CAR-T Therapy Displays Favorable Gains in Health Outcomes and Competitive Cost-Effectiveness When Compared with Past Innovative Cancer Treatments

Abstract Background: Recent literature provides conflicting views on whether there is a negative value trend in pharmaceutical oncology treatments. A previous study (J Econ Perspect 2015;29:1) found that the price of pharmaceutical oncology treatments has outpaced the improvements in survival benefits over time, with most treatments developed since 1995 offering marginal improvements in survival with significant increases in costs. In contrast, other literature suggests pharmaceutical oncology treatments have produced significant value. Chimeric antigen receptor t-cell (CAR-T) therapy represents a novel approach for treating particular hematologic cancers-including pediatric acute lymphoblastic leukemia and diffuse large b-cell lymphoma-but a remaining question is whether CAR-T represents a continued trend of low-value innovation, or a significant break from past trends. In this study, we investigate three key questions: (i) what are the trends over the past 10 to 20 years in incremental quality-adjusted life years (QALYs) and incremental cost per incremental quality-adjusted life year (cost/QALY) for newly approved anti-cancer innovations? (ii) how do innovations for hematologic cancers differ from those for other cancers in terms of this value trend? and (iii) how does CAR-T therapy compare with the recent history of innovations for both hematologic and non-hematologic cancers? Methods: We identified all analyses of pharmaceutical treatments for cancer published since 2007 that appear in the Tufts Medical Center Cost-Effectiveness Analysis (CEA) Registry, a comprehensive database focusing on a subset of CEAs called cost-utility analyses (CUAs), which quantify health benefits in terms of QALYs. CUA results on CAR-T therapies came from an analysis conducted by the Institute for Clinical and Economic Review (2018). We limited the CUAs in our study to those conducted in the US context with at least one of the following measures of value: incremental QALYs or cost/QALY, and with intervention/indication approval year 1995 or later. We measured linear trend in the value measures as a function of approval year and compared interventions for non-hematologic cancers with non-CAR-T interventions for hematologic cancers and, in turn, with CAR-T therapy. Regression analysis was used to control for the potential influence of characteristics of a CUA such as discount rate chosen, time horizon, number of years between publication and approval of the intervention for the indication in question, and an indicator for rare diseases as defined by the Genetic and Rare Diseases Information Center of the NIH. Indicators for CAR-T therapy and for non-CAR-T treatments for hematologic cancers were included to test for differences from innovations for other cancer types. Results: 103 incremental QALY and 108 cost/QALY measures met our inclusion criteria. The figures show incremental QALYs and cost/QALY, respectively, by approval year. The regression analysis shows that -- for innovations as a whole -- incremental QALYs gained have declined with approval year by 0.079 per year (95% CI -0.128 to -0.030). Cost effectiveness has worsened somewhat over time although that trend is not statistically significant (cost/QALY increase of $36,147 per year, 95%CI -$29,575 to $101,868). CAR-T is substantially more effective than both pharmaceutical cancer innovations outside of hematology (5.17 more incremental QALYs, 95%CI 4.09 to 6.25) and other innovations within hematology (4.67 more incremental QALYs, 95%CI 3.44 to 5.90). Innovations in hematology other than CAR-T are somewhat more effective than innovations outside of hematology (0.5 more incremental QALYs, 95%CI -0.09 to 1.09), although the difference is not statistically significant. Differences in cost/QALY between CAR-T and other pharmaceutical interventions are not statistically significant. Conclusions: CAR-T therapy improved health outcomes (measured in QALYs) to a greater extent than both treatments for non-hematologic cancers and non-CAR-T treatments for hematologic cancers, with no significant differences in cost/QALY. Those improvements represent a break from a trend previously reported in the literature of negligible incremental effectiveness and rising costs per life-year gained. Disclosures Baumgardner: Precision Health Economics: Employment. Everson:Precision Health Economics: Employment. Brauer:Precision Health Economics: Employment. Zhang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Liu:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lakdawalla:Precision Health Economics: Consultancy; Novartis Pharmaceuticals Corporation: Other: PHE conducted the research underlying this study with funding from Novartis.; Precision Medicine Group: Equity Ownership.

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Cost-Effectiveness Of Lenalidomide and Bortezomib In Patients With Previously Untreated Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v122.21.5604.5604 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5604-5604 ◽

Cited By ~ 1

Author(s):

Gerry Oster ◽

Ariel Berger ◽

Rebecca Bornheimer ◽

Gary Binder ◽

Yasir Nagarwala

Keyword(s):

