B-cell Lymphoma Model Research Articles

An autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies

AbstractBispecific antibodies (BsAbs) can induce long-term responses in patients with refractory and relapsed B-cell lymphoma. Nevertheless, response rates across patients are heterogeneous, and the factors determining quality and duration of responses are poorly understood. To identify key determinants of response to BsAbs, we established a primary, autologous culture model allowing us to mimic treatment with CD3xCD19 and CD3xCD20 BsAbs within the lymph node microenvironment ex vivo. T cell–mediated killing of lymphoma cells and proliferation of T cells varied significantly among patients but highly correlated between BsAbs targeting CD20 or CD19. Ex vivo response to BsAbs was significantly associated with expansion of T cells and secretion of effector molecules (eg, granzyme B, perforin) but not with expression of T-cell exhaustion (eg, PD1, TIM3) or activation markers (eg, CD25, CD69) or formation of intercellular contacts. In addition, we identified a distinct phenotype of regulatory T cells that was linked to ex vivo response independently from T-cell frequency at baseline. High expression levels of Aiolos (IKZF1), ICOS, and CXCR5 were positively associated with ex vivo response, whereas strong expression of Helios (IKZF2) had an unfavorable impact on ex vivo response to BsAbs. We further showed that lenalidomide, nivolumab, and atezolizumab improved ex vivo response to BsAbs by potentiating T-cell effector functions. In summary, our ex vivo study identified a distinct regulatory T-cell phenotype as a potential contributor to treatment failure of BsAbs and suggests drug combinations of high clinical relevance that could improve the efficacy of BsAbs.

835P Enhancement of the International Prognostic Index with hematologic parameters: A new prognostic model for diffuse large B-cell lymphoma treated with R-CHOP

835P Enhancement of the International Prognostic Index with hematologic parameters: A new prognostic model for diffuse large B-cell lymphoma treated with R-CHOP

Distinct roles for PARP-1 and PARP-2 in c-Myc–driven B-cell lymphoma in mice

AbstractDysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc–driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc–driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc–driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc–driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc–driven tumors.

Allogeneic CAR Invariant Natural Killer T Cells Exert Potent Antitumor Effects through Host CD8 T-Cell Cross-Priming.

The development of allogeneic chimeric antigen receptor (CAR) T-cell therapies for off-the-shelf use is a major goal that faces two main immunologic challenges, namely the risk of graft-versus-host disease (GvHD) induction by the transferred cells and the rejection by the host immune system limiting their persistence. In this work we assessed the direct and indirect antitumor effect of allogeneic CAR-engineered invariant natural killer T (iNKT) cells, a cell population without GvHD-induction potential that displays immunomodulatory properties. After assessing murine CAR iNKT cells direct antitumor effects in vitro and in vivo, we employed an immunocompetent mouse model of B-cell lymphoma to assess the interaction between allogeneic CAR iNKT cells and endogenous immune cells. We demonstrate that allogeneic CAR iNKT cells exerted potent direct and indirect antitumor activity when administered across major MHC barriers by inducing tumor-specific antitumor immunity through host CD8 T-cell cross-priming. In addition to their known direct cytotoxic effect, allogeneic CAR iNKT cells induce host CD8 T-cell antitumor responses, resulting in a potent antitumor effect lasting longer than the physical persistence of the allogeneic cells. The utilization of off-the-shelf allogeneic CAR iNKT cells could meet significant unmet needs in the clinic.

A Novel Prognostic Model for Primary Gastric Diffuse Large B-Cell Lymphoma in the Rituximab Era, Integrating EBV Harboring on Tumor Cells

Introduction: EBV‐positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) often shows an aggressive clinical course with frequent extranodal disease including gastrointestinal involvement. However, the clinicopathological and prognostic significance of the EBV+ disease among primary gastric DLBCL (gDLBCL) has not been confirmed. Recently targeted therapies using antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have shown great promise in the treatment of relapsed or refractory DLBCL, but there remains a need for reliable methods to identify the candidates for novel immune-therapies.We analyzed the clinicopathological characteristics of gDLBCL and shed the light on the EBV harboring on tumor cells and PD-L1 expression as prognostic indicators for the future clinical trials of PD-1 blockade.Patients and methods: A total of 157 patients previously diagnosed as primary gDLBCL and treated with rituximab-containing chemotherapies were retrospectively examined. All cases were tested for EBV-encoded small RNA (EBER) by in situ hybridization (ISH). The expression of PD-L1 was immunohistochemically evaluated (clone SP142, Spring Bioscience, Pleasanton, CA).Results: Our series consisted of 157 patients: 92 males and 65 females (male: female ratio = 1.4), with a median onset age of 67 years (range, 32-89 years). 66 patients (42%) showed Lugano stage Ⅱ2/ⅡE/Ⅳ, 59 (40%) with high levels of soluble interleukin -2 receptors (sIL-2R >1000U/ml), 45 (29%) with IPI HI/H, and 34 (22%) with B symptoms. 39 patients (38%) had multiple gastric lesions, 19 (12%) with the presence of Bulky mass, and 29 (60%) with Helicobacter pylori infection. 92 patients (61%) had a non-germinal center B-cell immunophenotype (non-GCB). All of 157 patients received multiagent chemotherapy combined with rituximab, with an additional irradiation in 55 (35%). EBV harboring was found on the tumor cells in 12 (7.6%). There was no significant difference in the clinicopathological findings between EBV+ and EBV‐negative (EBV−) subgroups. But, notably, the EBV+ patients had a significantly worse overall survival (OS) than EBV− ones (P=0.004). Multivariate analysis of survival revealed that EBER positivity (P=0.012), the presence of multiple gastric lesions (P=0.014), and IPI HI/H (P=0.017) were adverse independent prognostic factors in gDLBCL. We constructed a prognostic model by combining these prognostic variables as follows: patients with a score of 0 (n=43), no adverse factors; patients with a score of 1 (n=36), one factor; and patients with a score of 2/3 (n=24), two or three factors. The 5-year OS rates for these 3 groups were 100%, 91%, and 43%, respectively. Furthermore, this model significantly stratified gDLBCL patients separately by survival (P <0.001, Figure). Although none of gDLBCL cases expressed PD-L1 on tumor cells, 7 (78%) of 9 cases with EBV+ gDLBCL were positive for PD-L1 in ≥20% of nonmalignant stromal cells in microenvironment (miPD-L1+), which showed a higher frequency than in EBV− ones (78% vs 42%, P=0.13).Conclusions: EBV+ gDLBCL showed a significantly worse prognosis. Our prognostic model appeared to well define the clinical outcome of gDLBCL patients. PD-L1 expression in nonmalignant stromal cells was a common feature of EBV+ gDLBCL. They could be good candidates to benefit from anti-PD-1/PD-L1 therapy. A novel prognostic model by integrating EBV harboring on tumor cells may serve as a risk‐stratification for future clinical trials in which high‐risk patients can be treated with newly developing immune-therapies to improve their outcomes. [Display omitted] DisclosuresShimada:Kyowa Hakko Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria.

