The Outer Retinal Membrane Protein 1 Could Inhibit Lung Cancer Progression as a Tumor Suppressor.

Some related reports indicate that the outer retinal membrane protein 1 (ROM1) functions importantly in the regulation of the biological process of tumor. Nevertheless, studies towards the role of ROM1 in lung cancer are few. Here, our data demonstrated that ROM1 displayed a relation with lung cancer tumorigenesis and development. In the Tumor Genome Atlas (TCGA) cohort, reduced ROM1 level was observed in lung cancer tissues, instead of normal tissues. After bioinformatics analysis, the data revealed that ROM1 level was associated with the tumor stage. Additional results indicated that highly expressed ROM1 exhibited a positive correlation with the overall survival rate, and ROM1 was probably a promising prognostic biomarker of lung cancer. Additionally, our results indicated that knocking out ROM1 could promote cell proliferation, migration, and invasion. Our data conclusively demonstrated that ROM1 modulated lung cancer tumorigenesis and development, as a prognosis and treatment biomarker.

miR-573 suppresses pancreatic cancer cell proliferation, migration, and invasion through targeting TSPAN1.

PURPOSE: To explore whether miR-573 can suppress pancreatic cancer cell proliferation, migration, and invasion by targeting TSPAN1. METHODS: The expression of miR-573 and TSPAN1 in pancreatic cancer tissues and cells lines was analyzed using RT-qPCR. The human pancreatic cancer cell line PANC­1 was transfected with miR-573 mimic, pcDNA3.1-TSPAN1, or genOFFTM st-h-TSPAN1. The effects of miR-573 and TSPAN1 on cell proliferation, colony formation, migration, and invasion were analyzed by CCK­8, colony formation, transwell migration, and invasion assay, respectively. Target genes of miR-573 were screened using bioinformatics tools and confirmed by dual-luciferase reporter assay and real-time PCR. The effects of miR-573 in vivo were observed using tumor xenografts. RESULTS: We found that miR-573 is downregulated and TSPAN1 is upregulated in pancreatic cancer tissues and cells lines. Function assays demonstrated that overexpression of miR-573 inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells, as well as suppressing tumor growth in vivo. Target genes of miR-573 were predicted using bioinformatics tools and confirmed by dual-luciferase reporter assay and RT-qPCR or western blotting. Downregulation of TSPAN1 also inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells. Furthermore, overexpression of TSPAN1 attenuated miR-573-induced inhibition of pancreatic cancer cell proliferation and migration. CONCLUSION: Our findings indicated that miR-573 suppresses pancreatic cancer cell proliferation, migration, and invasion through targeting TSPAN1. TSPAN1 targeted by miR-573 might be a potential therapeutic target for clinical treatment of pancreatic cancer.

Targeted alpha therapy for chronic lymphocytic leukaemia and non-Hodgkin's lymphoma with the anti-CD37 radioimmunoconjugate 212Pb-NNV003.

Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy.

Tetraspanin 8 (TSPAN8) is a member of the tetraspanin superfamily that forms TSPAN8-mediated protein complexes by interacting with themselves and other various cellular signaling molecules. These protein complexes help build tetraspanin-enriched microdomains (TEMs) that efficiently mediate intracellular signal transduction. In physiological conditions, TSPAN8 plays a vital role in the regulation of biological functions, including leukocyte trafficking, angiogenesis and wound repair. Recently, reports have increasingly shown the functional role and clinical relevance of TSPAN8 overexpression in the progression and metastasis of several cancers. In this review, we will highlight the physiological and pathophysiological roles of TSPAN8 in normal and cancer cells. Additionally, we will cover the current status of monoclonal antibodies specifically targeting TSPAN8 and the importance of TSPAN8 as an emerging therapeutic target in cancers for monoclonal antibody therapy.

Inhibition of Tetraspanin Functions Impairs Human Papillomavirus and Cytomegalovirus Infections.

