Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients

Soft tissue sarcomas (STSs) are heterogeneous and aggressive malignancies with few effective therapies available. We have developed T cells expressing a vascular endothelial growth factor receptor 2 (VEGFR2)-specific chimeric antigen receptor (CAR) to establish a tumor angiogenesis-specific CAR-T cells impacting cancers (TACTICs) therapy. In this study, we optimized the manufacturing and transportation of mRNA-transfected anti-VEGFR2 CAR-T cells and collected information that allowed the extrapolation of the efficacy and safety potential of TACTICs therapy for STS patients. Although 5-methoxyuridines versus uridines did not improve CAR-mRNA stability in T cells, the utilization of CleanCap as a 5′ cap-structure extended the CAR expression level, increasing VEGFR2-specific cytotoxicity. Furthermore, 4 °C preservation conditions did not affect the viability/cytotoxicity of CAR-T cells, contrarily to a freeze-thaw approach. Importantly, immunohistochemistry showed that most of the STS patients’ specimens expressed VEGFR2, suggesting a great potential of our TACTICs approach. However, VEGFR2 expression was also detected in normal tissues, stressing the importance of the application of a strict monitoring schedule to detect (and respond to) the occurrence of adverse effects in clinics. Overall, our results support the development of a “first in humans” study to evaluate the potential of our TACTICs therapy as a new treatment option for STSs.

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The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia

Annals of Pharmacotherapy ◽

10.1177/1060028017736539 ◽

2017 ◽

Vol 52 (3) ◽

pp. 268-276 ◽

Cited By ~ 3

Author(s):

Troy Z. Horvat ◽

Amanda N. Seddon ◽

Adebayo Ogunniyi ◽

Amber C. King ◽

Larry W. Buie ◽

...

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Data Extraction ◽

Lymphoblastic Leukemia ◽

Adult Patients ◽

Efficacy And Safety ◽

Car T Cells ◽

Car T ◽

American Society

Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

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Decitabine in Combination with Fludarabine and Cyclophosphamide As Lymphodepletion Regimen Followed By CD19/CD22 Bispecific Targeted CAR-T Therapy Significantly Improves Survival in Relapsed/Refractory B-ALL Patients: A Pilot Study

Blood ◽

10.1182/blood-2021-152041 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1754-1754

Author(s):

Yunju Ma ◽

Changju Qu ◽

Haiping Dai ◽

Sining Liu ◽

Qingya Cui ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

Efficacy And Safety ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background: CD19/CD22 bispecific targeted chimeric antigen receptor T cell (CAR-T) therapy has achieved impressive progress in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL), with high rates of complete remission (CR). However, T cell exhaustion caused by de novo DNA methylation restricts the capacity of CAR-T. Decitabine (DAC), a DNA methyltransferase inhibitor, has been demonstrated to reverse exhaustion-associated DNA-methylation programs, promote the rejuvenation of CAR-T cells and enhance anti-leukemic effect of CAR-T cells in vitro. To date, there are limited reports about the use of DAC as a part of lymphodepletion therapy before CAR-T cell therapy. Here, we report efficacy and safety of DAC in combination with fludarabine and cyclophosphamide (FC) regimen followed by CD19/CD22 CAR-T cell therapy for patients with R/R B-ALL. Method:We conducted a phase 1/2 clinical trial to investigate the efficacy and safety of CD19/CD22 CAR-T in the treatment of R/R B-ALL (NCT03614858). Fourteen patients were treated with DAC (total dose 100mg/m 2 in 3 days) followed by FC regimen (fludarabine 30mg/m 2 × 3d and cyclophosphamide 300mg/m 2 × 3d) (DAC group), while twelve patients received FC regimen prior to CAR-T cell infusion (CON group). A total of 1 or 2 × 10 7 CAR-T cells/kg were infused at dose escalation. Results: Baseline characteristics of patients in both groups had no significant differences except previous hematopoietic stem cell transplantation (HSCT). There were more patients with relapse after HSCT in DAC group (42.9% versus 0%, P=0.017). All patients did not achieve remission before lymphodepletion. The day 28 CR rates were 100% in DAC group and 91.7% in CON group. Furthermore, minimal residual disease (MRD) negative CR rates were 71.4% and 58.3%, respectively (P = 0.683). There was no significant difference in the proportion of nontransplant patients after CAR-T treatment between two groups. Among the nontransplant patients after CAR-T infusion in DAC group, 16.7% (1/6) of patients relapsed at 4 months. However, among 4 nontransplant patients in CON group, 1 patient achieved NR after CAR-T therapy and 3 patients relapsed at 1.5, 5, and 10 months. There were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 88.9% (DAC) versus 33.3% (CON), P = 0.01 and 3-year LFS, 92.3% (DAC) versus 21.8% (CON), P = 0.002. Multivariable analysis showed that addition of DAC to the lymphodepletion regimen was associated with better OS (hazard ratio [HR] 0.107, [95% CI, 0.013-0.875], P = 0.037) and LFS (HR 0.081, [95% CI, 0.01-0.65], P = 0.018). Cytokine release syndrome was observed in all patients. Conclusion: In summary, DAC in combination with FC regimen followed by CD19CD22 CAR-T cells was feasible and well tolerated. Our study demonstrated DAC combined with FC was an independent prognostic factor correlated with better survival in relapsed/refractory B-ALL patients. Disclosures No relevant conflicts of interest to declare.

