Showing papers by "Stephan A. Grupp published in 2018"
University of Pennsylvania1, University of Texas Southwestern Medical Center2, University of Oslo3, Boston Children's Hospital4, University of Utah5, Université de Montréal6, Goethe University Frankfurt7, University of Minnesota8, Children's Mercy Hospital9, Emory University10, Ghent University11, Kyoto University12, Stanford University13, Duke University14, Oregon Health & Science University15, University of Michigan16, Medical University of Vienna17, University of Paris18, Royal Children's Hospital19, University of Milan20, University of Toronto21, Novartis22, University of Southern California23
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f
3,237 citations
25 Dec 2018
TL;DR: In 2018, the American Society for Blood and Marrow Transplantation (ASBMT) recognized the need to harmonize the definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity associated with CAR T cell therapies.
Abstract: Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years "?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
463 citations
TL;DR: A patient relapsing 9 months after CD19-targeted CAR T cell infusion with CD19– leukemia that aberrantly expressed the anti-CD19 CAR was reported.
Abstract: We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19– leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.
401 citations
Novartis1, Icahn School of Medicine at Mount Sinai2, Emory University3, Children's Hospital of Philadelphia4, University of Utah5, Ghent University Hospital6, Oregon Health & Science University7, Kyoto University8, Oslo University Hospital9, Cincinnati Children's Hospital Medical Center10, University of Minnesota11
TL;DR: Mutations in the CD19 gene suggesting irreversible loss of its surface expression are identified in the majority of analyzed cases of CD19– relapse in two clinical trials of pediatric ALL CD19 CAR T therapy, offering considerations for the rational choice of follow-up therapies.
Abstract: We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
356 citations
TL;DR: Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania was used to develop the Penn grading scale for Cytokine release syndrome (CRS), which provides reproducible CRS grading that can be useful to guide therapy and applied across clinical trials and treatment platforms.
Abstract: Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
300 citations
TL;DR: The data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen.
Abstract: We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944-57. ©2018 AACR.See related commentary by Keung and Tawbi, p. 914This article is highlighted in the In This Issue feature, p. 899.
278 citations
TL;DR: The fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in these studies suggests that GD2 may be a difficult target antigen forCAR T- cell therapy without additional strategies that can control CART-cell function within the CNS.
Abstract: The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are under way. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR and compared their properties in vivo We included the E101K mutation of GD2 scFv (GD2-E101K) that has enhanced antitumor activity against a GD2+ human neuroblastoma xenograft in vivo However, this enhanced antitumor efficacy in vivo was concomitantly associated with lethal central nervous system (CNS) toxicity comprised of extensive CAR T-cell infiltration and proliferation within the brain and neuronal destruction. The encephalitis was localized to the cerebellum and basal regions of the brain that display low amounts of GD2. Our results highlight the challenges associated with target antigens that exhibit shared expression on critical normal tissues. Despite the success of GD2-specific antibody therapies in the treatment of neuroblastoma, the fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in our studies suggests that GD2 may be a difficult target antigen for CAR T-cell therapy without additional strategies that can control CAR T-cell function within the CNS. Cancer Immunol Res; 6(1); 36-46. ©2017 AACR.
174 citations
TL;DR: It is demonstrated that T cells with a CAR-targeting CD19 (CART19) exhibited less differentiation and enhanced effector function in vitro when harvested from cultures at earlier compared with later timepoints, and the antileukemic activity inversely correlated with ex vivo culture time.
Abstract: The success of chimeric antigen receptor (CAR)-mediated immunotherapy in acute lymphoblastic leukemia (ALL) highlights the potential of T-cell therapies with directed cytotoxicity against specific tumor antigens. The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Most protocols for T-cell engineering routinely expand T cells ex vivo for 9-14 days. Because the potential for engraftment and persistence is related to the state of T-cell differentiation, we hypothesized that reducing the duration of ex vivo culture would limit differentiation and enhance the efficacy of CAR T-cell therapy. We demonstrated that T cells with a CAR targeting CD19 (CART19) exhibited less differentiation and enhanced effector function in vitro when harvested from cultures at earlier (day 3 or 5) compared with later (day 9) timepoints. We then compared the therapeutic potential of early versus late harvested CART19 in a murine xenograft model of ALL and showed that the anti-leukemic activity inversely correlated with ex vivo culture time: day 3 harvested cells showed robust tumor control despite using a 6-fold lower dose of CART19, whereas day 9 cells failed to control leukemia at limited cell doses. We also demonstrated the feasibility of an abbreviated culture in a large-scale cGMP-compliant process. Limiting the interval between T-cell isolation and CAR treatment is critical for patients with rapidly progressing disease. Generating CAR T cells in less time also improves potency, which is central to the effectiveness of these therapies.
166 citations
University of Pittsburgh1, Emory University2, Memorial Sloan Kettering Cancer Center3, University of Texas MD Anderson Cancer Center4, Harvard University5, University of Pennsylvania6, Fred Hutchinson Cancer Research Center7, Children's Hospital of Philadelphia8, Stanford University9, University of Chicago10
TL;DR: This review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
Abstract: Chimeric Antigen Receptor (CAR) T cell therapies – adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
165 citations
TL;DR: It is demonstrated that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy, suggesting that CD38 may be an ideal target for targeted immunotherapy.