Combined Inhibition of mTOR and BTK Signaling Is Required for Optimal Long Term Growth Inhibition in DLBCL Models

Introduction: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell signalling, growth, metabolism and survival. Many B-cell lymphomas exhibit aberrant mTOR activation, coupled with dysregulated B-cell receptor (BCR) signalling. However, clinical trials with allosteric mTORC1 inhibitors (rapamycin and its analogues), have shown only modest efficacy in most contexts. Vistusertib (AZD2014) is an orally active dual mTORC1/2 inhibitor in clinical development for treatment of several malignancies. We investigated the potential for combining vistusertib with acalabrutinib (ACP-196), a highly selective Bruton tyrosine kinase (BTK) inhibitor, in cellular and in vivo preclinical models of diffuse large B cell lymphoma (DLBCL).Methods and Results: We demonstrate that the combination of mTOR and BTK inhibition causes additive growth inhibition in a panel of DLBCL cell lines, but synergistic growth inhibition in a subset of ABC-DLBCL cell lines (such as OCI-LY10 and TMD8 cell lines). In the same cell lines, the combination causes profound effects on BTK and mTOR downstream signalling markers (>50% inhibition of phosphorylation of AKT and S6). We therefore treated a number of mouse models of diffuse large B-cell lymphomas (e.g. OCI-LY10 xenograft model, Figure 1) with a combination of vistusertib (TORC1/2 inhibitor) and acalabrutinib (BTK inhibitor). Dose -response and pharmacodynamic studies in this mouse model confirmed optimal inhibition of both BTK and mTOR signalling pathways. Further in vivo studies using patient derived models of DLBCL have also demonstrated that this combination is highly efficacious.Conclusions: Based on these data, a phase 1/2 trial of vistusertib plus acalabrutinib in patients with relapsed/refractory DLBCL has opened for accrual (NCT03205046) [Display omitted] DisclosuresBrugger:AstraZeneca: Employment, Equity Ownership. Hattersley:AstraZeneca: Employment, Equity Ownership. Bussey:AstraZeneca: Employment, Equity Ownership. Reimer:AstraZeneca: Employment, Equity Ownership. Tron:AstraZeneca: Employment, Equity Ownership. Staniszewska:AstraZeneca: Employment. Delpuech:AstraZeneca: Employment, Equity Ownership. Carnevalli:AstraZeneca: Employment, Equity Ownership. Krejsa:Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Mayo:AstraZeneca: Employment, Equity Ownership. Neveras:AstraZeneca: Employment, Equity Ownership. San Martin:AstraZeneca: Employment, Equity Ownership. Rideout:AstraZeneca: Employment, Equity Ownership. Proia:AstraZeneca: Employment. Willis:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Cosulich:AstraZeneca: Employment, Equity Ownership.

Clinical BET Inhibitor RG6146 Induces Intrinsic Apoptosis and Down-Regulates PD-L1 Expression and Induces Potent Anti-Tumor Activity in Models of Hematological Malignancy

