TRU-016, An Anti-CD37 SMIP™ Biologic, In Combination with Other Therapeutic Drugs In Models of Non-Hodgkin's Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3931-3931 ◽  
Author(s):  
Paul A. Algate ◽  
Jennifer Wiens ◽  
Christy Nilsson ◽  
Mien Sho ◽  
Debra T. Chao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
Combination Index ◽  
Growth Delay ◽  
Tumor Growth Delay ◽  
B Cell Malignancies

Abstract Abstract 3931 Background: CD37 is a 50–55 kDa heavily glycosylated member of the tetraspanin superfamily of molecules. This cell surface protein is expressed on normal and transformed B-cells, and has been implicated in diverse processes including cellular activation and proliferation, cell motility, and cell-cell adhesion. TRU-016 is a novel humanized anti-CD37 SMIP™ protein. Pre-clinical studies have demonstrated that anti-CD37 SMIP™ protein mediates caspase-independent direct killing of normal and malignant B-cells, a mechanism of action that appears to be different than CD20 therapies. In addition, TRU-016 results in indirect killing through NK cell mediated SMIP-protein directed cellular cytotoxicity (SDCC). The therapeutic potential of TRU-016 against several subsets of B-cell malignancies is currently being investigated in the clinic. Methods: The ability of TRU-016 to interact and increase cell killing with established therapeutics rituximab (anti-CD20 antibody), bendamustine (bi-functional alkylating agent/nucleoside analog), LY294002 (PI3K inhibitor) and temsirolimus (mTOR inhibitor) was investigated in vitro using the Rec-1 (mantle cell lymphoma) and SU-DHL-6 (diffuse large B cell lymphoma) cell lines. Individual drugs were tested in combination with TRU-016 as well as in a multiple drug cocktail. Combination index analyses were performed for drug combinations over the 20–90% effect levels. To determine whether in vitro synergy could be recapitulated in vivo, DoHH-2 (follicular lymphoma) xenografts were treated with TRU-016, bendamustine, and the combination of TRU-016 and bendamustine with or without rituximab. Furthermore, the effect of the dosing schedule with the combination of TRU-016 and rituximab was explored by comparing the treatment over a short time period to an extended (maintenance) dosing regimen. CD37 expression on the tumor xenografts was evaluated post different treatment by immunohistochemistry. Results: Combination index analyses determined that the killing effects of TRU-016 was synergistic with rituximab, bendamustine and temsirolimus in NHL models. Furthermore, TRU-016 provided additional efficacy when added to the combination of rituximab and bendamustine. In vivo results demonstrated that the in vitro synergy results were applicable to a more complex in vivo disease model. The combination of TRU-016 with bendamustine or rituximab resulted in increased tumor growth delay compared to that attained with the individual drugs. The addition of TRU-016 to the combination of bendamustine and rituximab resulted in increased tumor growth delay compared to the two drugs alone. The observed efficacy of the combination of TRU-016 and rituximab could be extended with repeated (maintenance) dosing with tumor free survival being observed beyond the 35 days of dosing. The combination of TRU-016 with temsirolimus also resulted in a reduction of tumor growth compared to either molecule alone. CD37 target expression was detected in the xenograft tumors post-treatment with all drugs tested. Conclusions: TRU-016 in combination with rituximab, bendamustine or temsirolimus increased cell killing of NHL cells in vitro over that observed for each agent alone. Furthermore, the triple combination of TRU-016 with rituximab, bendamustine or temsirolimus displayed greater anti-tumor activity in vivo than each of the agents alone against a follicular lymphoma tumor model. The addition of TRU-016 to a combination of rituximab and bendamustine resulted in increased killing in vitro and in vivo. The combinatorial activity of TRU-016 and rituximab in vivo was increased when the drugs were administered over a longer period. These results provide preclinical rationale for the potential different combinations of TRU-016 with several established therapeutics for the treatment of NHL and related B-cell malignancies. Disclosures: Algate: Trubion Pharmaceuticals: Employment. Wiens:Trubion Pharmaceuticals: Employment. Nilsson:Trubion Pharmaceuticals: Employment. Sho:Facet/Abbott: Employment. Chao:Facet/Abbott: Employment. Starling:Facet/Abbott: Employment. Gordon:Trubion Pharmaceuticals: Employment.

