane protein found on monocytes and antigen presenting cells, including dendritic cells (DCs). LILRB4 upregulation in DCs induces a tolerogenic phenotype that facilitates the generation of antigen-specific T regulatory cells. LILRB4 is also expressed on acute myeloid leukemia (AML) with monocytic differentiation, in which it promotes T cell suppression and tumor infiltration. IO-202 is a first-in-class LILRB4 antagonist antibody that is being evaluated in a Phase I trial (NCT04372433) for the treatment of AML and chronic myelomonocytic leukemia (CMML). RNA-seq data from TCGA database indicates that LILRB4 expression is upregulated in many solid tumor types. Therefore, the therapeutic potential of IO-202 in solid tumors was investigated in this study. Using computational biology approaches, we found that high LILRB4 expression in solid tumors from TCGA database is associated with macrophage infiltration in the tumor microen...
Patients with myelomonocytic and monocytic AML are often resistant to current standards of care. ... more Patients with myelomonocytic and monocytic AML are often resistant to current standards of care. LILRB4, an immunosuppressive myeloid checkpoint, is expressed in myelomonocytic and monocytic AML and CMML. Preclinical evaluation of a novel anti-LILRB4 IgG1 monoclonal antibody, IO-202, demonstrated 3 mechanisms of action: 1) activation of effector T-cells; 2) prevention of leukemic blast infiltration; and 3) killing of LILRB4-high blasts via ADCC and ADCP. IO-202 exhibits high affinity binding to human LILRB4, blocking APOE binding and activation of LILRB4. Inhibiting this pathway activates T-cell cytotoxicity against leukemic cells, reversing T-cell suppression mediated by AML cells in vitro. In a syngeneic mouse AML model, IO-202 increases CD8+ T cells, resulting in tumor growth inhibition. In mouse xenograft models, IO-202 inhibits AML tumor growth, prolongs survival, and blocks tissue infiltration of leukemia cells. IO-202 depletes leukemic cells expressing high levels of LILRB4 i...
CD133 is a unique antigen found on hematopoietic precursor cells, with a limited expression on no... more CD133 is a unique antigen found on hematopoietic precursor cells, with a limited expression on non-hematopoietic cells. These features make it an attractive marker for obtaining tumor-free hematopoietic grafts. We conducted a prospective clinical trial for patients with solid tumors and lymphomas who required autologous HSCT. 11 children (6 male, 5 female) had CD133+ peripheral blood stem cells (PBSC) collected for subsequent autologous HSCT. The median age was 12.4 yrs (range, 2.2–26). Diagnosis included Hodgkin lymphoma (1 stable disease, 2 PR), neuroblastoma (2 PR), NHL (2PR), Ewing sarcoma (1 stable disease), CNS PNET (1 PR), and desmoplastic small round cell tumor (1 PR). All had received priming chemotherapy with growth factor support. PBSC were collected in 1 or 2 procedures when the absolute CD34+ count was ≥ 40/ul. A stem cell product was cryopreserved as a backup. The PBSC product was processed on the CliniMACS device with positive selection methodology using the CD133 ant...
Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapse... more Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has ...
Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sick... more Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m2, and OKT3/methylprednisolone and infusion of CD34+ HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34+ cells and CD3+ cells with a fixed T-cell addback of 1.0–1.5 x 105 CD3+ cel...
Adenovirus (ADV) infections are increasingly recognized as significant cause of morbidity and mor... more Adenovirus (ADV) infections are increasingly recognized as significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Early diagnosis and prompt initiation of effective treatment are important in preventing often fatal disseminated ADV disease. We report our experience with using cidofovir (CDV) for the treatment of adenovirus infection in 57 HSCT patients, median age 8 years (range 0.5–26). Fifty-four patients received allogeneic HSCT, 35 of whom were T-cell depleted with 3 patients receiving autologous marrow. Blood was tested weekly for ADV by quantitative real-time PCR, with viral culture performed on urine, stool and throat swabs. Antiviral therapy was initiated immediately upon detection of ADV by PCR, culture or tissue histopathology. Cidofovir was given at 5mg/kg once weekly for 2 weeks, then every 2 weeks untill 3 negative PCR or cultures were documented. ADV was first detected at a median of 53 days (range 6–319 days) after HSCT. The...
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