Bromodomain and extra terminal (BET) family of bromodomains BET proteins are epigenetic ‘readers’ that bind acetylated histone residues and transcription factors at the chromatin interface and drive the expression of oncogenic transcription programs. BET inhibition using small molecules is an anti-cancer strategy being evaluated in early phase clinical trials. RG6146 is a novel small molecule, non-covalent inhibitor of (BET) family of bromodomains and potently inhibits BRD2, BRD3, BRD4 and BRDT. RG6146 is in clinical development for hematological malignancies including diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and solid tumors. In this study, we comprehensively examined the pre-clinical activity of RG6146 in genetically distinct models of hematological malignancy.To understand the effects of BET inhibition on myc-levels and viability hematological malignancies, a panel of human MM and DLBCL cell lines were treated with RG6146 for 24-72 hours. Treatment with RG6146 potently down-regulated c-myc levels that was concomitant with induction of apoptosis and loss of viability.To elucidate additional Myc-independent effects of RG6146, we used the Eμ- Myc model of aggressive B-cell lymphoma where the expression of transgenic Myc is insensitive to BET inhibition. Recapitulating the biological activity of prototypical BET inhibitor JQ1, RG6146 potently activated the intrinsic apoptotic cascade independently of p53 mutational status. Moreover, ectopic Bcl-2 overexpression or genetic loss of Bim were sufficient to attenuate RG6146-induced apoptosis. In the setting of ectopic Bcl-2 expression and protection from apoptosis, RG6146 impairs cell cycle progression leading to G1 cell cycle arrest.We next compared the transcriptional consequences of RG6146 or JQ1 treatment in cell derived from the Eμ- Myc model using RNA sequencing. Acute BET inhibition following 2 hours treatment with JQ1 or RG6146 was associated with a highly concordant modulation of global transcription. Accordingly, gene ontology analysis revealed that identical biological pathways were affected by either inhibitor. As a bona fide BET inhibitor target gene, we demonstrated rapid suppression of Il7r mRNA by qPCR and subsequent loss of cell surface CD127 expression by flow cytometry following exposures to RG6146.Finally, we demonstrate single-agent activity of RG6146 in Eμ- Myc lymphoma-bearing syngeneic recipient mice. Administration of a single-dose of RG6146 significantly depleted tumor cells in the lymph node, spleen, and peripheral blood within 24 hours. Chronic RG6146 therapy was well tolerated in vivo and led to dose-dependent reduction in tumor burden and significant prolongation of survival. In this setting, we also demonstrated that RG6146 therapy suppressed the BRD4-dependent expression of immune checkpoint ligand PD-L1 on Eμ- Myc lymphomas.Taken together, these data indicate that RG6146 is an on-target BET bromodomain inhibitor with potent anti-cancer activity. We demonstrated disruption of the intrinsic apoptotic pathway was sufficient to reduce the activity of RG6146. Moreover, we have previously demonstrated that acquired resistance to BET inhibition is associated with elevated expression of pro-survival Bcl-2 and cell surface CD20 expression. We are now investigating the efficacy RG6146 in combination with BH3 mimetics or monoclonal antibodies. Finally, we are investigating the ability of RG6146 to modulate the immunogenicity of tumors and augment anti-tumor immunity. DisclosuresWellinger:Roche: Employment. Rueflibrasse:Roche: Employment.

A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies

IntroductionDysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple hematological and solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2, blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. Significant anti-tumor activity has been observed in preclinical models of diffuse large B-cell lymphoma (DLBCL), particularly in tumor models that have a mutation in MyD88. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models.The current study is a first-in-human dose escalation and cohort expansion trial of eFT508 in patients with advanced hematological malignanciesMethodsUsing a 3+3 dose escalation schema, cohorts of 3-6 patients (pts) with performance status 0-1, adequate bone marrow, hepatic and renal function and advanced hematological tumors of mainly B cell origin were treated with eFT508 administered orally once daily at a starting dose of 300 mg. A study in pts with solid tumors had previously shown that a dose of 450 mg once daily was well tolerated and based on a pharmacodynamic assay was associated with a degree of target engagement sufficient for maximal efficacy in preclinical models. Efficacy evaluations were performed every 6 weeks.Results6 pts (4 male, 2 female, median age 65 years, range 32-79 years) were treated; 3 at 300 mg daily and 3 at 450 mg daily using an oral suspension of eFT508. 3 pts had DLBCL, 1 had Waldenström macroglobulinemia (WM), 1 had Hodgkin lymphoma (HL) and 1 had follicular lymphoma (FL). The mean number of prior therapies was 4 (range 2-7). Two patients had relapsed after autologous stem cell transplant.The most common adverse events occurring in ≥ 2 pts irrespective of causality, were Grade 1 or 2 unless specified. These included fatigue (n=5), constipation (n=3), hypercalcemia (n=3 with 2 patients experiencing grade 3 toxicity), gastroesophageal reflux (n=2), nausea (n=2) and upper respiratory tract infection (n=2). One of the cases of grade 3 hypercalcemia, felt to be possibly drug related in a patient treated at 450 mg, resolved after a single infusion of zoledronateIn 6 pts evaluated for PK, eFT508 was bioavailable and rapidly absorbed, with a median Tmax of 3 hours and a mean T1/2 of 9.7 hours. Minimal accumulation was observed between Days 1 and 15 in 4 evaluable pts, with a mean accumulation factor of 1.3-fold determined for AUC0-24. Target engagement is being assessed with a pharmacodynamic assay measuring P-eIF4E in peripheral blood cells. In addition, a set of circulating cytokines (including IL-6, IL-8, IL-10, CXCL10 and TNFα) are being measured throughout treatment as MNK1/2 have been shown to regulate cytokine production.Preliminary signs of efficacy were observed with 3 of the 6 pts experiencing stable disease. These included a 32 year old patient with classical HL who had relapsed following multiple lines of chemotherapy, autologous transplant, brentuximab and immune checkpoint inhibition who was treated with 300 mg daily of eFT508. He experienced rapid resolution of B symptoms (fever and night sweats) and at a 6 week scan had a 30% reduction in measurable nodal disease. This nodal reduction was maintained at 12 weeks but a new bone lesion was observedA pt with WM treated at the 450 mg dose level had a reduction in M protein of 22% and remains on treatment for 102 daysA pt with rituximab refractory FL treated at 300 mg remains on treatment with stable disease (6% reduction in tumor volume) for 156 daysConclusionsPreliminary data suggest that eFT508 has acceptable safety and pharmacological activity at the tested dose levels. Dosing has now switched to a capsule formulation that will be used to determine a recommended phase 2 dose. Expansion cohorts for more formal evaluation of efficacy will follow. Updated results will be presented at the ASH meeting. DisclosuresGopal:Seattle Genetics: Consultancy, Research Funding. Ramchandren:Curis: Consultancy; Gilead Sciences: Consultancy; Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Patel:Gilead: Speakers Bureau; Exelixis: Speakers Bureau; Medivation: Speakers Bureau; Genentech: Speakers Bureau; BMS: Speakers Bureau. Miller:Sunesis Pharmaceuticals, Inc: Consultancy; PRONAI Therapeutics, Inc: Consultancy, Equity Ownership; Presage Biosciences, Inc: Consultancy; FLX Bio, Inc: Consultancy; EpiThany, Inc: Consultancy, Equity Ownership; Acerta Pharma, LLC: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cleveland BioLabs, Inc: Employment, Equity Ownership; Oncternal Therapeutics, Inc: Consultancy, Equity Ownership; LAM Therapeutics, Inc: Consultancy, Equity Ownership; eFFECTOR Therapeutics, Inc: Consultancy, Equity Ownership; Zucero Pty Ltd: Consultancy. Goel:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Chiang:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Webster:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Sperry:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Vallner:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Casseday:eFFECTOR THERAPEUTICS: Employment, Equity Ownership. Barton:eFFECTOR THERAPEUTICS: Employment, Equity Ownership.

