Gene Modification of Human Primary Natural Killer Cells by Electroporation with mRNA or DNA Coding for An Anti-GD2 Chimeric Antigen Receptor.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2467-2467 ◽  
Author(s):  
Srinivas S. Somanchi ◽  
Cecele J Denman ◽  
Atharva Amritkar ◽  
Vladimir Senyukov ◽  
Simon Olivares ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Conflicts Of Interest ◽  
Antigen Receptor ◽  
Sleeping Beauty ◽  
Vector System ◽  
Target Cells ◽  
Gene Modification

Abstract Abstract 2467 Poster Board II-444 Natural killer (NK) cells play an important role in immune surveillance against a variety of infectious microorganisms and tumors. The main restrictions to developing NK cells for immunotherapy are the limited quantity of cells available for adoptive transfer and their relative resistance to gene transfer by any method. We have developed an efficient method to expand CD3-CD56+ primary NK cells in vitro using K562 artificial APCs expressing membrane-bound IL21. Here we have investigated the potential of these expanded human NK cells to be gene modified through electroporation of DNA and mRNA. Expanded NK cells were electroporated (Amaxa Nucleofector device, program X-01) with DNA or mRNA coding for the GFP reporter gene, and expression of the transgene was evaluated by flow cytometry. Analysis at 48 hours post electroporation revealed that the viability of NK cells electroporated with GFP mRNA was 78% and those electroporated with GFP DNA was 69%. When electroporated with DNA, 32% of the viable NK cells were positive for GFP but had heterogeneous expression level, whereas 98% of viable cells were positive for GFP following mRNA electroporation, with much more homogeneous GFP expression (Figure). Based on this success we further investigated the potential of expanded NK cells to be gene modified with a Sleeping Beauty transposon/transposase vector system carrying the transgene for a second-generation Chimeric Antigen Receptor (CAR) against the GD2 ganglioside antigen, with signaling via the CD28 and CD3z endodomains. The GD2 antigen is abundantly expressed in neuroblastoma and melanoma and is therefore a relevant target for adoptive immunotherapy. Electroporation of expanded NK cells with the GD2-CAR transposon alone yielded 25% electroporation efficiency, with a viability of 55%. Electroporation of expanded NK cells with the GD2-CAR transposon and the transposase plasmid decreased the transfection efficiency to 14%. Nonetheless, expanded NK cells modified with the GD2-CAR showed improved killing of the target cell CHP-134 using the calcein AM release assay, as compared to unelectroporated expanded NK cells from the same donor. While freshly isolated human NK cells are highly resistant to gene modification, in this study we show that expanded human NK cells can be efficiently electroporated with both DNA and mRNA. NK cells modified with DNA to express CAR gain improved cytotoxic function against target cells, but viability and gene transfer efficiency are low. Since electroporation of GFP mRNA resulted in increased transduction efficiency and viability, we are now evaluating electroporation of expanded NK cells with GD2-CAR mRNA. Disclosures: No relevant conflicts of interest to declare.

The Contribution of Signaling Endodomains to CD33-Mediated Killing of Acute Myeloid Leukemia by Natural Killer Cells Transiently Modified with Chimeric Antigen Receptor.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2463-2463
Author(s):  
Jeffrey Friesen ◽  
Vladimir Senyukov ◽  
Cecele J Denman ◽  
Srinivas S. Somanchi ◽  
Simon Olivares ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Transfer ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
Related Donor ◽  
Acute Myeloid