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SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma

Science Translational Medicine ◽

10.1126/scitranslmed.abe7378 ◽

2021 ◽

Vol 13 (591) ◽

pp. eabe7378 ◽

Cited By ~ 1

Author(s):

Joseph H. Choe ◽

Payal B. Watchmaker ◽

Milos S. Simic ◽

Ryan D. Gilbert ◽

Aileen W. Li ◽

...

Keyword(s):

T Cells ◽

Specific Antigen ◽

Growth Factor Receptor ◽

Memory State ◽

Immunodeficient Mice ◽

Car T Cells ◽

Car T ◽

Heterogeneous Expression ◽

Tumor Killing ◽

Specific Priming

Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.

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Development of CAR T cells designed to improve antitumor efficacy and safety

Pharmacology & Therapeutics ◽

10.1016/j.pharmthera.2017.03.012 ◽

2017 ◽

Vol 178 ◽

pp. 83-91 ◽

Cited By ~ 46

Author(s):

Janneke E. Jaspers ◽

Renier J. Brentjens

Keyword(s):

T Cells ◽

Antitumor Efficacy ◽

Efficacy And Safety ◽

Car T Cells ◽

Car T

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Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers

Journal of Translational Medicine ◽

10.1186/s12967-021-03132-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zhifen Yang ◽

Lingyu Li ◽

Ahu Turkoz ◽

Pohan Chen ◽

Rona Harari-Steinfeld ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor Receptor ◽

Checkpoint Inhibition ◽

Single Chain ◽

Tev Protease ◽

Car T Cells ◽

Car T

Abstract Background Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells combined with checkpoint inhibition may prevent T cell exhaustion and improve clinical outcomes. However, the approach is limited by cumulative costs and toxicities. Methods To overcome this drawback, we created a CAR-T (RB-340-1) that unites in one product the two modalities: a CRISPR interference-(CRISPRi) circuit prevents programmed cell death protein 1 (PD-1) expression upon antigen-encounter. RB-340-1 is engineered to express an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3ζ co-stimulatory domains linked to the tobacco etch virus (TEV) protease and a single guide RNA (sgRNA) targeting the PD-1 transcription start site (TSS). A second constructs includes linker for activation of T cells (LAT) fused to nuclease-deactivated spCas9 (dCas9)-Kruppel-associated box (KRAB) via a TEV-cleavable sequence (TCS). Upon antigen encounter, the LAT-dCas9-KRAB (LdCK) complex is cleaved by TEV allowing targeting of dCas9-KRAB to the PD-1 gene TSS. Results Here, we show that RB-340-1 consistently demonstrated higher production of homeostatic cytokines, enhanced expansion of CAR-T cells in vitro, prolonged in vivo persistence and more efficient suppression of HER2+ FaDu oropharyngeal cancer growth compared to the respective conventional CAR-T cell product. Conclusions As the first application of CRISPRi toward a clinically relevant product, RB-340-1 with the conditional, non-gene editing and reversible suppression promotes CAR-T cells resilience to checkpoint inhibition, and their persistence and effectiveness against HER2-expressing cancer xenografts.

