Specific transcription factors (TFs) modulate cardiac gene expression in murine models of heart failure, but their relevance in human subjects remains untested. We developed and applied a ...computational approach called transcriptional genomics to test the hypothesis that a discrete set of cardiac TFs is associated with human heart failure.
RNA isolates from failing (n=196) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays, and differentially expressed heart failure genes were determined. TF binding sites overrepresented in the -5-kb promoter sequences of these heart failure genes were then determined with the use of public genome sequence databases. Binding sites for TFs identified in murine heart failure models (MEF2, NKX, NF-AT, and GATA) were significantly overrepresented in promoters of human heart failure genes (P<0.002; false discovery rate 2% to 4%). In addition, binding sites for FOX TFs showed substantial overrepresentation in both advanced human and early murine heart failure (P<0.002 and false discovery rate <4% for each). A role for FOX TFs was supported further by expression of FOXC1, C2, P1, P4, and O1A in failing human cardiac myocytes at levels similar to established hypertrophic TFs and by abundant FOXP1 protein in failing human cardiac myocyte nuclei.
Our results provide the first evidence that specific TFs identified in murine models (MEF2, NKX, NFAT, and GATA) are associated with human heart failure. Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. These findings provide a crucial link between animal models and human disease and suggest a specific role for FOX signaling in modulating the hypertrophic response of the heart to stress in humans.
Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would ...correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes.
We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944).
These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive ...tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
Purpose: We attempted to confirm recent findings of Kanemoto et al. that demonstrated a positive association (p < 0.017) between a polymorphism in the promoter region of the interleukin 1‐β (IL‐1β) ...gene and the clinical phenotype of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS).
Methods: We determined the frequency of this polymorphism in a group of 61 TLE+HS patients of European ancestry and compared it with that found in 119 ethnically matched control subjects.
Results: Analysis of genotype and allele frequencies showed no statistically significant difference in the distribution of the polymorphism between the two groups (p = 0.10).
Conclusions: These data suggest that this IL‐1β promoter polymorphism does not act as a strong susceptibility factor for TLE+HS in a population of individuals of European ancestry.
Introduction: Tisagenlecleucel (CTL019, tisa-cel) was recently approved for treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), high grade B cell lymphoma (r/r HGBCL), and ...transformed follicular lymphoma (r/r tFL) after second line therapy. Prior to tisa-cel release for commercial use in the United States (US), the final manufactured, patient-specific product must meet specific Lot Release Specifications including requirements that the product's dose contains 0.6 to 6.0 x 108 CAR-positive viable T cells and total cell viability is at least 80%. CAR T cell products that do not meet predetermined release specifications are considered “out of specification” (OOS) and may only be administered via an expanded access protocol or a single patient IND. To date, there are no prospectively reported data with regard to the reasons that commercially manufactured CTL019 products are OOS or clinical outcomes after infusion of OOS CTL019 products.
Methods: We are participating in a prospective, managed access protocol to allow administration of CTL019 to patients (pts) with r/r aggressive B-cell lymphomas meeting the approved prescribing information who are intended for treatment with US commercial tisa-cel but have OOS products. Pts were provided product via this managed access program and consent was obtained from all pts enrolled. Pts were unable to receive commercially manufactured product due to failure of apheresis material to meet acceptance specifications, failure of final manufactured product to meet the commercial release specifications, or failure to meet other product specifications within the prescribing information (e.g., interferon gamma release testing). Response was assessed at 3 months post CTL019 infusion by 2014 Lugano Classification criteria applied to FDG-PET/CT imaging. Adverse events were defined by CTCAE and ASTCT criteria.
Results: From 9/2018 to 7/2019, 16 pts were enrolled at our institution. Nine pts were diagnosed with r/r DLBCL, 5 pts had r/r HGBCL, and 2 pts had r/r tFL; 44% of all pts had “double-hit” lymphoma. Median age at CTL019 infusion was 68 years (range: 42-75 years); 7 pts (44%) were female. Twelve pts (75%) had advanced stage lymphoma at leukapheresis. Median prior therapies before leukapheresis was 3 (range: 2-5). Median ECOG performance status was 0 (range: 0-2). Median absolute lymphocyte count and CD3 count were 900/uL (range: 200-1300/uL) and 614/uL (range: 228-1343/uL), respectively. Median CTL019 dose was 1.3 x 108 CAR-positive viable T cells (range: 0.5 x 108 to 2.1 x 108). Median product viability was 78.4% (range: 70.8-87.4%). Thirteen of 16 pts (81%) were enrolled due to low viability products (viability < 80%). The median viability for pts enrolled due to low product viability was 78.0% (range: 70.8-79.8%). The remaining 3 pts' products did not meet release specifications due to T cell dose below 0.6 x 108 CAR-positive T cells (dose administered, 0.5 x 108; n=1), residual beads by microscopy (n=1), or IFN gamma release level above the upper range (>1000 fg/transduced cell; n=1). All pts with low viability products had CAR-positive T cell doses that were within the product dose specifications for tisa-cel (13 of 13 pts).