Abstract Abstract 2463 Poster Board II-440 Acute myeloid leukemia (AML) is an aggressive malignancy for which current therapy fails to provide durable remission in approximately half of cases. Natural killer (NK) cells, as a key component of innate immunty, have recently shown clinical potential for adoptive immunotherapy against AML, particular when the donor and recipient are KIR mismatched. In addition to patients who do not have a suitable related donor, approximately 30% of patients bear all three families of KIR ligands and therefor can not benefit from KIR mismatch. Thus, the major obstacles for adoptive NK cell immunotherapy are 1) obtaining sufficient numbers of NK cells for effective thereapy and 2) finding a related donor with predicted KIR mismatch. Clinical trials with humanized or engineered mAbs against CD33 have validated this antigen as a target for immunotherapy of AML, but are complicated by side effects such as a hepatotoxicity due to CD33 expression on normal hepatocytes. To address the first hurdle, we developed a method to expand CD3-CD56+ primary NK cells in vitro using artificial APCs expressing membrane-bound IL21, and have validated electroporation as an efficient method for gene modification of these NK cells. To address the second hurdle and expand the therapeutic potential of KIR-matched expanded NK cells, we hypothesized that gene transfer of CD33 Chimeric Antigen Receptor (CAR) could provide additional activation signal to increase the lysis of AML blasts by expanded NK cells, and sought to compare signaling endodomains for this purpose. CD3z is a signal adapter molecule for NKp30, NKp46, and CD16 in NK cells. We developed a CD33CAR composed of a CD33 single-chain variable fragment fused with the CD3z transmembrane domain expressed in Sleeping Beauty transposon vector system, and compared a first generation (CD3z only) endodomain with second generation endodomains (CD3z plus either CD28 or CD137). Transient gene transfer of the CD33CAR DNA into NK cells was accomplished using the Amaxa Nucleofector device. Functional expression of the CAR was determined by binding of a Siglec3-IgG fusion protein to the cell surface followed by secondary staining with anti-IgG-FITC. Cytotoxicity of the NK cells against CD33+ AML cells and CD33-transduced HEK293T cells was determined in a 4h lysis assay using Calcein-AM. While the maximum electroporation efficiency was only 15% at 24h, expression levels as low as 4% significantly increased the cytotoxic activity of NK cells compared to unelectroporated NK cells. Each of the CD33CAR constructs harboring different endodomains yielded an equivalent increase in target cell lysis (Figure). This data supports recent observations that signal transduction through CD3z is sufficient to activate cytotoxic activity in NK cells. However, to increase the percentage of CAR-expressing NK cells we are further evaluating the role of endodomain signaling in CAR-dependent proliferation of NK cells electroporated with both transposon and transposase. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective Cytotoxicity of Single and Dual Anti-CD19 and Anti-CD138 Chimeric Antigen Receptor-Natural Killer Cells against Hematologic Malignancies

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Sudjit Luanpitpong ◽  
Jirarat Poohadsuan ◽  
Phatchanat Klaihmon ◽  
Surapol Issaragrisil
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Antigen Expression ◽  
In Vivo Studies ◽  
Selective Cytotoxicity

Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients’ antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.

Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 653-664 ◽  
Author(s):  
Yu Zhao ◽  
Xiaorong Zhou
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Structural Characteristics ◽  
Antigen Receptor ◽  
Adoptive Cell Transfer ◽  
Antitumor Effects ◽  
Treatment Regimens ◽  
Existing Problems

Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.

scholarly journals C/Ebpg (CCAAT/Enhancer Binding Protein Gamma) Balances Cytotoxic and Secretory Potential of Natural Killer Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3721-3721
Author(s):  
Izabela Aparecida Lopes ◽  
Miroslava Kardosova ◽  
Thiago Mantello Bianco ◽  
Adriana Queiroz Arantes ◽  
Cleide Araújo Silva ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Nk Cells ◽  
Natural Killer ◽  
Cellular Proliferation ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Secretory Cells ◽  
Target Cells ◽  
Functional Assay ◽  
Cell Functions