151 citations
TL;DR: Responsibility to tisagenlecleucel was associated with increased expansion across a wide dose range and the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy is highlighted.
Abstract: Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Patients and Methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. Conclusions: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.
TL;DR: P promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease, suggesting a different mechanism such as AICD may be responsible for poor initial responses.
TL;DR: Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'
Abstract: Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'
TL;DR: In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%; post hoc analyses were performed], and all patient subgroups without MOD had higher Day + 100 survival than those with MOD.
Abstract: Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; {"type":"clinical-trial","attrs":{"text":"NCT00628498","term_id":"NCT00628498"}}NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T‐IND study was similar to previous reports.
University of Pennsylvania1, Children's Hospital of Philadelphia2, Hospital Sant Joan de Déu Barcelona3, University of Utah4, Université de Montréal5, Goethe University Frankfurt6, Oslo University Hospital7, University of Texas Southwestern Medical Center8, University of Minnesota9, Children's Mercy Hospital10, Emory University11, Children's Hospital Los Angeles12, Ghent University Hospital13, Boston Children's Hospital14, Stanford University15, Duke University16, Oregon Health & Science University17, Sunnybrook Research Institute18, University of Milan19, Saint Louis University20, Royal Children's Hospital21, Novartis22, Kyoto University23
TL;DR: The primary objective was met, with an overall remission rate (ORR) of 81% (complete remission [CR] + CR with incomplete blood count recovery [CRi], and the primary endpoint, ORR within 3 mo and maintained for ≥28 d among infused pts, was assessed by an independent review committee.
TL;DR: It is demonstrated that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019.
Abstract: The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model.
TL;DR: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, and to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurot toxicity following C TL019 infusion.
Abstract: OBJECTIVE To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion METHODS We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity RESULTS Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 00001) but was not associated with demographic characteristics or prior oncologic treatment history Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity INTERPRETATION Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies Ann Neurol 2018;84:537-546
TL;DR: Even the intact domains of CD19ex2vs cannot be easily targeted with ADCs or current CD19 CARTs but could serve as sources of peptides for major histocompatibility complex (MHC)-restricted presentation and T-cell receptor (TCR)-mediated killing.
Abstract: We previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing vesicular stomatitis virus G protein (VSVg) tags. These lines were negative by live-cell flow cytometry with an anti-VSVg antibody and resistant to killing by VSVg-directed antibody-drug conjugates (ADCs), suggestive of a defect in surface localization. Indeed, pulse-chase and α-mannosidase inhibitor assays showed that all CD19ex2vs acquired endoplasmic reticulum (ER)-specific high-mannose-type sugars but not complex-type glycans synthesized in the Golgi apparatus. When fused with green fluorescent protein (GFP), CD19ex2vs (including a mutant lacking the relevant disulfide bond) showed colocalization with ER markers, implying protein misfolding. Mass spectrometric profiling of CD19-interacting proteins demonstrated that CD19ex2vs fail to bind to the key tetraspanin CD81 and instead interact with ER-resident chaperones, such as calnexin, and ER transporters involved in antigen presentation. Thus, even the intact domains of CD19ex2vs cannot be easily targeted with ADCs or current CD19 CARTs but could serve as sources of peptides for major histocompatibility complex (MHC)-restricted presentation and T-cell receptor (TCR)-mediated killing.
TL;DR: This pilot trial used nonviral RNA CART19 cells, which are expected to express CAR protein for only a few days, as opposed to Cart19 generated by viral vector transduction, which expand in vivo and retain CAR expression.
TL;DR: Results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
Abstract: ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
University of California, San Francisco1, Columbia University2, New York Medical College3, Children's Oncology Group4, University of Southern California5, University of North Carolina at Chapel Hill6, Nationwide Children's Hospital7, University of Minnesota8, St. Jude Children's Research Hospital9, Children's Hospital of Philadelphia10, Seattle Children's11, Cincinnati Children's Hospital Medical Center12
TL;DR: ASCT1221 was designed to test whether the potentially less‐toxic myeloablative conditioning regimen containing busulfan‐fludarabine (Bu‐Flu) would be associated with equivalent outcomes in patients with juvenile myelomonocytic leukemia.
Abstract: Background Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. Procedure Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. Results Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. Conclusions The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.
TL;DR: A post hoc analysis of nontransplant‐associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.
Abstract: Background Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented. Procedure Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended). Results Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%. Conclusions In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.
TL;DR: Early phase trials indicate that tisagenlecleucel significantly improves survival for patients with B-ALL that is refractory or in second or later relapse, which may herald a dramatic shift in the treatment paradigm of this largely fatal disease.
Abstract: Introduction: Cure rates for pediatric and young adult patients with refractory or recurrently relapsed acute lymphoblastic leukemia (ALL) are dismal. Survival from time of relapse is typically mea...