Multiple Myeloma ◽

Cost Effectiveness ◽

Incremental Cost ◽

Research Funding ◽

Quality Adjusted Life Year ◽

Novel Agents ◽

Published Data ◽

Employment Equity ◽

Equity Ownership ◽

Quality Adjusted Life

Abstract Introduction The efficacy and safety of the novel agents, lenalidomide and bortezomib, in previously untreated MM has been demonstrated in several randomized controlled trials (Online-OnlyTs). In this study, we examine the cost-effectiveness of lenalidomide-melphalan–prednisone induction followed by lenalidomide maintenance (MPR-R), and bortezomib-melphalan-prednisone (VMP), respectively, versus melphalan-prednisone (MP), in patients with previously untreated MM. Methods We developed a partitioned-survival model to estimate expected clinical outcomes and costs in newly diagnosed MM patients receiving MPR-R, VMP, or MP as first-line therapy. The model had 3 mutually exclusive health states: (1) “progression-free, alive”; (2) “post-progression, alive”; and (3) “death.” Progression-free survival (PFS) for MP was estimated by aggregating data across five Online-OnlyTs (Palumbo 2012, San Miguel 2008, Facon 2007, Hulin 2009, Palumbo 2006). Estimates of PFS for MPR-R and VMP were based on an adjusted indirect treatment comparison with MP, using data from MM-015 for MPR-R (Palumbo 2012) and VISTA for VMP (San Miguel 2008). Since many MP patients in both MM-015 and VISTA “crossed over” to lenalidomide and bortezomib following disease progression in these trials, we estimated post-progression survival (PPS) for MPR-R and VMP based on a review of novel agents in MM (Messori 2011), which reported mean PPS of 30.9 months. Costs of MPR-R and VMP were estimated based on actual use of study drug in Online-OnlyTs; costs of adverse events as well as other disease-related costs were estimated based on published data. Health-state utilities also were estimated using published data. All costs were expressed in 2012 US$. Cost-effectiveness of MPR-R and VMP versus MP was examined in terms of cost per life-year (LY) gained, cost per quality-adjusted life-year (QALY) gained, and cost per progression-free life-year gained. Future costs and benefits were discounted at 3% annually. Results Mean estimated PFS was 3.4 years for MPR-R, 2.6 years for VMP, and 1.7 years for MP; corresponding estimates for OS were 6.0 years, 5.2 years, and 4.3 years, respectively (Table 1). Mean total expected lifetime costs (discounted) are reported in the Table. The incremental cost per life-year (LY) gained versus MP was $75,392 for MPR-R and $86,213 for VMP; corresponding estimates of the incremental cost per QALY gained were $91,794 and $106,211, respectively (Figure 1). The incremental cost per progression-free LY (PFLY) gained versus MP was $70,666 for MPR-R and $80,565 for VMP. Conclusions In patients with previously untreated MM, cost-effectiveness ratios for MPR-R and VMP are well within the range reported for other well-accepted novel therapies in oncology. $/LY: Incremental cost per life-year gained; $/QALY: Incremental cost per quality-adjusted life-year gained; $/PFLY: Incremental cost per progression-free life-year gained Support Funded by Celgene Corporation Disclosures: Oster: Celgene: Research Funding. Off Label Use: Lenalidomide (immunomodulatory agent), bortezomib (proteosome inhibitor), melphalan (alkylator), and prednisone (steroid), are all treatments for multiple myeloma. Berger:Celgene: Research Funding. Bornheimer:Celgene: Research Funding. Binder:Celgene: Employment, Equity Ownership. Nagarwala:Celgene: Employment, Equity Ownership.

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Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) for Relapsed and Refractory Multiple Myeloma (RRMM): Results from a Pharmacoeconomic Evaluation

Blood ◽

10.1182/blood.v124.21.2649.2649 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2649-2649

Author(s):

Steve Schey ◽

Sujith Dhanasiri ◽

Dawn Lee ◽

Lars Sternas ◽

Xin Yu ◽

...

Keyword(s):

Cost Effectiveness ◽

Cost Effective ◽

Pharmacoeconomic Evaluation ◽

Base Case ◽

Employment Equity ◽

Lifetime Horizon ◽

Equity Ownership ◽

The Uk ◽

The Cost ◽

Over Time

Abstract Background: Multiple myeloma remains an incurable disease, placing a significant burden on patients (pts), families, and healthcare systems. Bortezomib (BORT) and IMiDs® immunomodulatory agents (thalidomide and lenalidomide [LEN]) have improved progression-free survival (PFS), time to progression, and overall survival (OS). However, over time, nearly all pts become refractory which greatly impacts prognosis (median OS, 3-9 mos). In the absence of approved treatments, guidelines recommend clinical trials or retreatment with agents that were previously effective, but published data in the appropriate pt population for current care (CC) options are limited to those from small, observational, early-phase studies. There is a need for newer effective treatments; however, access is increasingly being determined by the demonstration of both clinical and economic value. POM + LoDEX demonstrated a significant OS benefit vs. high-dose dexamethasone (HiDEX) in the pivotal phase 3 MM-003 study (San Miguel, Lancet Oncol, 2013). POM + LoDEX has EU approval in RRMM pts in whom BORT and LEN failed. Objective: Explore the cost-effectiveness of POM + LoDEX vs. CC from a UK and Ireland healthcare payer perspective. Methods: A de novo pharmacoeconomic evaluation was conducted to compare costs and outcomes of POM + LoDEX to CC in the UK and Ireland. CC included BORT retreatment (intravenous [IV] or subcutaneous), LEN (oral), and bendamustine (IV) regimens. Efficacy data were sourced from MM-003 and 2 observational studies: a dataset for CC (Gooding, 2013; n = 30 pts primarily treated with BORT, bendamustine, or LEN; 100% received prior BORT and LEN) and a dataset for BORT + LEN (Jimenez-Zepeda, 2013; n = 30, 80% received prior BORT, 73% prior LEN). Validation of the approach and all model assumptions was achieved through extensive clinical and health economic expert consultation and by comparing comparator arm outcomes from observational data to the MM-003 (HiDEX) control arm data. The health economic model used a partitioned survival structure with OS and PFS parametric curves fitted to the datasets to estimate the number of pts at each time point expected to be preprogression, postprogression, or dead. Time to treatment failure curves were estimated to allow treatment discontinuation modelling. EQ-5D data, collected as part of MM-003, were used to inform quality of life (QOL) weights. A utility regression equation was developed to account for important covariates and allow utility to vary over time. The economic evaluation included the cost of treatment, administration, monitoring, tests, adverse events (AEs), blood transfusions, concomitant medication, and terminal care. Costs are presented in US dollars using an exchange rate of 0.74 per € and 0.58 per £. Costs and outcomes were modeled to estimate cost per life year (LY) and cost per quality-adjusted life year (QALY) gained over a lifetime horizon. Results: In the base-case analysis, POM + LoDEX was associated with a total incremental cost of $59,250 per pt over a lifetime horizon compared with CC (Table 1). Pts who receive POM + LoDEX are predicted to live for a mean of 2.2 years, compared with 1.2 years with CC. This represents an additional 0.6 QALYs. The model predicts a deterministic incremental cost-effectiveness ratio (ICER) of $100,920/QALY compared with CC, while the probabilistic ICER obtained through 1000 probabilistic model runs was consistent at $101,947/QALY. Table 1 : Base-Case Cost-Effectiveness Results Model Results POM + LoDEX CC Difference Clinical outcomes Median OS, mos 12.7 5.5 7.2 Mean predicted life-years (over a pt lifetime) 2.2 1.2 1.0 QALYs 1.3 0.7 0.6 Cost outcomes, US dollars Medication and administration $84,698 $29,880 $54,818 Monitoring $8230 $4489 $3741 AE management (outpatient visits and hospitalization) $7135 $6444 $691 Total $100,063 $40,813 $59,250 ICER—Cost/LY $58,112 ICER—Cost/QALY $100,920 Conclusion: There are limited alternative treatment options available in the UK and Ireland for RRMM pts. None have a proven effect on survival leaving pts to face potentially ineffective retreatments. End-of-life drugs that significantly improve survival and QOL and address unmet need can be considered to be cost-effective at a higher “willingness to pay” threshold. POM, an oral therapy with significant PFS, survival, and QOL with a known safety profile, is likely to be a cost-effective use of healthcare resources. Disclosures Dhanasiri: Celgene Corp: Employment, Equity Ownership. Lee:Celgene Corp: Consultancy. Sternas:Celgene Corp: Employment, Equity Ownership. Yu:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Elvidge:Celgene Corp: Consultancy.