Circulating Micrornas (miRNA) As a Novel Liquid Biopsy and Therapeutic Platform in MYC and Non-MYC Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Broadly, applicable strategies for liquid biopsies to diagnose and monitor lymphomas could transform patient management and potentially lead to novel therapeutic targets. MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression, contribute to various facets of cancer pathogenesis, and may potentially serve as novel therapeutic targets. We recently identified a key circulating serum miRNA signature (Beheshti et al Plos One 2017) in an in vivo spontaneous DLBCL model (ie, Smurf2T/T; Ramkumar et al. Nat Comm 2013) that was detectable many months prior to the formation of visible tumor. This signature consisted of 10 unique miRNAs (miR-15a, let-7c, let-7b, miR-27a, miR10b, miR-18a, miR-497, miR130a, miR24, and miR155) that each were present/overlapping in 2 lymphoid related organs (i.e., spleen and bone marrow) in addition to the serum in the Smurf2T/Tmodel. We hypothesized that this circulating miRNA signature would be similarly detected and elevated above non-tumor controls in serum of mice with DLBCL patient-derived xenografts (PDX) as well as serum from patients with DLBCL and that these miRNAs may be leveraged as an innovative therapeutic platform.Methods: We utilized multiple MYC- rearranged and -unrearranged DLBCL PDX models (Townsend et al. Cancer Cell 2016) from tumors of patients with DLBCL. Following tumor transplantation, 200μL of serum was drawn from the PDX mice to analyze circulating miRNA. Serum from age-matched NSG mice without xenografts served as controls. We also analyzed circulating miRNAs in PDX models of peripheral T-cell lymphoma (PTCL) and several indolent B-cell lymphomas. Furthermore, we collected 2 mL of serum from 81 patients with DLBCL in the following conditions: untreated (active disease) (n=8); relapsed/refractory (with active disease) (n=11); long-term remission (24+ months) (n=25); and healthy non-tumor bearing individuals for control (n=8). Using Droplet Digital PCR (ddPCR), we quantified the 10 circulated miRNAs in the serum for all PDX and primary human samples. In addition, we targeted the top 4 predicted miRNAs from the signature utilizing novel self-deliverable antagomirs (AUM Biotech) in DLBCL cell lines (SUDHL2, SUDHL4, and SUDHL10) and performed in vitro assays to test cell viability after single antagomir treatment.Results: Comparisons across models identified significant differences in serum miRNA expression between PTCL versus DLBCL PDXs and between indolent versus aggressive B-cell lymphomas (P <0.05), but not between DLBCLs that had MYC alterations versus those lacking MYC alterations (i.e., molecular single translocation or double hits; or protein double expressers of Myc and Bcl2 protein). Examining quantitative ddPCR from serum obtained in the DLBCL PDX models after human tumor implantation, we identified that the miRNA signature was present and highly elevated in DLBCL PDX mice with prominent alterations confirmed in 7 of the 10 miRNAs (Fig. 1A). Furthermore, we identified significantly increased circulating levels of the miRNA signature from the serum of untreated and relapsed/refractory DLBCL patients with similar patterns of change as seen in the PDX models (Fig. 1A) that were independent of cell of origin (COO). In terms of leveraging these miRNAs as a potential therapeutic platform, we targeted the top 4 miRNAs from the aforementioned signature with antagomirs in several DLBCL cell lines (i.e., germinal center and non-germinal center) with one acute dose at 1.6µM for each single self-deliverable antagomir treatment. Four days following this treatment, there was a significant decrease (P <0.01) in cell viability noted for 3 of the 4 miRNAs examined (Fig. 1B).Conclusions: Collectively, we show here that circulating miRNAs established using a murine knockout model of DLBCL have broader application to serum from PDX models and patients with human lymphoma. The circulating miRNA alterations in DLBCL patients appeared to be independent of both MYC alterations and COO, suggesting a broadly applicable approach. Finally, the ease of detection and quantification in as little as 200μL of serum makes this approach an attractive strategy for prospective validation in larger patient cohorts. [Display omitted] DisclosuresEvens:Affimed: Consultancy; AbbVie: Consultancy; Seattle Genetics: Consultancy; Amgen: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; • Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy; Merck: Consultancy.