Of 16 pts enrolled, 11 pts have at least 3 months follow-up; 3 pts were never treated due to progressive lymphoma and 2 pts have not had 3 month response assessments. Median follow-up is 3.4 months. There were 3 pts with CRS grades 1 or 2 by ASTCT criteria and no pts had neurotoxicity. Of 3 pts with CRS, one received a low dose of CTL019 (grade 2 CRS), one had higher levels of IFN gamma (grade 1 CRS), and one had low viability (grade 1 CRS). For all pts infused with OOS products, the 3-month overall response rate (ORR) was 64% including 6/11 (55%) CR and 1/11 (9%) PR. Progression-free survival (PFS) is 64% at 3 months (median not reached, 95%CI: 30-85%). For OOS products due to low viability, ORR was 4/8 (50%) CR and 4/8 (50%) PD; 3-month PFS was 50% (95%CI: 15-77%).
Conclusions: We report the first experience with commercially produced CTL019 products that do not meet product release specifications, primarily due to low viability. Three-month ORRs appear similar to published tisa-cel outcomes for aggressive B-cell non-Hodgkin lymphomas. Our results suggest that other product release characteristics such as potency and replicative capacity should also be more carefully evaluated prior to establishing criteria for release.
Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Porter:Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Barta:Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Mundipharma: Honoraria. Levine:Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy; CRC Oncology: Consultancy; Cure Genetics: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria.
Out of specificity product release of tisagenlecleucel
Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous ...RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.
Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.
Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.
Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.
Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to ...cardiovascular biology would thus contribute to heart failure risk.
We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in approximately 2000 genes of predicted importance to cardiovascular biology. Our design was a 2-stage case-control study. In stage 1, genotypes in Caucasian patients with heart failure (n=1590; ejection fraction, 32+/-16%) were compared with those in unaffected controls (n=577; ejection fraction, 67+/-8%) who were recruited from the same referral centers. Associations were tested for independent replication in stage 2 (308 cases and 2314 controls). Two intronic single-nucleotide polymorphisms showed replicated associations with all-cause heart failure as follows: rs1739843 in HSPB7 (combined P=3.09x10(-6)) and rs6787362 in FRMD4B (P=6.09x10(-6)). For both single-nucleotide polymorphisms, the minor allele was protective. In subgroup analyses, rs1739843 associated with both ischemic and nonischemic heart failure, whereas rs6787362 associated principally with ischemic heart failure. Linkage disequilibrium surrounding rs1739843 suggested that the causal variant resides in a region containing HSPB7 and a neighboring gene, CLCNKA, whereas the causal variant near rs6787362 is probably within FRMD4B. Allele frequencies for these single-nucleotide polymorphisms were substantially different in African Americans (635 cases and 714 controls) and showed no association with heart failure in this population.
Our findings identify regions containing HSPB7 and FRMD4B as novel susceptibility loci for advanced heart failure. More broadly, in an era of genome-wide association studies, we demonstrate how knowledge of candidate genes can be leveraged as a complementary strategy to discern the genetics of complex disorders.
Abstract 717
Chimeric antigen receptors (CARs) combine the antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein. CD19 is an ideal target for ...CARs since expression is restricted to normal and malignant B cells. Inclusion of the CD137 (4-1BB) signaling domain results in potent antitumor activity and in vivo persistence of anti-CD19 CARs in mice. We reported anti-tumor activity of CAR-modified autologous T cells targeted to CD19 (CART19 cells) in 3 patients (pts) with CLL with relatively short follow up (Porter, et al NEJM 2011; Kalos et al Sci Trans Med 2011). We now report on outcomes and longer follow up from 10 pts treated with CART19 cells.
Autologous T cells collected by leukapheresis were transduced with a lentivirus encoding anti-CD19 scFv linked to 4-1BB and CD3-z signaling domains. Gene-modified T cells were expanded and activated ex-vivo by exposure to anti-CD3/CD28 beads. Pts had CLL or ALL with persistent disease after at least 2 previous treatments.