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Possible Factors on Efficacy and Safety of CAR-T Therapy in Relapsed or Refractory Aggressive B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-114727 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5386-5386

Author(s):

Haiwen Huang ◽

Yibin Jiang ◽

Zhengming Jin ◽

Caixia Li ◽

Depei Wu

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Objective Response ◽

B Cell Lymphoma ◽

Efficacy And Safety ◽

B Cell Lymphomas ◽

Car T Cells ◽

Car T ◽

Grade 3

Abstract Background: Recent advances have improved the treatment of B-cell malignancies, but patients who have disease resistant to primary or salvage treatment or who relapse after transplantation have an extremely poor prognosis. Studies of chimeric antigen receptor T-cell (CAR-T) therapy have shown high response rates and long response duration in refractory B-cell lymphomas after the failure of conventional therapy, which suggest that this therapy may be potentially curative. To explore the possible factors on efficacy and safety of CAR T-Cell therapy in relapsed or refractory aggressive B-cell lymphomas, we conducted the clinical trial of CAR-T Cell Treating Relapsed/Refractory B-cell lymphomas (NCT03196830). Methods: From March 2017 to April 2018, 25 patients were enrolled into our clinical trial. According to the surface expression of tumor cells by either flow cytometry or immunohistochemistry, different targets of CAR T-cells were infused, ionly anti-CD19 (n=11), sequential infusion of anti-CD22 and anti-CD19 (n=8), and sequential infusion of anti-CD20 and anti-CD19 (n=6). Patients received conditioning treatment (low-dose cyclophosphamide, 300 mg/m² per day, and fludarabine, 30 mg/m² per day) on days -5, -4, and -3 before the administration of autologous CAR T-cells. The primary endpoint was the proportion of patients with an objective response. Secondary endpoints included safety and biomarker assessments. Results: Among the 25 patients who were enrolled, response was successfully evaluated for 24. The objective response rate was 75%, and the complete response rate was 33%. With a median follow-up of 3.2 months, 54% of the patients continued to have a response, with 25% continuing to have a complete response. Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 24% and 16% of the patients, respectively. One of the patients died during treatment. Serum biochemical index analysis confirmed the associations of peak serum interleukin-2, -6, -10, INF-γ, ferritin, C-reactive protein (CRP) concentrations and the level of lactate dehydrogenase (LDH) before therapy with the grade 3 or higher CRS, as well as peak serum interleukin-6, -10, INF-γ, CRP, ferritin and the level of LDH before therapy with grade 3 or higher neurologic events. Conclusion: Our study demonstrates the efficacy and safety of CAR-T therapy relapsed or refractory aggressive B-cell lymphoma. The level of LDH before therapy was higher in patients who developed grade 3 or serious CRS, which suggest that we should improve safety by reducing tumor burden before CAR T-cells infusion. Due to the small number of enrolled cases, no significant improvement of efficacy was observed, this result needs to be further confirmed by expanding the number of study cases. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Efficacy and Safety of CD19-Targeted CAR-T Cell Therapy for Refractory/Relapsed B-Cell Lymphoma: A Single Center of Real World Data

Blood ◽

10.1182/blood-2021-144997 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4827-4827

Author(s):

Jing Huang ◽

Jia Fei ◽

Ruiming Ou ◽

Zhi Liu ◽

Liling Zheng ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Disease Progression ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Efficacy And Safety ◽