Novel Combination Therapies with the RNA Polymerase I Inhibitor CX-5461 Significantly Improve Efficacy in Multiple Myeloma

BACKGROUNDrDNA transcription is consistently dysregulated in cancer, mediated through oncogenic and tumour-suppressive pathways, and in particular by cMYC1. RNA polymerase I (Pol I) transcriptional hyperactivity is a consistent feature of many cancers, and has been shown to provide a survival checkpoint in haematological tumour cells2.Our laboratory developed CX-5461, a highly selective small molecule inhibitor of Pol I transcription of ribosomal genes3, currently in a phase 1 clinical trial in relapsed/refractory haematological malignancies (Peter MacCallum Cancer Centre, Australia). CX-5461 induces cell death via a p53-dependent nucleolar surveillance response, and a p53-independent nucleolar-specific DNA damage response (DDR), killing malignant cells while sparing normal cells2,4. We demonstrated that single-agent treatment with CX-5461 provides a significant survival benefit in murine models of B-cell lymphoma, acute myeloid leukaemia and now multiple myeloma (MM)2,4-6. However, despite this improvement, drug resistance eventually occurs, indicating combination drug therapy is essential. AIMto examine the efficacy of CX-5461 in combination with other agents having proven clinical or promising preclinical efficacy in MM. METHODSwe conducted a boutique, high-throughput screen in human myeloma cell lines of CX-5461 combined with a targeted range of agents. We measured the effect of CX-5461 on proliferation, cell death, cell cycle distribution, biomarkers of DDR and on-target effects. The effect of combining CX-5461 with one candidate, the histone deacetylase inhibitor (HDACi) panobinostat, was tested in vivo using both the tVk*MYC murine model of MM6 and in KaLwRij mice transplanted with 5T33 cells. RESULTSCX-5461 showed increased anti-proliferative effect and cell death in combination with multiple drug classes. The proteasome inhibitor carfilzomib and the HDACi panobinostat demonstrated the most impressive synergy with CX-5461. Using both the MYC-driven tVk*MYC model and the non-MYC-driven 5T33-KaLwRij models of MM, we showed that CX-5461 with panobinostat provides a significant survival advantage. Prolonged combination dosing in the slower tVk*MYC model did not cause haematological toxicity beyond that seen with single agents.We are currently interrogating the molecular synergistic response of this combination, including p53-dependent and -independent responses, and the ATM/ATR signalling pathway. Ongoing work is investigating the efficacy of the triplet drug combination of CX-5461, panobinostat and carfilzomib, both in vitro and in vivo. CONCLUSIONCX-5461 shows increased efficacy when combined with multiple drug classes, with panobinostat and carfilzomib showing the most promise in vitro. Combination of CX-5461 with panobinostat produces a survival advantage in both the tVk*MYC and the 5T33-KaLwRij models of MM. These results will direct the subsequent clinical trial using combination drug therapy. REFERENCES1.Bywater et al., Nature Reviews Cancer 20132.Bywater et al., Cancer Cell 20123.Drygin et al., Cancer Research 20114.Quin et al, Oncotarget, 20165.Devlin et al., Cancer Discovery 20166.Hein et al., Blood 20177.Chesi et al., Blood 2012Figure 1. Combination treatment with CX-5461 + panobinostat gives increased survival in the tVk*MYC model of MM. Mice were transplanted with 3.5x10^5 cells, then treatment was started 49 days post-transplant. Mice were treated with CX-5461 35mg/kg orally weekly and panobinostat 7.5mg/kg IP MWF. [Display omitted] DisclosuresHarrison:Celgene: Consultancy, Research Funding, Speakers Bureau.