10 pts have received CART19 cells; 9 adults median age 65 yrs (range 51–78) were treated for relapsed, refractory CLL and one 7 yr old was treated for relapsed refractory ALL. CLL pts had received a median of 5 prior regimens (range 2–10) and all had active disease at the time of infusion. 3/9 CLL patients had deletion of the p53 gene. The ALL pt had chemorefractory relapse, having received chemotherapy 6 weeks prior to infusion. All CLL pts received lymphodepleting chemotherapy 4–6 days before infusions (FC, PC or bendamustine, while the ALL pt had an ALC <10 after prior chemotherapy and did not require further lymphodepletion). A median of 7.5 × 108 total cells (range 1.7–50) corresponding to 1.45 × 108 (range 0.14–5.9) genetically modified cells were infused on day 0. Median follow-up as of 8/12/2012 was 5.6 mo (range 1–24 mo). 9 pts are evaluable for response (<30d follow up in 1 pt). No pt has died. There were no infusional toxicities >grade 2. CART19 homed to the marrow in the CLL pts and marrow and CSF for the ALL patient with detectable CART19 cells in the CSF (21 lymphs/uL, 78% CAR+) day 23 after infusion. 4/9 evaluable pts achieved CR. (3 CLL, 1 ALL). 2 CLL pts had a PR lasting 3 and 5 months, and 3 pts did not respond. In the 4 pts who achieved CR, maximal expanded cells in the blood were detected at an average of 27 fold higher than the infused dose (range 21–40-fold) with maximal in-vivo expansion between day 10 and 31 post infusion. No patient with CR has relapsed. All pts who responded developed a cytokine release syndrome (CRS) manifested by fever, and variable degrees of nausea, anorexia, and transient hypotension and hypoxia. In responding CLL pts the maximal fold elevation from baseline for IFN-γ was 89–298x, IL-6 6–40x, and IL2R 5– 25x, while no significant elevation in systemic levels of TNFα or IL2 were observed. For the ALL pt, maximal elevations from baseline were: IFNγ: 6040x; IL-6: 988x; IL2R: 56x, while significant elevations in TNFα (17x) and IL2 (163x) were also observed. The timing for maximum cytokine elevation differed but in all cases correlated with peak T cell expansion in the PBMC. 5 pts with CRS required treatment; patient 03 was treated with high dose steroids with resolution of symptoms but only achieved a PR. While steroid treatment had a variable effect on the CRS, we noted that these symptoms were temporally associated with significant elevations in serum IL-6. Accordingly, 4 of these pts were treated with the IL6-receptor antagonist tocilizumab on day 3–10 with prompt resolution of fevers, hypotension and hypoxia. 3 of these patients are evaluable for response and 2 achieved a CR. For the pts in CR, CART19 expression in the blood was documented by flow cytometry at the most recent follow up for each patient: 24 mo (pt 01), 22 mo (pt 02), 3 mo (pt 100), and 2 mo (pt 09).
Autologous T cells genetically engineered to express an anti-CD19 scFv coupled to 4-1BB/CD3-z signaling domains can undergo robust in-vivo expansion, persist for at least up to 2 yrs, and can be associated with a significant CRS that responds to anti-cytokine therapy. CART19 cells can induce potent and sustained responses (6/9 responses, 4 CR) for patients with advanced, refractory and high risk CLL and relapsed refractory ALL.
Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Off Label Use: The use of CART19 cells to treat CD19+ malignancy and the use of tocilizumab to treat cytokine activation syndrome related to CART19 cells. Kalos:University of Pennsylvania: Employment, Patents & Royalties. Levine:TxCell: Consultancy, Membership on an entity’s Board of Directors or advisory committees; University of Pennsylvania: financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight Patents & Royalties. June:Novartis: Research Funding, entitled to receive royalties from patents licensed to Novartis, entitled to receive royalties from patents licensed to Novartis Patents & Royalties.
Patients (pts) with relapsed, and/or refractory (R/R) CLL have a poor prognosis with few effective treatment options. We have shown that infusion of autologous T cells genetically modified to express ...a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain, with the CD3ζ and 4-1BB signaling domains (CTL019 cells), can mediate potent anti-tumor effects in pts with advanced, relapsed refractory CLL. In our initial pilot study, doses of 1.7-50, x 108 mononuclear cells, corresponding to 0.14-5.9 x 108genetically modified cells, were given as a split dose infusion on days 0, 1 and 2 to 14 pts with R/R CLL and overall response rate (PR plus CR) was 57%. The majority of responses were sustained, and associated with marked expansion and long-term persistence of transduced cells. Notably, there was no obvious dose:reponse or dose:toxicity effect noted over a wide range of cell doses. To better define an optimal CTL019 cell dose, we are performing a randomized phase II study of 2 doses of CTL019 cells in pts with R/R CLL.