Abstract C/EBPs (CCAAT/enhance-binding proteins) are a family of transcription factors involved in a variety of hematopoietic processes, regulating both terminal differentiation and cellular proliferation. Among these, it was previously reported that C/EBP gamma (C/EBPg) has a role in the development of Natural Killer (NK) cells. However, the mechanisms of such regulation are unknown. NK cells are lymphocytes with effector functions of cytotoxicity and production of cytokines, both dependent on a dynamic equilibrium between the expression of activating and inhibitory receptors as well as cytokine receptors. The two functions (cytotoxic and secretory) make NK cells important components of hematopoiesis, able to eliminate susceptible targets as well as recruit other cells to amplify inflammatory responses. With the aim of studying the regulation of NK cells by C/EBPg, we isolated NK cells from transgenic Cebpg knockout (KO) mice and controls to analyze their function. To characterize NK cells, we analyzed their frequency (Lineage-/CD3-/NK1.1+ cells) and the expression of the receptors NKG2D, Ly49D and NKG2A by flow cytometry of splenocytes. Both analyses showed no difference between control or Cebpg KO NK cells. Although the numbers of NK cells and their receptors were similar between Cebpg WT and KO animals, a functional assay that measured NK cell degranulation by CD107a expression after co-incubation with YAC-1 target cells showed that the expression of this marker was 5-times lower in Cebpg KO splenocytes than in controls (CT = 12.44 ± 2.50%; KO = 2.255 ± 0.67%, p=0.007), suggesting that Cebpg deficient NK cells are not fully activated after target cell recognition. In addition, a cytotoxicity assay by flow cytometry was performed using a fluorescent probe (Cell Tracker Orange) that was incorporated to YAC-1 cells upon exposure to sorted and IL-2 activated NK cells in culture. In the 10:1 NK:target cells ratio, Cebpg KO cells were significantly less cytotoxic than NK control cells (CT = 23.36 ± 8.67%; KO = 10.60 ± 1.66%, p=0.038). The other NK:target cells ratios of 5:1 and 1:1 showed the same tendency. In addition, the functional subtypes of these cells were characterized according to the expression of CD27 and CD11b, which allowed the identification of NK subpopulations as immature secretory, mature secretory, cytotoxic or tolerant. The KO animals showed higher percentages of secretory cells (CT = 10.77 ± 5.38%; KO = 12.98 ± 13.63%, p=0.0002) and a reduction of cytotoxic cells in comparison to the NK control cells (CT = 12.22 ± 11.08%; KO = 10.65 ± 3.82% p=0.013). Cytokine levels of IL-2, IL-4, IL-6, IL-10, IL-17α, TNFα and IFNγ, obtained from NK culture supernatants, were measured by flow cytometry, after IL-2 activation. Among these cytokines, the production of IFNγ by Cebpg-deficient NK cells was reduced (CT = 37.68 ± 0.51 pg/mL; KO = 22.34 ± 0.14 pg/mL, p=0.023). Together, these experiments indicate that C/EBPg regulates NK cell cytotoxicity. This may be explained, at least in part, by the reduced frequency of the mature cytotoxic NK subpopulation as compared to the secretory subtypes. Moreover, IFNγ may be an important target for the regulation of NK cell function. Finally, C/EBPg seems to be critical to mediate NK cell functions and not only for their development from the ontogenetic point of view. Disclosures No relevant conflicts of interest to declare.

scholarly journals Systematic Combinatorial Chimeric Antigen Receptor Therapies to AML

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 856-856
Author(s):  
Fabiana Perna ◽  
Samuel Berman ◽  
Rajesh K Soni ◽  
Jorge Mansilla-Soto ◽  
Justin Eyquem ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Chimeric Antigen Receptor ◽  
Normal Tissue ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Antigen Receptor ◽  
The Other ◽  
Target Cells ◽  
Normal Tissues