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Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽

10.1182/blood-2019-127893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1848-1848

Author(s):

Maria Karvouni ◽

Heyue Zhou ◽

Arnika Kathleen Wagner ◽

Qiangzhong Ma ◽

Alamdar H. Baloch ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Therapeutic Potential ◽

Ex Vivo ◽

Phase 1 ◽

Employment Equity ◽

Multiple Myeloma Patient ◽

Myeloma Cells ◽

Car T ◽

Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

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Preclinical Evaluation of ALLO-819, an Allogeneic CAR T Cell Therapy Targeting FLT3 for the Treatment of Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-129025 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3921-3921 ◽

Cited By ~ 1

Author(s):

Cesar Sommer ◽

Hsin-Yuan Cheng ◽

Yik Andy Yeung ◽

Duy Nguyen ◽

Janette Sutton ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Target Cells ◽

Employment Equity ◽

T Cell Therapy ◽

Cell Therapies ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Equity Ownership

Autologous chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B-cell leukemias, lymphomas and multiple myeloma, raising interest in using CAR T cell therapies in AML. These therapies are produced using a patient's own T cells, an approach that has inherent challenges, including requiring significant time for production, complex supply chain logistics, separate GMP manufacturing for each patient, and variability in performance of patient-derived cells. Given the rapid pace of disease progression combined with limitations associated with the autologous approach and treatment-induced lymphopenia, many patients with AML may not receive treatment. Allogeneic CAR T (AlloCAR T) cell therapies, which utilize cells from healthy donors, may provide greater convenience with readily available off-the-shelf CAR T cells on-demand, reliable product consistency, and accessibility at greater scale for more patients. To create an allogeneic product, the TRAC and CD52 genes are inactivated in CAR T cells using Transcription Activator-Like Effector Nuclease (TALEN®) technology. These genetic modifications are intended to minimize the risk of graft-versus-host disease and to confer resistance to ALLO-647, an anti-CD52 antibody that can be used as part of the conditioning regimen to deplete host alloreactive immune cells potentially leading to increased persistence and efficacy of the infused allogeneic cells. We have previously described the functional screening of a library of anti-FLT3 single-chain variable fragments (scFvs) and the identification of a lead FLT3 CAR with optimal activity against AML cells and featuring an off-switch activated by rituximab. Here we characterize ALLO-819, an allogeneic FLT3 CAR T cell product, for its antitumor efficacy and expansion in orthotopic models of human AML, cytotoxicity in the presence of soluble FLT3 (sFLT3), performance compared with previously described anti-FLT3 CARs and potential for off-target binding of the scFv to normal human tissues. To produce ALLO-819, T cells derived from healthy donors were activated and transduced with a lentiviral construct for expression of the lead anti-FLT3 CAR followed by efficient knockout of TRAC and CD52. ALLO-819 manufactured from multiple donors was insensitive to ALLO-647 (100 µg/mL) in in vitro assays, suggesting that it would avoid elimination by the lymphodepletion regimen. In orthotopic models of AML (MV4-11 and EOL-1), ALLO-819 exhibited dose-dependent expansion and cytotoxic activity, with peak CAR T cell levels corresponding to maximal antitumor efficacy. Intriguingly, ALLO-819 showed earlier and more robust peak expansion in mice engrafted with MV4-11 target cells, which express lower levels of the antigen relative to EOL-1 cells (n=2 donors). To further assess the potency of ALLO-819, multiple anti-FLT3 scFvs that had been described in previous reports were cloned into lentiviral constructs that were used to generate CAR T cells following the standard protocol. In these comparative studies, the ALLO-819 CAR displayed high transduction efficiency and superior performance across different donors. Furthermore, the effector function of ALLO-819 was equivalent to that observed in FLT3 CAR T cells with normal expression of TCR and CD52, indicating no effects of TALEN® treatment on CAR T cell activity. Plasma levels of sFLT3 are frequently increased in patients with AML and correlate with tumor burden, raising the possibility that sFLT3 may act as a decoy for FLT3 CAR T cells. To rule out an inhibitory effect of sFLT3 on ALLO-819, effector and target cells were cultured overnight in the presence of increasing concentrations of recombinant sFLT3. We found that ALLO-819 retained its killing properties even in the presence of supraphysiological concentrations of sFLT3 (1 µg/mL). To investigate the potential for off-target binding of the ALLO-819 CAR to human tissues, tissue cross-reactivity studies were conducted using a recombinant protein consisting of the extracellular domain of the CAR fused to human IgG Fc. Consistent with the limited expression pattern of FLT3 and indicative of the high specificity of the lead scFv, no appreciable membrane staining was detected in any of the 36 normal tissues tested (n=3 donors). Taken together, our results support clinical development of ALLO-819 as a novel and effective CAR T cell therapy for the treatment of AML. Disclosures Sommer: Allogene Therapeutics, Inc.: Employment, Equity Ownership. Cheng:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Yeung:Pfizer Inc.: Employment, Equity Ownership. Nguyen:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Sutton:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Melton:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Valton:Cellectis, Inc.: Employment, Equity Ownership. Poulsen:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Djuretic:Pfizer, Inc.: Employment, Equity Ownership. Van Blarcom:Allogene Therapeutics, Inc.: Employment, Equity Ownership. Chaparro-Riggers:Pfizer, Inc.: Employment, Equity Ownership. Sasu:Allogene Therapeutics, Inc.: Employment, Equity Ownership.