Tetraspanins are suggested to regulate the composition of cell membrane components and control intracellular transport, which leaves them vulnerable to utilization by pathogens such as human papillomaviruses (HPV) and cytomegaloviruses (HCMV) to facilitate host cell entry and subsequent infection. In this study, by means of cellular depletion, the cluster of differentiation (CD) tetraspanins CD9, CD63, and CD151 were found to reduce HPV16 infection in HeLa cells by 50 to 80%. Moreover, we tested recombinant proteins or peptides of specific tetraspanin domains on their effect on the most oncogenic HPV type, HPV16, and HCMV. We found that the C-terminal tails of CD63 and CD151 significantly inhibited infections of both HPV16 and HCMV. Although CD9 was newly identified as a key cellular factor for HPV16 infection, the recombinant CD9 C-terminal peptide had no effect on infection. Based on the determined half-maximal inhibitory concentration (IC50), we classified CD63 and CD151 C-terminal peptides as moderate to potent inhibitors of HPV16 infection in HeLa and HaCaT cells, and in EA.hy926, HFF (human foreskin fibroblast) cells, and HEC-LTT (human endothelial cell-large T antigen and telomerase) cells for HCMV, respectively. These results indicate that HPV16 and HCMV share similar cellular requirements for their entry into host cells and reveal the necessity of the cytoplasmic CD151 and CD63 C-termini in virus infections. Furthermore, this highlights the suitability of these peptides for functional investigation of tetraspanin domains and as inhibitors of pathogen infections.

Anti-CD37 targeted immunotherapy of B-Cell malignancies.

CD37 is a member of tetra-spanning superfamily (characterized by their four transmembrane domains). It is one of the specific proteins for normal and malignant mature B cells. Anti CD37 monoclonal antibodies are reported to improve the overall survival in CLL. These therapeutics will increase the efficacy and reduce the toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics. Long-term follow-up of combination regimens has even raised the question of whether the patients with CLL could be treated with intensive chemo-immunotherapy. In the present study, CD37 is introduced as an appealing target to treat B cell malignancies. The anti-CD37 antibodies as one of the most successful therapeutics against CD37 are introduced and the clinical outcomes of their exploitation are explained.

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas.

Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment of patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin lymphomas, in chronic lymphocytic leukemia, and in some cases of cutaneous and peripheral T-cell lymphomas. We found that CAR-37 T cells demonstrated antigen-specific activation, cytokine production, and cytotoxic activity in models of B- and T-cell lymphomas in vitro and in vivo, including patient-derived xenografts. Taken together, these results are the first showing that T cells expressing anti-CD37 CAR have substantial activity against 2 different lymphoid lineages, without evidence of significant T-cell fratricide. Furthermore, anti-CD37 CARs were readily combined with anti-CD19 CARs to generate dual-specific CAR T cells capable of recognizing CD19 and CD37 alone or in combination. Our findings indicate that CD37-CAR T cells represent a novel therapeutic agent for the treatment of patients with CD37-expressing lymphoid malignancies.

Monocyte Subsets Have Distinct Patterns of Tetraspanin Expression and Different Capacities to Form Multinucleate Giant Cells.

Monocytes are able to undergo homotypic fusion to produce different types of multinucleated giant cells, such as Langhans giant cells in response to M. tuberculosis infection or foreign body giant cells in response to implanted biomaterials. Monocyte fusion is highly coordinated and complex, with various soluble, intracellular, and cell-surface components mediating different stages of the process. Tetraspanins, such as CD9, CD63, and CD81, are known to be involved in cell:cell fusion and have been suggested to play a role in regulating homotypic monocyte fusion. However, peripheral human monocytes are not homogenous: they exist as a heterogeneous population consisting of three subsets, classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14+CD16+), at steady state. During infection with mycobacteria, the circulating populations of intermediate and non-classical monocytes increase, suggesting they may play a role in the disease outcome. Human monocytes were separated into subsets and then induced to fuse using concanavalin A. The intermediate monocytes were able to fuse faster and form significantly larger giant cells than the other subsets. When antibodies targeting tetraspanins were added, the intermediate monocytes responded to anti-CD63 by forming smaller giant cells, suggesting an involvement of tetraspanins in fusion for at least this subset. However, the expression of fusion-associated tetraspanins on monocyte subsets did not correlate with the extent of fusion or with the inhibition by tetraspanin antibody. We also identified a CD9High and a CD9Low monocyte population within the classical subset. The CD9High classical monocytes expressed higher levels of tetraspanin CD151 compared to CD9Low classical monocytes but the CD9High classical subset did not exhibit greater potential to fuse and the role of these cells in immunity remains unknown. With the exception of dendrocyte-expressed seven transmembrane protein, which was expressed at higher levels on the intermediate monocyte subset, the expression of fusion-related proteins between the subsets did not clearly correlate with their ability to fuse. We also did not observe any clear correlation between giant cell formation and the expression of pro-inflammatory or fusogenic cytokines. Although tetraspanin expression appears to be important for the fusion of intermediate monocytes, the control of multinucleate giant cell formation remains obscure.