Abstract Chimeric antigen receptor (CAR) therapy targeting CD19 yields remarkable outcomes in patients with ALL. Three molecules (CD123, CD33 and CLEC12A) are currently targeted in clinical trials by CAR T cells for patients with AML. However, they do not feature expression profiles favorable as that of CD19. An ideal target should be expressed in all tumor cells, at high density and in most patients. To prevent undue toxicity, the ideal target should not be expressed on any normal tissue, or at least not in vital tissues, including normal counterparts. This task requires comprehensive sources of antigen annotation, as well as analytical tools specifically designed to identify potential CAR targets. To identify CAR targets in AML in an unbiased manner, we probed the AML surfaceome for highly abundant molecules with little to no expression in vital tissues. We assembled a comprehensive database of 4,942 AML surface molecules by combining public protein repositories and our own cell-surface proteomics from 6 distinct AML cell lines. We computed molecule-specific AML/normal HSPC expression ratios by comparing the RNA expression levels of 26 genetically defined AML subtypes to normal BM CD34+ CD38- CD90+ CD45RA- HSCs and MPP, GMP, CMP, MEP progenitor cells, identifying 682 molecules. We combined three proteomics databases including both immunohistochemistry (HPA) and mass spectrometry (HPM and PDB) data, prioritizing antigens with membrane-associated sub-localization and expression data supported by multiple sources, thus removing 321 molecules. Finally, we selected top 24 molecules exhibiting low average expression across 43 clusters of normal tissues, and no high expression in any normal tissue, excluding blood, bone marrow and spleen. We further defined the expression of these candidate targets in a panel of 30 primary AML samples and AML LSCs, and focused on nine candidate molecules with >75% expression in most patients. Four of these, ADGRE2, CCR1, CD70 and LILRB2, showed <5% expression in normal BM HSCs and T cells, which is critical to prevent HSC toxicity and T cell self-elimination. While they may have therapeutic potential, they are not ideal or as good as CD19. This prompted us to explore combinatorial targeting strategies, which fall in two major categories (Figure 1). One is based on cumulative CAR targeting through the generation of bi-specific T cells that co-express two CARs and recognize target cells expressing any of two given antigens (CAR/CAR). Some low or moderate expression in normal tissues, albeit not optimal, may be tolerable depending on the tissues in question. The other takes advantage of split signaling to target two antigens, using one antigen to direct costimulation to enhance or rescue the suboptimal function of a CAR or TCR targeting the other antigen. In the latter approach (CAR/CCR), T cells are more restricted to dual-antigen positive tumor cells, thus relaxing the expression criteria for at least one of the paired antigens. However, pan-tumor expression of the CAR target is required. In both instances, target pairings depend on the systemic expression and co-expression of the two prospective matches to minimize cumulative expression in normal tissues. We optimized target selection by pairing targets with non-overlapping expression in normal tissues. Starting from 12 molecules with the best expression profiles (9 candidate targets described above in addition to CD123, CD33, and CLEC12A), the 66 possible pairings, yielded few promising therapeutic combinations. We studied four combinations: CD33+ADGRE2, CLEC12A+CCR1, CD33+CD70, and LILRB2+CLEC12A, which exhibit expression profiles unlikely to exacerbate on-target/off-tumor activity of either target alone and stained <5% of normal HSCs and T cells. Three pairings positively stained >97% of cells in AML samples, significantly above either marker alone. It is however noteworthy that total positivity was significantly higher than dual-positivity, suggesting the presence of cells expressing one antigen only. This finding is consistent with AML clonal heterogeneity and favors using such antigen pairs in the dual-targeting approach (CAR/CAR). This present study represents a new approach to the discovery of CAR targets and will help advance the development of CAR therapy for AML and other cancers. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor

2020 ◽  
Author(s):  
May Daher ◽  
Rafet Basar ◽  
Elif Gokdemir ◽  
Natalia Baran ◽  
Nadima Uprety ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Aerobic Glycolysis ◽  
Protein A ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
Combined Strategy ◽  
Anti Tumor Activity

AbstractImmune checkpoint therapy has produced remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with chimeric antigen receptor (CAR) engineering of natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that combining CIS checkpoint deletion with CAR engineering promotes the metabolic fitness of NK cells in an otherwise suppressive tumor microenvironment. This approach, together with the prolonged survival afforded by CAR modification, represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.

Anti-CD20 Chimeric Antigen Receptor (CAR) Modified Expanded Natural Killer (NK) Cells Significantly Mediate Burkitt Lymphoma (BL) Regression and Improve Survival In Human BL Xenografted NSG Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3263-3263 ◽  
Author(s):  
Yaya Chu ◽  
Ashlin Yahr ◽  
Janet Ayello ◽  
Carmella van de Ven ◽  
Xianzheng Zhou ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Burkitt Lymphoma ◽  
Antigen Receptor ◽  
Treated Group ◽  
Multiple Injections ◽  
Nsg Mice ◽  
Anti Cd20