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Translocations Involving the IGH@locus Occur In 3.7% of Chronic Lymphocytic Leukemia and Are Associated with Unmutated IGHV Status and a Shorter Time to Treatment: A Study on 2,135 Cases

Blood ◽

10.1182/blood.v116.21.3596.3596 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3596-3596

Author(s):

Claudia Haferlach ◽

Frank Dicker ◽

Susanne Schnittger ◽

Wolfgang Kern ◽

Torsten Haferlach

Keyword(s):

Multivariate Analysis ◽

Regression Analysis ◽

Chronic Lymphocytic Leukemia ◽

Cox Regression ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Mutation Status ◽

Cox Regression Analysis ◽

Igh Locus ◽

Equity Ownership

Abstract Abstract 3596 Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course and a large spectrum of treatment options. Based on FISH data, a prognostic classification system has been established with 13q deletions as sole abnormality associated with a favorable prognosis and 17p and 11q deletions correlating with an unfavorable outcome. Recently, the combined evaluation of FISH data, IGHV mutation status and chromosome banding analysis (CBA) revealed that the impact of distinct genetic parameters differs with respect to overall survival (OS) and time to treatment (TTT). Thus far only few data is available on less frequent genetic abnormalities such as 14q deletions and translocations involving the IGH@ locus (tIGH). Therefore, we analyzed CLL with tIGH in detail with respect to frequency, partner genes and impact on prognosis. Methods/Patients: 78 CLL cases with tIGH were identified from 2,135 CLL sent to our laboratory for diagnostic work-up. All cases had been evaluated by immunphentotyping, FISH and CBA. Result: The most frequent tIGH was t(14;19)(q32;q13) (BCL3, n=21) followed by t(14;18)(q32;q21) (BCL2, n=19), t(8;14)(q24;q32) (CMYC, n=7) and t(11;14)(q13;q32) (CCND1, n=6). In the remaining 25 cases 5 recurrent translocations (t(2;14)(p13;q32), n=3; t(4;14)(p16;q32), FGFR3, n=2; t(11;14)(p15;q32), n=2; t(14;17)(q32;q25), n=2; and t(7;14)(q21;q32), n=2) were observed while the remaining 14 translocations were identified in single cases only. In 9/78 cases (11.5%) the tIGH was the sole abnormality. Recurrent additional chromosome abnormalities were +12 (n=7), del(13q) (n=9), del(11q) (n=3). A 17p deletion was observed in 1 case. In two cases tIGH was present only in a subclone and was a secondary abnormality occurring in addition to an del(11q) and a +12, respectively. CLL with tIGH were compared to 401 CLL without tIGH comprising all other genetic subgroups (subdivided according to Döhner et al.: del(17p) n=26, del(11q) n=42, +12 n=42, “normal” n=88, del(13q) sole n=177 and del(14q) n=26). An unmutated IGHV status was more frequent in CLL with tIGH as compared to all others (26/46 (54.3%) vs 128/353 (36.3%); p=0.023). For 53 cases with tIGH and all cases of the non-tIGH cohort clinical follow-up data was available. Median OS was 143.8 months (mo) in CLL with tIGH and 72.9 mo in patients with del(17p) while it was not reached in all other subgroups. In Cox regression analysis only del(17p) and mutated IGHV status were significantly associated with OS (p<0.0001, relative risk (RR)=7.0; p=0.014, RR=0.38). Median TTT was as follows: total cohort: 60.9 mo; tIGH: 27.8 mo; del(17p): 58.9 mo; del(11q): 19.7 mo; +12: n.r.; “normal” 63.9 mo; del(13q) sole: 83.0 mo and del(14q): 21.0 mo. In univariate Cox regression analysis the following parameters were significantly associated with shorter TTT: tIGH (p=0.004, RR=1.82), del(11q) (p<0.0001, RR=2.55), and del(14q) (p=0.007, RR=2.1), while del(13q) sole and mutated IGHV status were associated with longer TTT (p<0.0001, RR=0.40; p<0.0001, RR=0.23). In multivariate analysis including tIGH, del(11q), del(14q) and del(13q) sole all parameters retained their impact on TTT. However, if IGHV mutation status was included in the model only the mutated IGHV mutation status retained an impact on TTT (p<0.0001, RR=0.26). Next, patients with tIGH were subdivided according to their partner genes. Median OS was not reached in all subgroups, while median TTT was as follows: t(11;14): 101.2 mo, t(14;18): 47.9 mo, t(14;19): 11.0 mo, t(8;14): 18.5 mo and other partner genes: 27.8 mo. In univariate Cox regression analysis only t(14;19) was significantly associated with shorter TTT (p<0.001, RR=3.1). Including t(14;19) into multivariate analysis revealed a significant impact of both mutated IGHV mutation status and t(14;19) on TTT (p<0.0001, RR=0.286; p=0.004, RR=3.60). Conclusion: Translocations involving the IGH@ locus occur at low frequency in CLL. They are associated with unmutated IGHV status and a shorter TTT. TTT is especially short in cases with t(14;19). The prognostic impact of t(14;19) is independent of IGHV mutation status. In contrast CLL with t(11;14) and t(14;18) are neither associated with shorter OS nor shorter TTT. This data supports the application of CBA in CLL in order to identify all clinically relevant chromosomal aberrations, including those not detected by routine FISH analysis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Correlation of Symptom Assessment with Genotyping Analysis of Saliva Samples in a Large Cohort of Myeloproliferative Neoplasm Patients