Pts with R/R CLL are randomly assigned to receive either 5x108 vs. 5x107transduced CTL019 cells, with the rationale that both doses induced CRs in pts on our initial pilot trial. In the initial stage, 12 evaluable pts will be treated in each arm and in stage 2, an additional 8 pts will be treated with the selected dose level. Pts have to have relapsed or persistent disease after at least 2 previous treatments and progress within 2 years of their last therapy. All pts receive lymphodepleting chemotherapy ending 3-5 days before T cell infusion. Cell infusions are given as a single dose.
As of 7/15/2013, 27 pts have been enrolled; T cells did not adequately expand in 3, 1 patient was not eligible after screening, and 10 pts have been treated including 7 men and 3 women with a median age of 63 yrs (range 59-76). 5 pts had a mutation of p53. All pts had active disease at the time of CTL019 cell infusion. Lymphodepleting chemotherapy was Fludarabine/cyclophosphamide (8), pentostatin/cyclophosphamide (1), or bendamustine (1). 4 pts have been randomized to the higher dose level (5 x 108 CTL019 cells) and 6 pts have been randomized to the lower dose level (5 x 107CTL019 cells). There were no significant infusional toxicities. Median follow-up as of July 15, 2013 was 3 mo (1.3-5) for all pts and 3.3 mo (1.3-4) for responding pts. 2 pts have achieved a CR and 2 pts achieved PR, both with clearance of CLL from the blood and marrow and >50 reduction in adenopathy, for an overall response rate of 40%. In other recipients of CTL019 cells, we have observed ongoing improvement in adenopathy over time implying there can be a continued anti-tumor response. No responding patient has progressed. Seven of 10 pts experienced a delayed cytokine release syndrome (CRS) manifested by symptoms that included high fevers, nausea, myalgias and in some cases, capillary leak, hypoxia, and hypotension, typically correlated with peak CTL019 cell expansion.
We have noted that the CRS accompanying CTL019 therapy has been associated with marked increases of serum IL6 and can be rapidly reversed with the IL6-receptor antagonist tocilizumab. The CRS required intervention in 2 pts, one who responded and one who did not respond to CTL019. Treatment was initiated for hemodynamic or respiratory instability and was effective in reversing signs and symptoms of CRS in both pts.
A preliminary analysis through July 15, 2013 does not yet suggest a dose:response or dose:toxicity relationship. 2 of 4 recipients of the higher dose CTL019 responded, and 2 of 6 recipients at the lower dose level responded. The 7 pts who experienced a CRS included all 4 responding pts and 3 pts who did not respond. The CRS occurred in 3/4 recipients of higher dose CTL019 cells and 4/6 of recipients of lower dose CTL019 cells. CTL019 expansion in-vivo and persistence over the follow up period was noted in all responding pts.
In this ongoing dose optimization study of CTL019 cells, 4 of the first 10 pts treated have responded within 3 months. With short follow-up, as yet there is no suggestion that there is a dose:response or dose:toxicity relationship at the dose ranges being studied. These cells can undergo robust in-vivo expansion and from other studies (ASH 2013) can persist for at least 3 yrs. This trial confirms that CTL019 cells can induce potent responses for pts with advanced, relapsed and refractory CLL.
Porter:Novatis: IP and potential royalties with COI managed according to policies of the University of Pennsylvania, IP and potential royalties with COI managed according to policies of the University of Pennsylvania Patents & Royalties, Research Funding; Genentech: Spouse employment, Spouse employment Other. Off Label Use: CTL019 cells to treat CLL. Kalos:Novartis corporation: CART19 technology, CART19 technology Patents & Royalties; Adaptive biotechnologies: Member scientific advisory board , Member scientific advisory board Other. Grupp:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Shen:Novartis Pharmaceuticals: Employment, Equity Ownership. Wood:Novartis Pharmaceuticals: Employment, Equity Ownership. Litchman:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Zheng:Novartis: Patents & Royalties. Levine:Novartis: cell and gene therapy IP, cell and gene therapy IP Patents & Royalties. June:Novartis: Patents & Royalties, Research Funding.
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