Abstract Background Burkitt lymphoma (BL) is the most common form of non-Hodgkin lymphoma that occurs in children and adolescents (Miles/Cairo, BJH, 2012). The 5-year event-free survival (EFS) of children and adolescents with newly diagnosed BL has been significantly improved but for patients with relapsed/refractory disease, the prognosis is dismal due to chemotherapy resistance (Cairo, et al, J Clin Oncol, 2012; Cairo, et al Blood 2007). Novel, non-chemotherapy-based therapies are desperately needed for this specific poor risk population. We have previously demonstrated that CD20 is expressing in ≥98% of pediatric BL (Perkins/Cairo, Clin Adv Hematol Oncol. 2003) and also reported that expanded Peripheral Blood Natural Killer (exPBNK) Cells electroporated with anti-CD20 Chimeric Antigen Receptor (CAR) mRNA have significant cytotoxicity against CD20+ BL in vitro (Chu/Cairo, et al, ASH, 2012). Objective To examine the anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR+) modified expanded PBNK cells against disseminated CD20+ Burkitt Lymphoma in vivo using human CD20+ BL xenografted NSG mice. Methods PBMC were expanded with lethally irradiated K562-mbIL15-41BBL cells for 14 days as we previously reported. CD56+CD3- expanded PBNK (exPBNK) cells were isolated using Miltenyi NK cell isolation kit. Anti-CD20-4-1BB-CD3ζ mRNA (CAR mRNA) was produced using the mMESSAGE mMACHINE T7 Ultra kit. CAR mRNA was nucleofected and CAR expression was detected using anti-mouse IgG, F(ab’)2 fragment-specific antibody (Chu & Cairo, et al, ASH, 2012). 5x105 Raji cells expressing luciferase (Raji-Luc) were intraperitoneally (i.p.) injected into the NSG mice (6 weeks, Jackson Labs). Raji engraftment and progression was evaluated using the Xenogen IVIS-200 system (Caliper Life Sciences) after i.p. injection of 150mg D-luciferin/kg/mouse. Photons emitted from luciferase-expression cells were quantified using the Living Image software. After Raji-Luc engraftment was verified in mice at day 7, 5x106 anti-CD20 CAR exPBNK or MOCK exPBNK (no anti-CD20 CAR mRNA electroporation) were i.p. injected to each mouse once a week (day 9,16, 23). Control mice received culture medium instead of NK cells. The cumulative luciferase signals were measured weekly to indicate the tumor growth, dissemination and progression. Statistical probability of survival and comparison of survival curves were determined by Kaplan Meier Method and the log-rank test. The results with a P value < 0.05 were deemed statistically significant. Results We found that luciferase signals from Raji-luc were not significantly different between the untreated, mock exPBNK treated, and CAR exPBNK treated groups (p=0.0538) after the first NK injection. However, the luciferase signals measured in the CAR exPBNK treated group were significantly different than that in the control mice (two tailed P= 0.0013) and the mock exPBNK treated mice (two tailed P= 0.0229) after the second NK injection. After the third NK injection, the luciferase signals measured in the CAR exPBNK treated group were also significantly different than that in the control mice (two tailed P= 0.0173) and the mock exPBNK treated mice (two tailed P= 0.0256) (Fig. 1A). But luciferase signals were not significantly different between the untreated mice and the mock exPBNK treated mice (two tailed P= 0.0729). Consistent with the reduced luciferase signals, the CAR exPBNK treated mice had significantly extended survival time with median 40 days compared to the untreated mice (29 days, P<0.001) and the mock exPBNK treated mice (30 days, P<0.001) (Fig. 1B). There was no significant difference of survival between the untreated mice and the mock exPBNK treated mice. Conclusion Multiple injections of anti-CD20 CAR mRNA electroporated exPBNK cells can significantly mediate disseminated Raji tumor regression in Raji xenografted NSG mice compared to untreated and mock exPBNK treated mice. Furthermore, anti-CD20 CAR exPBNK significantly increased the survival of Raji xenografted mice. These results indicate therapeutic potential of multiple injections of anti-CD20 CAR mRNA modified exPBNK cells against BL in patients with chemo-immunotherapy resistance. Future directions include examining the anti-tumor activity of CAR+ exPBNK against rituximab/chemotherapy resistant BL in xenografted NSG mice. Disclosures: No relevant conflicts of interest to declare.

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