Car T Cells ◽

Car T Cell ◽

Car T

Abstract 【Abstract】 Objective To investigate the efficacy and safety of CD19-targeted chimeric antigen receptor T cell (CAR-T cell) for refractory/relapsed B-cell lymphoma. Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 12 patients with relapsed/refractory B-cell lymphoma from March 2018 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 9 patients (75%) with diffuse large B cell lymphoma, 1 patient with blastic variant of mantle cell lymphoma, 1 patient(8.3%) with Burkitt lymphoma, 1 patient with B cell non-Hodgkin lymphoma that cannot be classified. 3 patients (25%) with large mass (≥7.5cm) and 9 patients (75%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 4-9, the median number of chemotherapy courses was 7. All 12 patients were autogenous mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 3.69×10 6/kg. Results All 12 patients received CD19-targeted CAR-T cell therapy. There were 9 patients had treatment response, and the total effective rate was 75%. Among them, there were 3 patients with complete response (CR), with CR rate of 25%, and 6 patients with partial response (PR), with PR rate of 50%. Among the 3 patients with CR remained CR at the follow-up date. Among the 6 patients with PR, 4 showed disease progression in the second month after transfusion, and 2 showed disease progression in the third month after transfusion. All the 9 patients with effective treatment had different degrees of cytokine release syndrome (CRS), including 3 level-1 CRS, 4 level-2 CRS, and 2 level-3 CRS. Two of them had grade 2 CRES, and all CRS and CRES were controlled after treatment with IL-6 receptor antagonists and glucocorticoids. None of the 3 patients failed to respond to treatment had CRS. Conclusion CD19-targeted CAR-T cell immunotherapy has been shown to be effective in CD19-antigen positive B-cell lymphoma, and adverse CRS reactions during treatment can be controlled after treatment. Patients who obtained CR seemed to be able to maintain long-term CR status, while patients who failed to obtain CR showed disease progression within a short period of 3 months, suggesting that patients who obtained CR at an early stage could achieve better efficacy. Therefore, how to identify patients who receive CR at an early stage may be a research direction for the clinical application of CAR-T cell immunotherapy in B-cell lymphoma. 【Key words】Chimeric antigen receptor T-cell; Relapsed/refractory B cell lymphoma; Efficacy; Safety; Cytokine release syndrome Disclosures No relevant conflicts of interest to declare.

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Patients with Bone and Bone Marrow Involvement Had Better OS and PFS in Patients with Aggressive Non-Hodgkin Lymphoma Treated with CD19 CAR T Cells

Blood ◽

10.1182/blood-2019-130566 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5315-5315

Author(s):

Lili Zhou ◽

Liang Aibin ◽

Shaoguang Li ◽

Shiguang Ye ◽

Ping Li

Keyword(s):

Bone Marrow ◽

T Cells ◽

Soft Tissue ◽

Complete Remission ◽

Hodgkin Lymphoma ◽

Bone Marrow Involvement ◽

Car T Cells ◽

Non Hodgkin Lymphoma ◽

Soft Tissue Involvement ◽

Car T

Factors associated with complete remission and durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with CD19 CAR T cells. The best overall response rate was 71%, with 32% of patients achieving complete remission. The median PFS and OS of patients with aggressive NHL who achieved complete remission were 11 months and 12 months. The median PFS and OS of patients with bone and bone marrow involvement without soft tissue involvement were 14 months and 18 months. The median PFS and OS of patients with soft tissue involvement were 1 months and 4 months. We report complete remission rates and long-term survival rates in patients with bone and bone marrow involvement were significantly higher than those in patients with soft tissue involvement. Figure Disclosures No relevant conflicts of interest to declare.