Blood ◽

10.1182/blood.v120.21.1732.1732 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1732-1732

Author(s):

Huong (Marie) Nguyen ◽

David A. Hinds ◽

Kimberly E. Barnholt ◽

Amy K. Kiefer ◽

Chuong B. Do ◽

...

Keyword(s):

Regression Analysis ◽

Abdominal Pain ◽

Research Funding ◽

Bone Pain ◽

Symptom Burden ◽

Female Gender ◽

Symptom Assessment ◽

Employment Equity ◽

Web Based ◽

Equity Ownership

Abstract Abstract 1732 Background: In addition to chronic myelogenous leukemia (CML), the classic myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2 V617F mutation (V617F) can be detected through genomic analysis of peripheral blood in 95% of PV and 50–60% of ET and MF patients (pts). These MPNs are often associated with debilitating symptoms and decreased quality of life (QOL). Systemic mastocytosis (SM) is an uncommon MPN in which proliferation of mast cells can result in mediator symptoms, as well as organ damage in advanced disease. We sought to compare the symptom burden of individuals with CML and SM to pts with classic MPNs in a more quantitative manner using a web-based recruitment design. Methods: Individuals with MPN were recruited through a web-based outreach effort. Participants gave IRB-approved consent, and completed on-line surveys of demographic information and questions based on the validated MPN-symptom assessment form (MPN-SAF). In addition, pts submitted saliva samples which were genotyped with SNP arrays based on the Illumina OmniExpress BeadChip, including probes for V617F. Regression analysis was used to evaluate the correlation between symptom responses and genotype data for 495 pts (118 PV, 121 ET, 97 MF, 85 SM, and 74 CML). For each MPN diagnosis, mean scores were calculated based on six fatigue-focused questions (Fatigue-6) and for six other symptoms (Symptom-6): early satiety, abdominal pain/discomfort, inactivity, night sweats, pruritis, and bone pain (ranked from 0–10; 10 = worst). ET pts' scores were used as the reference in the regression analysis based on prior data showing that ET pts have the lowest symptom burden among the classic MPNs. Individual symptoms, Fatigue-6, Symptom-6, and QOL (ranked 0–10; 10=worst) were analyzed using regression analysis against age, gender, diagnosis and V617F status. Results: Median age was 56 years (7–87), with 70% women. V617F was detected in 63% of classic MPN pts (87% PV, 46% ET, 56% MF). Analysis of Fatigue-6 scores revealed that age in years was negatively correlated with reported fatigue (β=-0.007 per year, P=0.032), while female gender and SM diagnosis were positively correlated with fatigue (female: β=0.33, P=2.4×10−4; SM: β=0.46, P=7.6×10−4). This trend was also seen for the Symptom-6: age (β=-0.025, P=5.8×10−4), female gender (β=0.73, P=1.4×10−4), and SM (β=1.8, P=5.0×10−10). Both Fatigue-6 and Symptom-6 were positively correlated with QOL, but Fatigue-6 had a much stronger association with QOL than did Symptom-6 (β=1.3, P=1.5×10−28 vs. β=0.36, P=1.2×10−11). When analyzed individually, abdominal pain/discomfort, pruritis, and bone pain were significantly correlated with V617F (β=0.676, P=0.0371; β=0.768, P=0.0241; β=0.791, P=0.0341, respectively), though these associations were not significant when all six symptoms were evaluated together (Symptom-6: β=0.315, P=0.171). There was no statistically significant correlation between V617F and Symptom-6. In addition, there was no correlation between any symptom and a germline variant in telomerase reverse transcriptase (TERT) rs2853677, identified as a novel predisposition allele for MPNs using a genome-wide association study of this cohort. Conclusion: Using a novel, web-based recruitment design combining MPN symptom assessment and genotyping of saliva samples, we identified significant correlations between 3 specific symptoms (pruritis, abdominal pain/discomfort, and bone pain) with V617F. Fatigue was also more strongly associated than other symptoms with QOL. There was no association between symptoms and TERT. This design is a powerful tool for future studies seeking to correlate symptoms with genotyping analysis. Disclosures: Hinds: 23andMe: Employment, Equity Ownership, Patents & Royalties. Barnholt:23andMe, Inc.: Employment. Kiefer:23andMe, Inc.: Employment. Do:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Eriksson:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Mountain:23andMe, Inc.: Consultancy, Employment, Honoraria, Patents & Royalties, Research Funding. Francke:23andMe, Inc.: Employment, Honoraria, Research Funding; Locus Development: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tung:23andMe, Inc.: Employment. Zehnder:23andMe, Inc.: Unpaid advisor and collaborator Other. Gotlib:23andMe, Inc.: Unpaid advisor and collaborator Other. Mesa:23andMe, Inc: Unpaid advisor and collaborator Other.