scholarly journals Development of Multi-Engineered iPSC-Derived CAR-NK Cells for the Treatment of B-Cell Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1729-1729
Author(s):  
Luis Borges ◽  
Mark A Wallet ◽  
Chiamin-Liao Bullaughey ◽  
Michael F Naso ◽  
Buddha Gurung ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
B Cell ◽  
Nk Cells ◽  
Stock Options ◽  
Tumor Growth Inhibition ◽  
B Cell Malignancies ◽  
Privately Held

Abstract Induced-pluripotent stem cells (iPSCs) can be differentiated into various somatic cells, including different immune cell types. We have engineered iPSC-derived NK cells with multiple features to generate therapeutic candidates designed to eliminate cancer cells while avoiding recognition by the host immune system. The unlimited replication capacity of iPSCs facilitates the engineering of several genetic modifications without the risk of driving cells to exhaustion as in the case of cell products derived from fully differentiated immune cells. Once all edits are completed, our cells are single-cell cloned and each clone is genetically characterized to select clones without off-target insertions or deletions. Following the genetic characterization, selected clones are differentiated and tested in vitro and in vivo to identify the final clinical candidate. The use of a single-cell iPSC clone enables the generation of a master cell bank producing a highly uniform cell product that can be made available off-the-shelf at any clinical site. CNTY-101 is an iPSC-derived CAR-NK clinical candidate for the treatment of B-cell malignancies. It incorporates six gene edits designed to improve persistence and functionality as well as safety. These modifications include edits to reduce graft rejection due to alloreactivity, the expression of a homeostatic cytokine to improve functionality and persistence, the introduction of a chimeric antigen receptor (CAR) targeting CD19 to mediate tumor cell engagement and killing, as well a safety switch to eliminate the cells, if ever necessary. To prevent rejection by the patient's CD8 T cells, the beta-2-microbulin (ß2M) gene was disrupted with simultaneous insertion of a transgene encoding the HLA-E protein tethered with ß2M and a peptide. HLA-E was introduced to prevent NK cell cytotoxicity against the engineered cells, which lack HLA-I. For resistance to CD4 T cell-mediated allogenic immune rejection, the class II major histocompatibility complex transactivator (CIITA) gene was disrupted with simultaneous insertion of a transgene encoding the extra-cellular and transmembrane domains of EGFR, and the NK cell growth factor IL-15. EGFR provides an elimination tag that can be engaged by clinically approved anti-EGFR antibodies, such as cetuximab. Finally, the CAR transgene targeting the CD19 antigen was inserted into the AAVS1 safe harbor locus. Our data indicates that CNTY-101 iNK cells have strong antitumor activity against lymphoma cell lines both in vitro and in vivo. In vitro, CNTY-101 eliminates lymphoma cell lines through multiple rounds of killing without reaching exhaustion. Clones expressing higher levels of IL-15 tend to have better persistence and functionality, with some clones showing robust cytotoxicity for over fifteen rounds of serial killing. In vivo, the clones that demonstrated better in vitro serial killing tend to mediate the best anti-tumor activity in lymphoma xenograft models. Upon 3 weekly doses, the most active candidate clone demonstrated significant tumor growth inhibition after administration of fresh (91 % tumor growth inhibition) or cryopreserved cells (76 % tumor growth inhibition). The efficacy of the EGFR-safety switch was also investigated both in vitro and in vivo. In vitro, addition of cetuximab to co-cultures of IL-2-activated PBMC and cells mediated antibody-dependent cellular cytotoxicity (ADCC) in a concentration-dependent fashion, with an EC50 of 2 ng/ml. In vivo, there was a 96% reduction in the number of iPSC-derived CAR-NK cells in the lungs and a 95% reduction in the number of CAR-NK cells in the blood of mice that received cetuximab versus PBS-treated mice. In summary, CNTY-101 is a novel, multi-engineered, allogeneic CAR-iNK product candidate for the treatment of B-cell malignancies. It includes multiple immune evasion features to prevent recognition by the patient's immune system and expression of IL-15 to facilitate persistence and functionality. We have initiated GMP manufacturing of CNTY-101 and plan to enter clinical trials in 2022. Disclosures Borges: Century Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wallet: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Bullaughey: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Naso: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Gurung: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Keating: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Carton: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wheeler: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Mendonca: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Jessup: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Beqiri: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Chin: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Millar Quinn: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Morse: Century Therapeutics: Current Employment, Current holder of stock options in a privately-held company.