Immune Targeting of Tetraspanins Involved in Cell Invasion and Metastasis.

Metastasis is the ultimate consequence of cancer progression and the cause of patients' death across different cancer types. Patients with initial diagnosis of distant disease have a worst 5-year survival compared to patients with localized disease. Therapies that target primary tumors fail to eradicate distant dissemination of cancer. Recently, immunotherapies have improved the survival of patients with metastatic disease, such as melanoma and lung cancer. However, only a fraction of patients responds to immunotherapy modalities that target the host immune system. The need to identify new druggable targets that inhibit or prevent metastasis is, therefore, much needed. Tetraspanins have emerged as key players in regulating cell migration, invasion, and metastasis. By serving as molecular adaptors that cluster adhesion receptors, signaling molecules, and cell surface receptors; tetraspanins are involved in all steps of the metastatic cascade. They regulate cell proliferation, participate in EMT transition, modulate integrin-mediated cell adhesion, and participate in angiogenesis and invasion processes. Tetraspanins have also been shown to modulate metastasis indirectly through exosomes and by regulating cellular interactions in the immune system. Importantly, targeting individual tetraspanin with antibodies has impacted tumor progression. This review will focus on the contribution of tetraspanins to the metastatic process and their potential as therapeutic tumor targets.

TSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-κB signaling.

Beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) is crucial for the degradation of IκBα. Our previous transcriptome sequencing analysis revealed that tetraspanin 15 (TSPAN15) was significantly upregulated in clinical oesophageal squamous cell carcinoma (OSCC) tissues. Here, we show that high TSPAN15 expression in OSCC tissues is significantly associated with lymph node and distant metastasis, advanced clinical stage, and poor prognosis. Elevated TSPAN15 expression is, in part, caused by the reduction of miR-339-5p. Functional studies demonstrate that TSPAN15 promotes metastatic capabilities of OSCC cells. We further show that TSPAN15 specifically interacts with BTRC to promote the ubiquitination and proteasomal degradation of p-IκBα, and thereby triggers NF-κB nuclear translocation and subsequent activation of transcription of several metastasis-related genes, including ICAM1, VCAM1, uPA, MMP9, TNFα, and CCL2. Collectively, our findings indicate that TSPAN15 may serve as a new biomarker and/or provide a novel therapeutic target to OSCC patients.

Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study.

Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.

We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.

Tetraspanin 8 (TSPAN 8) as a potential target for radio-immunotherapy of colorectal cancer.