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Patterns of Total Costs of Care for Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽

10.1182/blood.v124.21.2656.2656 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2656-2656

Author(s):

Steven R. Arikian ◽

Dejan Milentijevic ◽

Gary Binder ◽

Mara Silvia Monzini ◽

X Henry Hu ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Direct Costs ◽

Drug Costs ◽

Newly Diagnosed ◽

Employment Equity ◽

Monthly Total ◽

Equity Ownership ◽

The Cost ◽

Over Time

Abstract Introduction: As clinical evidence has mounted in support of novel agents and longer treatment (Tx) durations for patients (pts) with newly diagnosed multiple myeloma (NDMM), questions have arisen regarding the economic impact of extending time to progression (TTP) in these pts, and the cost consequences once pts relapse and move to a second line of Tx. Previous analysis showed that relapsed myeloma pts incurred higher monthly costs once they advanced to later lines of Tx (Gaultney, 2013). There is limited information on the cost patterns of MM pts before and after their first relapse. A claims analysis was performed to evaluate the patterns of total direct costs of care, from Tx initiation until progression, for NDMM patients and for newly relapsed patients treated with novel agents, utilizing time to next therapy (TTNT) as a proxy measure for progression. Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million lives annually. NDMM patients were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM] code 203.0X), with the first such claim used to define the index date. Inclusion criteria required a minimum of 12 months' pre-index enrollment and 6 months' post-index continuous enrollment between 2006 and 2012. Pts with claims for stem cell transplantation (SCT) were excluded, to avoid confounding results from various factors based on timing, costs, and site of care of SCT. The analysis focused on NDMM and relapsed MM pts receiving lenalidomide (LEN)- or bortezomib (BORT)- based Tx, where complete claim history was available from Tx onset to initiation of subsequent Tx. Using methods similar to those described by Gaultney, patients' average monthly costs were determined, including medical (inpatient, ambulatory, and emergency room) and pharmacy (index and other drugs) costs, and total cost patterns over quarterly time periods were calculated. Average Charlson comorbidity scores were determined to compare baseline measures between pt groups. Results: 897 NDMM pts and 280 relapsed MM pts were identified with complete data through initiation of subsequent Tx. Monthly total direct costs for NDMM pts were $15,400 in the first 3 months (mos) of Tx, and declined each quarter, reaching approximately $5,000/mo at 18+ mos. At relapse, monthly costs increased to over $12,000 for the first 3 mos and followed a quarterly pattern of reduction similar to that seen for NDMM pts (Fig 1). Quarterly cost reduction patterns were consistent for patients treated with LEN or BORT for both NDMM and relapsed pts. Pts' total monthly NDMM costs over the full TTNT period averaged $8,942 with LEN vs. $11,139 for BORT (due to 54% higher monthly medical costs for BORT), while monthly drug costs were nearly identical (Table 1). The baseline Charlson comorbidity index was similar between Tx groups in both lines of Tx. Figure 1: Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Figure 1:. Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Table 1: Direct monthly costs for NDMM pts Table 1 Table 1. Conclusions: For a population of NDMM pts receiving either LEN- or BORT-based Tx without SCT, followed until TTNT, total direct monthly costs per pt declined steadily over time, decreasing by 68% from the initial quarter to the period post 18 mos. Costs spiked when pts began 2nd-line therapy, then followed a similar pattern of decline over time. This pattern may suggest that further extending the TTP for NDMM pts may also yield economic benefits for each month extended before relapse. Patterns of cost decline were similar between the LEN and BORT groups, for NDMM and for relapsed patients, although mean monthly total costs were lower for NDMM pts receiving LEN-based Tx due to lower medical costs and similar drug costs. Disclosures Arikian: Genesis Research: Consultancy. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients . Milentijevic:Celgene Corporation: Consultancy. Binder:Celgene Corporation: Employment, Equity Ownership. Monzini:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene Corporation: Employment. Nagarwala:Celgene Corporation: Employment. Hussein:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Surinach:Genesis Research LLC: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.