Establishing Mouse Models of B-Cell Non-Hodgkin's Lymphoma

There are numerous types of B-cell lymphoma including Burkitt lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma/mucosa-associated lymphoid tissue lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma and other less frequent subtypes. However, the molecular pathogenesis of B-cell lymphoma remain largely unknown. Here we chose three different B-cell lymphoma subtype cell lines to establish mouse models, which could be useful to determine the efficacy and mechanisms of novel therapies.Firstly, we injected subcutaneously lymphoma cells into the right axillary region of BALB/c (nu/nu) nude mice. DOHH2 F0, Ly8 F0, Raji F0 appeared 7, 7, 21 days later. When tumors growed to 1.5cm at length, successful passage of mouse models was established by injecting cell suspension obtained from mincing and grinding tumors through a 70-μm cell strainer. The cell suspension was cultured at 37°C in a humidified atmosphere containing 5% CO2. The cells were cryopreserved in cryopreservation-medium (90% FBS, 10% DMSO), stored in liquid nitrogen, thawed again (with a viability of more than 70%) and successfully reconstituted. The above cell lines mouse models have been passaged to the 16th, 18th, 13th generation.For histological examination, an autopsy was performed on each passage of nude mice, and immunohistochmistry was use to determine the expression of surface markers. The tumor tissues from DOHH2 F0, DOHH2 F6, DOHH2 F12 were positive for CD20, cytoplasmic CD3, CD10, CD5, CD21, Ki67, CyclinD1, Bcl-2, Bcl-6. EBV was also detected in situ hybridization. Grade 3B Follicular lymphoma was identified in this B-cell lymphoma and was consistent with the primary origination of DOHH2. Immunohistochemical staining of Ly8 F0, Ly8 F6, Ly8 F12 showed the large atypical cells were positive for CD20, CD3, CD10, Bcl-2, mum-1, no reactivity to antibodies for bcl-6 and negative to EBER. Ki-67 values were graded as 30%. The pathologic expression in Raji F0, Raji F6, Raji F12 is like the following: CD20+/CD3+-/Ki67+-/CD10+/Bcl2+-/ Bcl6- /Mum1+/EBER++.Flow cytometry analysis was performed on cell suspensions cultured from each passage tumor tissues. DOHH2 F0, DOHH2 F6,DOHH2 F12 cells were CD19+/CD20-/CD10+/CD5-/CD38+/HLA-DR+/ CD22+ /CD23+/Ki-67+CD71+, and the kappa light chain was expressed monoclonally. Similar to DOHH2 cells, the serial Ly8 cells were CD19+ /CD20-/CD10+/CD5-/CD38+/HLA-DR+/CD22+/CD23+Ki-67+CD71+/EBER-, and the kappa light chain was expressed monoclonally. As Burkitt lymphoma, Raji and its serial cell clones were CD19+/CD20+/CD10+/CD5-/CD38+/HLA-DR+/CD22+/Ki-67+/CD71+/EBER++.In conclusions, we firstly and systematically established mouse models of B-cell lymphoma and take into passage successfully. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Trph-222, a Novel Anti-CD22 Antibody Drug Conjugate (ADC), Has Signficant Anti-Tumor Activity in NHL Xenografts and Is Well Tolerated in Non-Human Primates

CD22 is a B-cell specific transmembrane glycoprotein belonging to the SIGLEC family of lectins. Its expression is restricted to B lineage cells from the early immature/pre-B-cell stage through the mature naïve stage, and is downregulated on the surface of plasma cells. CD22 is highly expressed on a wide range of malignancies arising from mature B-cells, including NHL (non-Hodgkin's lymphoma), DLBCL (diffuse large B cell lymphoma), MCL (mantle cell lymphoma), MZL, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and small lymphocytic leukemia. The restricted lineage of CD22 and rapid internalization upon antibody binding make CD22 an appealing target for an antibody-drug conjugate (ADC) therapeutic for B cell malignancies. Prior attempts at targeting CD22 using ADC technology have been limited clinically in NHL due to an unacceptable or poor therapeutic index. Subsequently the ADC field has focused on more stable and site specific conjugation of payloads to increase the therapeutic index of ADCs.TRPH-222 is an ADC comprised of an anti-CD22 antibody site-specifically modified at one site in each heavy chain to express formylglycine (FG), allowing for site-specific conjugation of a maytansinoid payload, a protease-insensitive spacer, and a functional group for coupling to an aldehyde on the antibody FG residues. This SMARTAG™ site specific non-cleavable conjugation enforces a maximum drug to antibody ratio (DAR) of 2.0.The aim of this study was to characterize the anti-tumor activity of TRPH-222 in mouse xenografts and tolerability in non-human primates (NHP).In the WSU-DLCL2 xenograft model, once weekly intravenous (IV) dosing of 1, 3 or 10mg/kg or TRPH-222 reduced tumor volume by 51%, 100% and 100% after 28 days. A once every three-week dose of 10mg/kg reduced tumor volume by 100% from pre-dosing measurements. In contrast, rituximab (30mg/kg, weekly) resulted in 55% tumor growth inhibition. In both SU-DHL-2 (DLBCL) and Granta-519 (MCL) xenograft models, weekly dosing at 10mg/kg resulted in tumor stasis.The tolerability and PK of TRPH-222 were evaluated in cynomolgus monkeys. Animals were dosed IV once every 3 weeks (the anticipated clinical dosing schedule) for either 2 (5, 12.5, or 25 mg/kg) or 3 (50 mg/kg) doses. TRPH-222 was well tolerated at all doses evaluated and all animals survived to study termination, with no TRPH-222-related effects on clinical observations or body weight. Aspartate aminotransferase (AST) activity was mildly increased in animals at ≥12.5 mg/kg/dose, while minimal increases in alanine aminotransferase (ALT) activity were noted at 50 mg/kg/dose. Minor microscopic findings of Kupffer cell hypertrophy/hyperplasia were noted in the livers of monkeys treated at 50 mg/kg IV; this finding was not considered adverse based on minimal severity and lack of degeneration/necrosis. Preliminary PK data demonstrate the stability of TRPH-222, as the ratio of the area under the curve (AUC) from day 0-42 for the ADC was ~76-88% that of the antibody backbone suggesting that the ADC has a long half-life and that the linker is stable in vivo.In conclusion, the studies reported here demonstrate that TRPH-222 has significant anti-tumor activity in a range of B-cell lymphoma models and that very high doses of TRPH-222 are well tolerated in monkeys. IND-enabling safety studies are ongoing to support clinical evaluation of TRPH-222 in 2018. These data support the argument that TRPH-222 will have a large therapeutic window due to the stability of conjugation of the maytansinoid payload to the anti-CD22 antibody; doses tolerated in the monkey study described above correspond to human equivalent doses significantly higher than for most ADCs approved or currently under clinical evaluation. To our knowledge, this is the highest dose of a maytansine containing ADC that has been tolerated in monkeys and raises the potential for a best in class therapy for NHL in addition to a best in class ADC technology. DisclosuresMaclaren:Triphase Accelerator: Employment. Levin:Triphase Accelerator: Employment. Lowman:Triphase Accelerator: Employment. Trikha:Triphase Accelerator: Employment; Encycle Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Combined Targeting of the Proteasome and Bcl-2 Sensitizes Human B-Cell Lymphoma and Multiple Myeloma to Cyclophosphamide in In Vitro and In Vivo Models of These Diseases.