TL;DR: Genetically reprogrammed T-cell therapy is a novel treatment approach being investigated in various hematologic malignancies, including relapsed and refractory pediatric B- cell acute lymphoblastic leukemia (B-ALL), multiple myeloma, diffuse large B-cell lymphoma, and chronic lymphoma.
Children's Hospital Los Angeles1, Novartis2, Hospital Sant Joan de Déu Barcelona3, University of Texas Southwestern Medical Center4, Children's Mercy Hospital5, Kyoto University6, Boston Children's Hospital7, Emory University8, Duke University9, University of Utah10, University of Minnesota11, Oslo University Hospital12, Goethe University Frankfurt13, Fred Hutchinson Cancer Research Center14, University of Pennsylvania15, Children's Hospital of Philadelphia16
TL;DR: Ig NGS was able to detect MRD positivity 1-4 months ahead of clinical relapse in a small number of relapsed patients, whether relapse was CD19+ or CD19-.
TL;DR: The original article contains several small errors and concurrent corrections, which are listed below.
Abstract: The original article contains several small errors. The errors & concurrent corrections are listed below [1].
TL;DR: A final report on the first USA Food and Drug Administration gene therapy approvals for chimeric antigen receptor T-cells (CAR-T), indicated for selected cancers of the haematopoietic system concludes that these therapies provide gains in quality-adjusted and overall survival over alternative chemotherapies.
Abstract: Cell and gene therapies are in the limelight after a bit of a bumpy ride. Several marketing authorisations have been granted by health authorities around the world, but perhaps the ones attracting most attention are the first USA Food and Drug Administration (FDA) gene therapy approvals for chimeric antigen receptor T-cells (CAR-T), indicated for selected cancers of the haematopoietic system. The approved CAR-T drugs are CD19-directed genetically modified autologous T-cell immunotherapies. Novartis’ Kymriah (tisagenlecleucel) was approved on 30th August 2017, for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse and was the first ever US-approved gene therapy [1, 2]. Kite Pharma/Gilead’s Yescarta (axicabtagene ciloleucel) was approved on 18th October 2017, indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large Bcell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma [3]. Most recently, on 1st May 2018, Kymriah was also approved for the B-cell lymphoma indication [4]. Both drugs have been granted Priority Medicines (PRIME) regulatory support and are undergoing accelerated assessment by the European Medicines Agency (EMA). The FDA-approved CAR-T drugs are autologous therapies involving the genetic modification of the patient’s own cells, but have been developed with global market logistics. So far, the EMA-approved (GSK/Orchard Therapeutics’ Strimvelis, for adenosine deaminase severe combined immunodeficiency, ADA-SCID) or successfully trialled therapies for rare genetic diseases of the blood involved genetic modification of the cells at the centre delivering the therapy. In contrast, the pivotal ELIANA CAR-T clinical trial demonstrated the feasibility of delivering a therapeutic product in study sites around the world despite the cell engineering being performed at a central facility. This approach greatly facilitates expanding the number of centres where the therapy can be delivered, as there is no requirement for local cell manipulation expertise. However, given the commonality and significance of potential side effects, it is critical that treatment centres are proficient at addressing the likely complications of the therapy, especially cytokine release syndrome (CRS) and potential neurotoxicity, the latter of which may be more pronounced in CD28 costimulatory domain-containing products [5, 6]. Kymriah has been marketed at a list price of $475,000 for ALL, while Kymriah and Yescarta have both been priced at $373,000 for lymphoma, with the real expense being approximately twice as much after considering administration and follow-up. At this cost, controversy has been unavoidable. The Institute for Clinical and Economic Review (ICER) has recently released a final report on these CAR-T therapies, based on the first indication approved for each drug. The report’s overall conclusion is that these therapies “provide gains in quality-adjusted and overall survival over alternative chemotherapies. With the evidence available at this time, these therapies seem to be priced in alignment with clinical benefits over a lifetime time horizon. However, the findings are sensitive to the time horizon and long-term benefit forecasting of the therapies.” ICER has also made a number of policy recommendations regarding early dialogue pre-FDA approval, innovative payment models, generation of additional evidence post-treatment, settings of care and patient education (https://icer-review. org/material/car-t-final-report/). While these CAR-T therapies have had remarkable success in clinical trials, many challenges remain, some of * Rafael J. Yáñez-Muñoz rafael.yanez@royalholloway.ac.uk ryanez-gt-editor@royalholloway.ac.uk
TL;DR: Traditional high-intensity chemotherapy for relapsed ALL that aims to minimize disease burden but carries significant morbidity may not be the best option for pre-CAR-T populations, as demonstrated in a population-based cohort of heavily pre-treated and high-risk patients.
TL;DR: A small number of patients with relapsed/refractory B-ALL either do not respond to or have limited response to CAR T cells targeting CD19, and these patients need to be referred to a second clinic for further studies.
Abstract: 3051Background: Chimeric antigen receptor (CAR) T cells targeting CD19 have shown excellent responses in patients with relapsed/refractory B-ALL. However, a subset of patients either do not respond...