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A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignances

Blood ◽

10.1182/blood.v126.23.3094.3094 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3094-3094 ◽

Cited By ~ 5

Author(s):

Alena A. Chekmasova ◽

Holly M. Horton ◽

Tracy E. Garrett ◽

John W. Evans ◽

Johanna Griecci ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lines ◽

Drug Product ◽

Single Chain ◽

Employment Equity ◽

Car T Cells ◽

Car T ◽

Equity Ownership

Abstract Recently, B cell maturation antigen (BCMA) expression has been proposed as a marker for identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM and some lymphoma tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Targeting BCMA maybe a therapeutic option for treatment of patients with MM and some lymphomas. We are developing a chimeric antigen receptor (CAR)-based therapy for the treatment of BCMA-expressing MM. Our anti-BCMA CAR consists of an extracellular single chain variable fragment (scFv) antigen recognition domain derived from an antibody specific to BCMA, fused to CD137 (4-1BB) co-stimulatory and CD3zeta chain signaling domains. Selection of our development candidate was based on the screening of four distinct anti-BCMA CARs (BCMA01-04) each comprised of unique single chain variable fragments. One candidate, BCMA02 (drug product name bb2121) was selected for further studies based on the robust frequency of CAR-positive cells, increased surface expression of the CAR molecule, and superior in vitro cytokine release and cytolytic activity against the MM cell lines. In addition to displaying specific activity against MM (U226-B1, RPMI-8226 and H929) and plasmacytoma (H929) cell lines, bb2121 was demonstrated to react to lymphoma cell lines, including Burkitt's (Raji, Daudi, Ramos), chronic lymphocytic leukemia (Mec-1), diffuse large B cell (Toledo), and a Mantle cell lymphoma (JeKo-1). Based on receptor density quantification, bb2121 can recognize tumor cells expressing less than 1000 BCMA molecules per cell. The in vivo pharmacology of bb2121 was studied in NSG mouse models of human MM and Burkitt's lymphoma. NSG mice were injected subcutaneously (SC) with 107 RPMI-8226 MM cells. After 18 days, mice received a single intravenous (IV) administration of vehicle or anti-CD19Δ (negative control, anti-CD19 CAR lacking signaling domain) or anti-BCMA CAR T cells, or repeated IV administration of bortezomib (Velcade®; 1 mg/kg twice weekly for 4 weeks). Bortezomib, which is a standard of care for MM, induced only transient reductions in tumor size and was associated with toxicity, as indicated by substantial weight loss during dosing. The vehicle and anti-CD19Δ CAR T cells failed to inhibit tumor growth. In contrast, treatment with bb2121 resulted in rapid and sustained elimination of the tumors, increased body weights, and 100% survival. Flow cytometry and immunohistochemical analysis of bb2121 T cells demonstrated trafficking of CAR+ T cells to the tumors (by Day 5) followed by significant expansion of anti-BCMA CAR+ T cells within the tumor and peripheral blood (Days 8-10), accompanied by tumor clearance and subsequent reductions in circulating CAR+ T cell numbers (Days 22-29). To further test the potency of bb2121, we used the CD19+ Daudi cell line, which has a low level of BCMA expression detectable by flow cytometry and receptor quantification analysis, but is negative by immunohistochemistry. NSG mice were injected IV with Daudi cells and allowed to accumulate a large systemic tumor burden before being treated with CAR+ T cells. Treatment with vehicle or anti-CD19Δ CAR T cells failed to prevent tumor growth. In contrast, anti-CD19 CAR T cells and anti-BCMA bb2121 demonstrated tumor clearance. Adoptive T cell immunotherapy approaches designed to modify a patient's own lymphocytes to target the BCMA antigen have clear indications as a possible therapy for MM and could be an alternative method for treatment of other chemotherapy-refractory B-cell malignancies. Based on these results, we will be initiating a phase I clinical trial of bb2121 for the treatment of patients with MM. Disclosures Chekmasova: bluebird bio, Inc: Employment, Equity Ownership. Horton:bluebird bio: Employment, Equity Ownership. Garrett:bluebird bio: Employment, Equity Ownership. Evans:bluebird bio, Inc: Employment, Equity Ownership. Griecci:bluebird bio, Inc: Employment, Equity Ownership. Hamel:bluebird bio: Employment, Equity Ownership. Latimer:bluebird bio: Employment, Equity Ownership. Seidel:bluebird bio, Inc: Employment, Equity Ownership. Ryu:bluebird bio, Inc: Employment, Equity Ownership. Kuczewski:bluebird bio: Employment, Equity Ownership. Horvath:bluebird bio: Employment, Equity Ownership. Friedman:bluebird bio: Employment, Equity Ownership. Morgan:bluebird bio: Employment, Equity Ownership.

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Identification of Small Molecule Modulators to Enhance the Therapeutic Properties of Chimeric Antigen Receptor T Cells

Blood ◽

10.1182/blood.v128.22.4712.4712 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4712-4712

Author(s):

Jonathan Rosen ◽

Betsy Rezner ◽

David Robbins ◽

Ian Hardy ◽

Eigen Peralta ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Small Molecules ◽