The balance of apoptotic proteins is a critical mechanism used by the cell to maintain the mitochondrial transmembrane potential, which plays a critical role in governing apoptosis. Bortezomib (B) is a proteasome inhibitor that selectively inhibits the 26S proteasome, leading to an increase in many intracellular proteins, including proteins that lead to inhibition of NF-kB, as well as proapoptotic proteins like bik and Bax. Oblimersen (Obl) is a 18 mer oligonucleotide results in decreased transcription of the antiapoptotic protein bcl-2. We hypothesized that the mitochondrial membrane potential could be influenced by the co-administration of these agents to favor aopotosis. We report results of pre-clinical in vitro and in vivo experiments using these agents in combination in various lymphoma (NHL) & myeloma (MM) models. NHL & MM cell lines were exposed to Obl in the presence of cationic lipid and incubated for 48 hours. DNA synthesis & cell growth arrest was quantified by 3H-thymidine incorporation assays at 72 hrs, & revealed a concentration dependent cell killing. Induction of apoptosis in the presence or absence of different concentrations of B was detected by multiparameter flow cytometric analysis. Data reveals addition of bortezomib, even at relatively low concentrations (10 nM), additively improved the effects of Obl in all the cell lines studied. A SCID beige model of aggressive large B-cell lymphoma was used by injecting 1x10e7 cells (SKI-DLCL-1 or RL, a cell line over expressing bcl-2 through the 14:18 translocation) as a subcutaneous flank tumor. In over 6 in vivo experiments, the combination of B (0.5 mg/kg days 3 & 7) + Obl (3 mg/kg days 1,3,5, &7) consistently resulted in about 50% inhibition of growth of both SKI-DLCL-1 & RL compared to that in the control. Surprisingly, results were evident even using a low dose schedule of bortezomib (about one quarter of the MTD), suggesting the possibility of a small sensitizing dose of this drug. In all experiments, growth delay seen with the doublet exceeded the results noted with any singlet (B or Obl alone). Integration of cyclophosphamide at a dose of 50 mg/kg produced marked tumor shrinkage that appeared synergistic in several circumstances. Single agent CTX produced excellent growth delay (similar to any doublet), but in all these cases, tumor re-growth was evident by 21–25 days post tumor transplant. CTX dose & schedule was also important. Same day ‘lump and dump' of all drugs failed to effect cured, while CTX preceding B consistently produced best results, with cures found only in this triplet cohort. Results suggest that optimal scheduling of agents requires a ‘lead in' exposure of Obl, followed by CTX preceding all doses of bortezomib. These studies support the efficacy of this regimen.

NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy

BackgroundNKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and...

Intraperitoneal Glucose Transport to Micrometastasis: A Multimodal In Vivo Imaging Investigation in a Mouse Lymphoma Model.

Bc-DLFL.1 is a novel spontaneous, high-grade transplantable mouse B-cell lymphoma model for selective serosal propagation. These cells attach to the omentum and mesentery and show dissemination in mesenteric lymph nodes. We aimed to investigate its early stage spread at one day post-intraperitoneal inoculation of lymphoma cells (n = 18 mice), and its advanced stage at seven days post-inoculation with in vivo [18F]FDG-PET and [18F]PET/MRI, and ex vivo by autoradiography and Cherenkov luminescence imaging (CLI). Of the early stage group, nine animals received intraperitoneal injections, and nine received intravenous [18F]FDG injections. The advanced stage group (n = 3) received intravenous FDG injections. In the early stage, using autoradiography we observed a marked accumulation in the mesentery after intraperitoneal FDG injection. Using other imaging methods and autoradiography, following the intravenous injection of FDG no accumulations were detected. At the advanced stage, tracer accumulation was clearly detected in mesenteric lymph nodes and in the peritoneum after intravenous administration using PET. We confirmed the results with immunohistochemistry. Our results in this model highlight the importance of local FDG administration during diagnostic imaging to precisely assess early peritoneal manifestations of other malignancies (colon, stomach, ovary). These findings also support the importance of applying topical therapies, in addition to systemic treatments in peritoneal cancer spread.

