Showing papers by "Stephan A. Grupp published in 2015"
TL;DR: The in vivo expansion of theCAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR, suggesting that disease eradication may be possible in some patients with advanced CLL.
Abstract: Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)-modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 10(8) to 11 × 10(8) CTL019 cells (median, 1.6 × 10(8) cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL.
1,373 citations
TL;DR: It is discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope, which suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms.
Abstract: The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.
Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR .
See related commentary by Jackson and Brentjens, [p. 1238][1] .
This article is highlighted in the In This Issue feature, [p. 1225][2]
[1]: /lookup/volpage/5/1238?iss=12
[2]: /lookup/volpage/5/1225?iss=12
909 citations
TL;DR: The current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges are discussed, including the importance of duration of remission and CAR-modified T-cell persistence.
569 citations
TL;DR: This work demonstrates aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL and establishes the preclinical in vivo efficacy of ruxolitinib in ETB, a biologically distinct subtype for which novel therapies are needed.
185 citations
TL;DR: Post-HCT NGS-MRD detection is highly predictive of relapse and survival, suggesting a role for this technique in defining patients early who would be eligible for post- HCT interventions.
164 citations
TL;DR: The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena and some of the challenges and opportunities are discussed.
Abstract: The field of adoptive cell transfer (ACT) is currently comprised of chimeric Ag receptor (CAR)- and TCR-engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and it holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology, and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. In this overview, we discuss some of the challenges and opportunities that face the field of ACT.
153 citations
TL;DR: CTL019 cells can undergo robust in vivo expansion and can persist for 3 years or longer in children and young adults with r/r ALL, allowing for the possibility of long-term disease control without subsequent therapy such as SCT.
132 citations
TL;DR: TSLPR-targeted CAR T cells thus represent a potent oncoprotein- targeted immunotherapy for high-risk ALL and have limited surface expression on normal tissues.
103 citations
University of Michigan1, Children's Hospital of Philadelphia2, Primary Children's Hospital3, University of British Columbia4, University of Manitoba5, University of Southern California6, University of California, San Francisco7, Boston Children's Hospital8, Nationwide Children's Hospital9, Case Western Reserve University10, Johns Hopkins University School of Medicine11
TL;DR: The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS, and Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients.
61 citations
TL;DR: Patients at high risk of relapse can be defined after transplant using leukemia risk category, presence of MRD pre or post HCT, and occurrence of aGvHD, an optimal window to initiate intervention to prevent relapse occurs between day +55 and +200 after HCT.
Abstract: We previously showed that minimal residual disease (MRD) detection pre-hematopoietic cell transplant (HCT) and acute GvHD (aGvHD) independently predicted risk of relapse in pediatric ALL. In this study we further define risk by assessing timing of relapse and the effects of leukemia risk category and post-HCT MRD. By multivariate analysis, pre-HCT MRD <0.1% and aGvHD by day +55 were associated with decreased relapse and improved event-free survival (EFS). Intermediate leukemia risk status predicted decreased relapse, and improved EFS and overall survival (OS). Patients with pre-HCT MRD ⩾0.1% who did not develop aGvHD compared with those with MRD <0.1% who did develop aGvHD had much worse survival (2 years EFS 18% vs 71%; P=0.001, 2 years OS 46 vs 74%; P=0.04). Patients with pre-HCT MRD <0.1% who did not experience aGvHD had higher rates of relapse than those who did develop aGvHD (40% vs 13%; P= 0.008). Post-HCT MRD led to a substantial increase in relapse risk (HR=4.5, P<0.01). Patients at high risk of relapse can be defined after transplant using leukemia risk category, presence of MRD pre or post HCT, and occurrence of aGvHD. An optimal window to initiate intervention to prevent relapse occurs between day +55 and +200 after HCT.
56 citations
TL;DR: Single agent CTL019 immunotherapy can induce potent and durable responses in pts with CNS involvement of their relapsed/refractory ALL, and Neurotoxicity does not appear to be enhanced in CNS pts, who tolerated therapy equally well.
TL;DR: It is hypothesized that repeat infusion may prolong persistence in some patients but would be ineffective in patients with immune-mediated rejection, and the safety and efficacy of CD19-directed CAR T cells with a humanized scFv domain in children with B cell recovery or CD19+ relapse after prior CAR T cell therapy is determined.
TL;DR: It is hypothesized that T cell deletion after CD123-redirected T cell-induced eradication of AML could minimize this bystander toxicity without impairing leukemia control, thereby increasing the therapeutic window of anti-AML CAR T cell immunotherapy.
TL;DR: Findings indicate that CD123 represents an ideal marker to target CD19-neg ALL blasts occurring after CART19 or blinatumomab, and shows intense anti-B-ALL ex vivo activity.