Tetraspanin 8 (TSPAN8) overexpression is correlated with poor prognosis in human colorectal cancer (CRC). A murine mAb Ts29.2 specific for human TSPAN8 provided significant efficiency for immunotherapy in CRC pre-clinical models. We therefore evaluate the feasability of targeting TSPAN8 in CRC with radiolabeled Ts29.2. Staining of tissue micro-arrays with Ts29.2 revealed that TSPAN8 espression was restricted to a few human healthy tissues. DOTA-Ts29.2 was radiolabeled with 111In or 177Lu with radiochemical purities >95%, specific activity ranging from 300 to 600 MBq/mg, and radioimmunoreactive fractions >80%. The biodistribution of [111In]DOTA-Ts29.2 in nude mice bearing HT29 or SW480 CRC xenografts showed a high specificity of tumor localization with high tumor/blood ratios (HT29: 4.3; SW480-TSPAN8: 3.9 at 72h and 120h post injection respectively). Tumor-specific absorbed dose calculations for [177Lu]DOTA-Ts29.2 was 1.89 Gy/MBq, establishing the feasibility of using radioimmunotherapy of CRC with this radiolabeled antibody. A significant inhibition of tumor growth in HT29 tumor-bearing mice treated with [177Lu]DOTA-Ts29.2 was observed compared to control groups. Ex vivo experiments revealed specific DNA double strand breaks associated with cell apoptosis in [177Lu]DOTA-Ts29.2 treated tumors compared to controls. Overall, we provide a proof-of-concept for the use of [111In/177Lu]DOTA-Ts29.2 that specifically target in vivo aggressive TSPAN8-positive cells in CRC.

TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495.

Studies have shown that TSPAN12 serves as an oncogenic gene or tumor suppressor depending on the types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) is still unknown. In this study, we investigated whether TSPAN12 regulates chemoresistance, proliferation and tumor growth of SCLC under the regulation of miR-495 using two drug resistant cell lines. The results showed that down-regulation of TSPAN12 inhibited cells chemoresistance, proliferation and tumor growth. Besides, TSPAN12 elevation in SCLC specimens correlated with poor pathologic stage and shorter survival time. In addition, the dual luciferase assay indicated that TSPAN12 was one of the directly targeted genes of miR-495. Our study revealed that TSPAN12 promoted chemoresistance of SCLC under the regulation of miR-495. TSPAN12 depletion is a promising strategy for inhibiting the chemoresistance in SCLC.

Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of ß-Catenin Signaling.

BACKGROUND: Anti-angiogenic biologicals represent an important concept for the treatment of vasoproliferative diseases. However, the need for continued treatment, the presence of nonresponders, and the risk of long-term side effects limit the success of existing therapeutic agents. Although Tspan12 has been shown to regulate retinal vascular development, nothing is known about its involvement in neovascular disease and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. METHODS: Rodent models of retinal neovascular disease, including the mouse model of oxygen-induced retinopathy and the very low density lipoprotein receptor knockout mouse model were analyzed for Tspan/ß-catenin regulation. Screening of a phage display of a human combinatorial antibody (Ab) library was used for the development of a high-affinity Ab against Tspan12. Therapeutic effects of the newly developed Ab on vascular endothelial cells were tested in vitro and in vivo in the oxygen-induced retinopathy and very low density lipoprotein receptor knockout mouse model. RESULTS: The newly developed anti-Tspan12 Ab exhibited potent inhibitory effects on endothelial cell migration and tube formation. Mechanistic studies confirmed that the Ab inhibited the interaction between Tspan12 and Frizzled-4 and effectively modulates ß-catenin levels and target genes in vascular endothelial cells. Tspan12/ß-catenin signaling was activated in response to acute and chronic stress in the oxygen-induced retinopathy and very low density lipoprotein receptor mouse model of proliferative retinopathy. Intravitreal application of the Ab showed significant therapeutic effects in both models without inducing negative side effects on retina function. Moreover, combined intravitreal injection of the Ab with a known vascular endothelial growth factor inhibitor, Aflibercept, resulted in significant enhancement of the therapeutic efficacy of each monotherapy. Combination therapy with the Tspan12 blocking antibody can be used to reduce anti-vascular endothelial growth factor doses, thus decreasing the risk of long-term off-target effects. CONCLUSIONS: Tspan12/ß-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents.

Red Marrow-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody-Radionuclide Conjugate.

Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. 177Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity. METHODS: Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the 177Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of 177Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity. CONCLUSION: Predosing with lilotomab reduces the RM-absorbed dose for 177Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images.

Tumor-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with the Anti-CD37 Antibody Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan.

177Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate currently tested in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin lymphoma. The aim of this work was to develop dosimetric methods and calculate tumor-absorbed radiation doses for patients treated with 177Lu-lilotomab satetraxetan. METHODS: Patients were treated at escalating injected activities (10, 15 and 20 MBq/kg) of 177Lu-lilotomab satetraxetan and with different predosing, with or without 40 mg of unlabeled lilotomab. Eight patients were included for the tumor dosimetry study. Tumor radioactivity concentrations were calculated from SPECT acquisitions at multiple time points, and tumor masses were delineated from corresponding CT scans. Tumor-absorbed doses were then calculated using the OLINDA sphere model. To perform voxel dosimetry, the SPECT/CT data and an in-house-developed MATLAB program were combined to investigate the dose rate homogeneity. RESULTS: Twenty-six tumors in 8 patients were ascribed a mean tumor-absorbed dose. Absorbed doses ranged from 75 to 794 cGy, with a median of 264 cGy across different dosage levels and different predosing. A significant correlation between the dosage level and tumor-absorbed dose was found. Twenty-one tumors were included for voxel dosimetry and parameters describing dose-volume coverage calculated. The investigation of intratumor voxel doses indicates that mean tumor dose is correlated to these parameters. CONCLUSION: Tumor-absorbed doses for patients treated with 177Lu-lilotomab satetraxetan are comparable to doses reported for other radioimmunotherapy compounds. Although the intertumor variability was considerable, a correlation between tumor dose and patient dosage level was found. Our results indicate that mean dose may be used as the sole dosimetric parameter on the lesion level.

New uses for brentuximab vedotin and novel antibody drug conjugates in lymphoma.

INTRODUCTION: Brentuximab vedotin (BV) is a potent anti-CD30 antibody drug conjugate (ADC) that has been approved in relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT) and anaplastic large-cell lymphoma (ALCL). Beyond these consolidated indications, BV has been tested in a number of different settings with promising results, leading for example to the recent approval as a consolidation after ASCT in high-risk HL patients. AREAS COVERED: Main emerging areas of clinical investigation of BV include the use as a single-agent or in combination with bendamustine in first-salvage therapy of HL (bridge to ASCT), in the frontline setting in combination with AVD chemotherapy in HL and with CHP in ALCL, in relapsed or refractory cutaneous T-cell lymphomas and finally in diffuse large B-cell lymphomas (DLBCL) expressing CD30. Moreover, many new ADCs are currently under clinical evaluation, as for example the anti-CD79A polatuzumab vedotin in DLBCL. Expert commentary: In few years BV changed the therapeutic scenario of relapsed or refractory HL and ALCL and is rapidly moving toward first-line approval in combination with standard chemotherapy if ongoing randomized trials will demonstrate improved results. Combination strategies with bendamustine in first-salvage HL and with R-CHP in first-line DLBCL appear very promising.

Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis.

Epithelial ovarian cancer (EOC) invasion and metastasis are complex phenomena that result from the coordinated action of many metastatic regulators and must be overcome to improve clinical outcomes for patients with these cancers. The identification of novel therapeutic targets is critical because of the limited success of current treatment regimens, particularly in advanced-stage ovarian cancers. In this study, we found that tetraspanin 8 (TSPAN8) is overexpressed in about 52% (14/27) of EOC tissues and correlates with poor survival. Using small interfering RNA-mediated TSPAN8 knockdown and a competition assay with purified TSPAN8 large extracellular loop (TSPAN8-LEL) protein, we identified TSPAN8-LEL as a key regulator of EOC cell invasion. Furthermore, monotherapy with TSPAN8-blocking antibody we developed shows that antibody-based modulation of TSPAN8-LEL can significantly reduce the incidence of EOC metastasis without severe toxicity in vivo. Finally, we demonstrated that the TSPAN8-blocking antibody promotes the internalization and concomitant downregulation of cell surface TSPAN8. Collectively, our data suggest TSPAN8 as a potential novel therapeutic target in EOCs and antibody targeting of TSPAN8 as an effective strategy for inhibiting invasion and metastasis of TSPAN8-expressing EOCs.