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Probing the AML Surfaceome for Chimeric Antigen Receptor (CAR) Targets

Blood ◽

10.1182/blood.v128.22.526.526 ◽

2016 ◽

Vol 128 (22) ◽

pp. 526-526

Author(s):

Fabiana Perna ◽

Samuel Berman ◽

Jorge Mansilla-Soto ◽

Mohamad Hamieh ◽

Rupa Juthani ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Hematopoietic Stem Cells ◽

Validation Studies ◽

Antigen Expression ◽

Hematopoietic Stem ◽

Normal Tissues ◽

Car T Cells ◽

Car T ◽

Low Expression

Abstract Adoptive T cell therapy using chimeric antigen receptors (CARs) to redirect the specificity and function of T lymphocytes has demonstrated efficacy in patients with lymphoid malignancies, in particular acute lymphoblastic leukemia (ALL). CD19 CAR therapy can induce durable complete remissions in subjects with CD19+ malignancies for whom chemotherapies have led to drug resistance and tumor progression. We previously obtained "breakthrough designation" from the US FDA for CD19 CAR therapy for adult ALL. The success of CD19 CAR therapy bodes well for tackling other hematological malignancies, including Acute Myeloid Leukemia (AML). The challenge for developing an effective CAR therapy for AML lies in the lack of suitable CAR targets. In ALL, CD19 is expressed on most if not all tumor cells, including tumor-initiating cells, and is only expressed in the normal B cell lineage. In contrast, the AML CAR targets proposed to date (Le-Y, CD123, CD33 and folate receptor-β) do not share this profile. They have not yielded effective and safe tumor eradication in early clinical studies. The clonal heterogeneity of AML and the similarity of AML cancer stem cells to normal hematopoietic stem cells pose additional challenges. Searching for better targets is thus essential. However, the identification of CAR targets is limited by the lack of reliable tools to assess antigen expression across all human tissues. In order to identify suitable CAR targets for AML, we integrated multiple transcriptomic and proteomic data sources and created an algorithm to identify proteins that can be targeted by single and combinatorial CAR strategies. To comprehensively probe the AML surfaceome, we compiled 474 molecules identified in previous studies and 3,675 molecules we identified by membrane protein biotinylation followed by Mass-Spectometry analysis. To assess whole body antigen expression, we integrated large sets of protein and mRNA expression data and annotated the expression of each AML surface molecule in normal cell types, tissues and organs, including hematopoietic stem cells (HSCs). We then established a "quality control" filter to assign priority antigens, based on their presence in at least two protein expression datasets (Human Protein Atlas, Human Protein Map and/or Proteomics Database) and their membrane-association. This step yielded 1,694 AML molecules. We further selected molecules with low expression in 64 normal tissues/organs and excluded antigens with high expression in bone marrow HSCs. These steps reduced candidate targets to 215 proteins. From these, we identified 32 targets overexpressed in diverse AML cells and showing very low overall expression in normal tissues. We performed systematic validation analyses by flow cytometry and identified 11 top candidates with low expression in normal CD34+ and CD34+CD38- HSCs and high expression in a panel of AML cells. Further elimination of molecules expressed in T cells reduced the candidate target number to 4, including 2 G-protein coupled receptors not previously reported as CAR targets in AML. These molecules were however still minimally expressed in some normal tissues, which prompted us to search for pairs of antigens with non-overlapping expression in normal tissues as a strategy to reduce on-target/off-tumor cytotoxicity. We identified 55 such pairs. Our validation studies have so far identified 3 unique pairs of targets showing absent co-expression in normal tissues and ~100% co-expression in a small panel of AML cells. These promising pairs are targeted by T cells co-expressing a CAR specific for one antigen and a chimeric costimulatory receptor (CCR) specific for the other. In a proof-of-principle study, we demonstrate that dual-targeted CAR T cells specific for CD33 and CD70 effectively lyse AML cells with diminished reactivity relative to single-targeted CAR T cells. Further validation studies in larger AML panels are in progress. This novel discovery approach to CAR target identification should prove very useful to expand CAR therapy applications to AML and other malignancies. Disclosures Sadelain: Juno Therapeutics: Consultancy.

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