TL;DR: An overview of the field for pediatric cell therapies in the transplant setting is presented and how to broaden applicability beyond phase I is discussed.
TL;DR: The goal of this study was to pre-clinically evaluate the impact of targeting both CD19 and CD123 with chimeric antigen receptor T cells for the treatment and prevention of CD19-negative relapses occurring after CD19/CD3-directed therapies.
Abstract: Anti-CD19 chimeric antigen receptor T cells (CART19) and bi-specific anti-CD19/CD3 antibodies (blinatumomab) are generating unprecedented complete responses in relapsing/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, a subset of patients still relapse and about 30-50% of these relapses are characterized by the loss of detectable CD19 [1-3]. The interleukin-3 receptor alpha, or CD123, was shown to be expressed in several hematologic neoplasms, including acute myeloid leukemia and more recently also B-ALL. The goal of this study was to pre-clinically evaluate the impact of targeting both CD19 and CD123 with chimeric antigen receptor T cells for the treatment and prevention of CD19-negative relapses occurring after CD19-directed therapies [4,5].
TL;DR: It is hypothesized and demonstrated that children with severe CRS develop clinical and laboratory manifestations similar to macrophage activation syndrome (MAS)/hemophagocytic syndrome (HLH), including hyperferritinemia.
TL;DR: A human-derived affinity-optimized TCR that recognizes the NY-ESO-1 derived SLLMWITQC peptide in complex with HLA‐A*0201 has been generated, and clinically tested as previously described using adoptive T cell transfer with supportive IL-21.
Abstract: TPS3102 Background: NY-ESO-1 (CTAG-1B) is a cancer testis antigen associated with spontaneous and vaccine-induced immunity that can lead to improved clinical outcomes. NY-ESO-1 is not expressed in vital tissues, and is expressed in approximately 40% of ovarian, 60% of advanced myeloma, and 70% of synovial sarcoma tumors. Expression is correlated with tumor proliferation and high risk features. A human-derived affinity-optimized TCR that recognizes the NY-ESO-1 derived SLLMWITQC peptide in complex with HLA‐A*0201 (NY-ESOc259) has been generated, and clinically tested as previously described using adoptive T cell transfer with supportive IL-21 Methods: Multiple clinical studies were initiated in HLA-A201+ patients with NY-ESO-1 expressing tumors. NY-ESO-1c259-engineered autologous T-cells are manufactured centrally, using a 12 day commercial-grade closed system, and are administered without supportive IL-2. 40 patients have been infused: 25/26 on a phase I/II study in adults with systemic or multifocal myel...
TL;DR: Defibrotide in pts with VOD was generally well tolerated in this population, with manageable toxicity and promising response rates and survival.
TL;DR: The relationship between lung radiation dose and transplant-related mortality (TRM), relapse-free (RFS) and overall survival (OS) in children and adolescents undergoing TBI-based HSCT for acute lymphoblastic leukemia (ALL) on Children’s Oncology Group trial ASCT0431 is examined.
Abstract: 10030 Background: Lung shielding is not standardized during total body irradiation (TBI) preparative regimens for hematopoietic stem cell transplantation (HSCT), leading to differences in pulmonary...
TL;DR: Empirical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT.
TL;DR: Earlier initiation of defibrotide was associated with higher survival rates, and was statistically significant for all cut-points considered except 14 days, with only 2.8% of patients beginning treatment post-day 14.
TL;DR: Dual PI3K/mTOR inhibition with gedatolisib monotherapy potently inhibited leukemia proliferation and demonstrated additive or synergistic activity in combination with JAK or SRC/ABL inhibition in JAK-mutant or ABL/PDGFR-mutants Ph-like ALL, respectively.
Harvard University1, University of North Carolina at Chapel Hill2, Memorial Sloan Kettering Cancer Center3, Hackensack University Medical Center4, University of Alabama at Birmingham5, Children's Hospital Los Angeles6, Stanford University7, Children's Hospital of Philadelphia8, Duke University9, University of Washington10, City of Hope National Medical Center11, Oregon Health & Science University12, Loyola University Medical Center13, Children's Memorial Hospital14, University of Manitoba15, University of Minnesota16, University of Texas Health Science Center at Houston17, Nationwide Children's Hospital18, Boston University19
TL;DR: Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival and analyses included patients treated with DF and HCs.
TL;DR: It is found that T cells with Bis-RNA encoding a CD19-CD3 BiTEs (Blinatumomab) could as efficiently recognize tumor as those T cell adoptive immunotherapy of leukemia with CD19 CAR, and it is discovered that theBiTEs secreted by BlinatumomAB Bis- RNA transfected T cells could enable non-transfecting T cells to specifically recognize CD19 positive tumors in vitro.