Establishment of a typing model for diffuse large B-cell lymphoma based on B-cell receptor repertoire sequencing

BackgroundThe purpose of this study was to construct a new typing model for diffuse large B-cell lymphoma (DLBCL) patients based on the B-cell receptor (BCR) and explore its potential molecular mechanism.MethodsBCR repertoire sequencing and whole-exome sequencing were performed on formalin-fixed paraffin-embedded samples from 12 DLBCL patients. Subsequently, a typing model was built with cluster analysis, and prognostic indicators between the two groups were compared to verify the typing model. Then, mutation and bioinformatics analyses were conducted to investigate the potential biomarkers of prognostic differences between the two groups.ResultsBased on BCR sequencing data, we divided patients into two clusters (cluster 1 and cluster 2); this classification differed from the traditional typing method (GCB and non-GCB), in which cluster 1 included some non-GCB patients. The progression-free survival (PFS), overall survival (OS), metastasis and Shannon diversity index of IGH V-J and survival after chemotherapy were significantly different (P < 0.05) between the two clusters, but no statistical significance was found between the GCB and non-GCB groups. The mutation status of 248 genes was significantly different between cluster 1 and cluster 2. Among them, FTSJ3, MAGED2, and ODF3L2 were the specific mutated genes in all patients in cluster 2, and these genes could be considered critical to the different prognoses of the two clusters of DLBCL patients.ConclusionWe constructed a new typing model of DLBCL based on BCR repertoire sequencing that can better predict the survival time after chemotherapy. FTSJ3, MAGED2, and ODF3L2 may represent key genes for the difference in prognosis between the two clusters.

Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma

Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.

Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy

Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.

BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

A New PET Probe for Imaging Chimeric Antigen Receptor T Cells.

HomeRadiology: Imaging CancerVol. 3, No. 2 PreviousNext Research HighlightsFree AccessA New PET Probe for Imaging Chimeric Antigen Receptor T CellsGary D. LukerGary D. LukerGary D. LukerPublished Online:Mar 26 2021https://doi.org/10.1148/rycan.2021219004MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: To investigate the feasibility of imaging chimeric antigen receptor (CAR) T cells with a zirconium 89–labeled antibody targeted to inducible T-cell costimulator (ICOS or CD278).■ Key Result: ImmunoPET imaging of ICOS enabled the visualization of activated CAR T cells without affecting persistence or function of these cells in a mouse model of B-cell lymphoma.■ Impact: ImmunoPET with antibody detection of the endogenous activation marker ICOS provides a potentially general approach to image any CAR T-cell therapy.CAR T cells are a type of cancer therapy based on engineering a patient’s own T cells with a receptor for a specific protein target on cancer cells. After expansion of the cells in a laboratory, a patient receives an infusion of the engineered CAR T cells. For efficacy, the cells must migrate to tumors, proliferate, as well as become and remain activated to kill target cancer cells. CAR T cells have shown impressive successes in some blood cancers, such as B-cell malignancies, but efficacy remains limited in solid tumors. A major challenge in understanding successes and failures of CAR T-cell therapy is the ability to monitor these cells in vivo. Current methods rely on measuring numbers of cells in the circulation, but this approach does not reliably reflect actual migration of CAR T cells into a tumor.Simonetta and colleagues analyzed human and mouse CAR T cells and identified ICOS as a promising marker of activation to an antitumor state. The team labeled an antibody to ICOS with zirconium 89, providing a probe for PET imaging of CAR T cells in a mouse model of B-cell lymphoma. PET imaging showed greater accumulation of the immunoPET probe to ICOS in mouse bone marrow sites of lymphoma. Tracer doses of the immunoPET antibody did not affect persistence or function of CAR T cells as cancer immunotherapeutics. While the current study investigated therapy in mice, the study suggests that immunoPET imaging of ICOS could become a clinically translatable, general approach to monitor cancer therapy with a wide range of CAR T cells.Highlighted ArticleSimonetta F, Alam IS, Lohmeyer JK, et al. Molecular imaging of chimeric antigen receptor T cells by ICOS-ImmunoPET. Clin Cancer Res 2021;27:1058–1068. doi: https://doi.org/10.1158/1078-0432.CCR-20-2770Highlighted ArticleSimonetta F, Alam IS, Lohmeyer JK, et al. Molecular imaging of chimeric antigen receptor T cells by ICOS-ImmunoPET. Clin Cancer Res 2021;27:1058–1068. doi: https://doi.org/10.1158/1078-0432.CCR-20-2770 Crossref, Medline, Google ScholarArticle HistoryPublished online: Mar 26 2021 FiguresReferencesRelatedDetailsRecommended Articles CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human ImagingRadiology2020Volume: 295Issue: 3pp. 606-615Nanotechnology for Cancer Imaging: Advances, Challenges, and Clinical OpportunitiesRadiology: Imaging Cancer2021Volume: 3Issue: 318F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in CancerRadiology2022Volume: 304Issue: 2pp. 246-264Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CTRadiology2020Volume: 296Issue: 2pp. 370-378Radiotheranostics in Cancer Diagnosis and ManagementRadiology2018Volume: 286Issue: 2pp. 388-400See More RSNA Education Exhibits Immune Effector Cell Therapy for Solid Tumors: Opportunities for Interventional RadiologyDigital Posters2019When Things Go Wrong, Characteristic PET CT Patterns of Triple and Double-Hit Lymphoma; A Pictorial ReviewDigital Posters2018Imaging Biomarkers in Targeted Therapies: From Quantitative Imaging to RadiomicsDigital Posters2019 RSNA Case Collection Benign bone marrow stimulation RSNA Case Collection2020Primary Calvarial Lymphoma RSNA Case Collection2021Primary Bone LymphomaRSNA Case Collection2020 Vol. 3, No. 2 Metrics Altmetric Score PDF download