Small Molecule ◽

Employment Equity ◽

Car T Cells ◽

Car T ◽

Equity Ownership

Abstract Adoptive cellular therapies using engineered chimeric antigen receptor T cells (CAR-T cells) are rapidly emerging as a highly effective treatment option for a variety of life-threatening hematological malignancies. Small molecule-mediated modulation of T cell differentiation during the in vitro CAR-T manufacturing process has great potential as a method to optimize the therapeutic potential of cellular immunotherapies. In animal models, T cells with a central or stem memory (TCM/SCM) phenotype display enhanced in vivoefficacy and persistence relative to other T cell subpopulations. We sought to identify small molecules that promote skewing towards a TCM/SCM phenotype during the CAR-T manufacturing process, with associated enhanced viability, expansion and metabolic profiles of the engineered cells. To this end, we developed a high-throughput functional screening platform with primary human T cells using a combination of high-content immunophenotyping and gene expression-based readouts to analyze cells following a high-throughput T cell culture platform that represents a scaled-down model of clinical CAR-T cell production. Multicolor flow cytometry was used to measure expansion, cell viability and the expression levels of cell surface proteins that define TCM cells (e.g., CCR7, CD62L and CD27) and markers of T cell exhaustion (e.g., PD1, LAG3, and TIM3). In parallel, a portion of each sample was evaluated using high content RNA-Seq based gene expression analysis of ~100 genes representing key biological pathways of interest. A variety of known positive and negative control compounds were incorporated into the high-throughput screens to validate the functional assays and to assess the robustness of the 384-well-based screening. The ability to simultaneously correlate small molecule-induced changes in protein and gene expression levels with impacts on cell proliferation and viability of various T cell subsets, enabled us to identify multiple classes of small molecules that favorably enhance the therapeutic properties of CAR-T cells. Consistent with results previously presented by Perkins et al. (ASH, 2015), we identified multiple PI3K inhibitors that could modify expansion of T cells while retaining a TCM/SCM phenotype. In addition, we identified small molecules, and small molecule combinations, that have not been described previously in the literature that could improve CAR-T biology. Several of the top hits from the screens have been evaluated across multiple in vitro (e.g., expansion, viability, CAR expression, serial restimulation/killing, metabolic profiling, and evaluation of exhaustion markers) and in vivo (e.g., mouse tumor models for persistence and killing) assays. Results from the initial screening hits have enabled us to further refine the optimal target profile of a pharmacologically-enhanced CAR-T cell. In addition, we are extending this screening approach to identify small molecules that enhance the trafficking and persistence of CAR-T cells for treating solid tumors. In conclusion, the approach described here identifies unique small molecule modulators that can modify CAR-T cells during in vitro expansion, such that improved profiles can be tracked and selected from screening through in vitro and in vivo functional assays. Disclosures Rosen: Fate Therapeutics: Employment, Equity Ownership. Rezner:Fate Therapeutics, Inc: Employment, Equity Ownership. Robbins:Fate Therapeutics: Employment, Equity Ownership. Hardy:Fate Therapeutics: Employment, Equity Ownership. Peralta:Fate Therapeutics: Employment, Equity Ownership. Maine:Fate Therapeutics: Employment, Equity Ownership. Sabouri:Fate Therapeutics: Employment, Equity Ownership. Reynal:Fate Therapeutics: Employment. Truong:Fate Therapeutics: Employment, Equity Ownership. Moreno:Fate Therapeutics, Inc.: Employment, Equity Ownership. Foster:Fate Therapeutics: Employment, Equity Ownership. Borchelt:Fate Therapeutics: Employment, Equity Ownership. Meza:Fate Therapeutics: Employment, Equity Ownership. Thompson:Juno Therapeutics: Employment, Equity Ownership. Fontenot:Juno Therapeutics: Employment, Equity Ownership. Larson:Juno Therapeutics: Employment, Equity Ownership. Mujacic:Juno Therapeutics: Employment, Equity Ownership. Shoemaker:Fate Therapeutics: Employment, Equity Ownership.

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Preclinical Development of CTX120, an Allogeneic CAR-T Cell Targeting Bcma

Blood ◽

10.1182/blood-2018-99-116443 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1921-1921 ◽

Cited By ~ 2

Author(s):

Henia Dar ◽

Daniel Henderson ◽

Zinkal Padalia ◽

Ashley Porras ◽

Dakai Mu ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Cell Targeting ◽

Employment Equity ◽

Term Survival ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Equity Ownership

Abstract Autologous CAR-T cells targeting BCMA have induced robust and durable responses in patients with relapsed/refractory multiple myeloma. However, autologous cell therapies face several challenges which will likely limit the number of patients that will have access to these therapies. These limitations include manufacturing failure rates, wait time and supply constraints in addition to other factors such as reimbursement. Allogeneic CAR-T cells can potentially overcome these access challenges, and may have several other advantages over autologous therapies. Allogeneic CAR-T cells are derived from robust healthy donor T cells through a batch manufacturing process, which may result in a highly consistent product with greater potency and enable better safety management. Here we show further development and preclinical data for CTX120, an allogeneic "off the shelf" CAR-T cell targeting BCMA. CTX120 is produced using the CRISPR/Cas9 system to eliminate TCR and MHC class I, coupled with specific insertion of the CAR at the TRAC locus. CTX120 shows consistent and high percent CAR expression from this controlled insertion and exhibits target-specific cytotoxicity and cytokine secretion in response to BCMA positive cell lines. CTX120 CAR-T cells retain their cytotoxic capacity over multiple in vitro re-challenges, demonstrating durable potency and lack of exhaustion. In mouse models of multiple myeloma, CTX120 showed typical CAR-T persistence and eliminated tumors completely, resulting in long-term survival as compared to untreated animals. These data support the ongoing development of CTX120 for treatment of patients with multiple myeloma and further demonstrate the potential for our CRISPR/Cas9 engineered allogeneic CAR-T platform to generate potent CAR-T cells targeting different tumor antigens. Disclosures Dar: CRISPR Therapeutics: Employment, Equity Ownership. Henderson:CRISPR Therapeutics: Employment, Equity Ownership. Padalia:CRISPR Therapeutics: Employment, Equity Ownership. Porras:CRISPR Therapeutics: Employment, Equity Ownership. Mu:CRISPR Therapeutics: Employment, Equity Ownership. Kyungah:CRISPR Therapeutics: Employment, Equity Ownership. Police:CRISPR Therapeutics: Employment, Equity Ownership. Kalaitzidis:CRISPR Therapeutics: Employment, Equity Ownership. Terrett:CRISPR Therapeutics: Employment, Equity Ownership. Sagert:CRISPR Therapeutics: Employment, Equity Ownership.

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