Evaluation of the effect of TRU-016, an anti-CD37 directed SMIP in combination with other therapeutic drugs in models of non-Hodgkin's lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8571-8571 ◽  
Author(s):  
P. R. Baum ◽  
C. Cerveny ◽  
B. Gordon ◽  
C. Nilsson ◽  
J. Wiens ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Combination Index ◽  
B Cell Lymphoma ◽  
Drug Combinations ◽  
Single Chain ◽  
Lymphoma Line

8571 Background: TRU-016, a single chain anti-CD37 Fc fusion molecule has been shown to display pro-apoptotic and Fc-dependent cellular cytotoxicity activities against primary CLL cells and NHL cell lines. The pro-apoptotic signal generated by TRU-016 binding to CD37 on CLL cells has been shown to be caspase-independent and distinct from the signal generated by many other therapeutics including rituximab. We have tested drug combinations using the mantle cell lymphoma line Rec-1 and diffuse large B-cell lymphoma line SU-DHL-6 in vitro and extended these results to in vivo settings using the follicular lymphoma cell line DOHH2 treated with the combination of TRU-016 and bendamustine. Methods: To determine TRU-016 interactions with the established therapeutics rituximab, doxorubicin, rapamycin, and bendamustine, drugs were tested alone or in combination with TRU-016 and the anti-proliferative effects on cell lines measured after 96 hours. Combination index analysis was performed for drug combinations over the 20–90% effect levels using the Calcusyn software package. To determine if in vitro synergy could be recapitulated in vivo, SCID mice were implanted with DOHH2 cells and therapeutic treatment was initiated when tumor volumes reached 200 mm3. Treatments consisted of TRU-016, bendamustine, or the combination of TRU-016 and bendamustine. Results: Combination index analyses determined that TRU-016 is synergistic with rituximab, bendamustine, or rapamycin and additive with doxorubicin in NHL models. In vivo results show that treatment with the combination of TRU-016 and bendamustine resulted in increased efficacy compared to the efficacy attained with the individual drugs. This demonstrates that the in vitro synergy results were extendable to a more complex in vivo disease model. Conclusions: TRU-016 in combination with rituximab, rapamycin, or bendamustine increases cell killing of NHL cells. Furthermore, the combination of TRU-016 and bendamustine displayed greater in vivo anti-tumor activity than either agent alone against a follicular lymphoma tumor model. [Table: see text]

scholarly journals The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest

Leukemia ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 1315-1328 ◽  
Author(s):  
Alexandre Pichard ◽  
Sara Marcatili ◽  
Jihad Karam ◽  
Julie Constanzo ◽  
Riad Ladjohounlou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Growth ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Growth Delay ◽  
M Cell ◽  
Cycle Arrest

AbstractSome patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt’s lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.

Combination Therapy with Novel Nanoparticle, SNS01-T, and Lenalidomide Triggers Synergistic Cytotoxicity in Vitro and in Vivo in Multiple Myeloma and Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4223-4223
Author(s):  
Catherine A Taylor ◽  
Terence Tang ◽  
Zhongda Liu ◽  
Sarah Francis ◽  
Zheng Qifa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
B Cell ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
Significant Activity ◽  
Rpmi 8226

Abstract Abstract 4223 SNS01-T is a novel nanoparticle that is designed to selectively initiate apoptosis in B-cell cancers such as multiple myeloma and B-cell lymphomas. SNS01-T is comprised of a plasmid encoding a pro-apoptotic form of the eukaryotic translation initiation factor 5A (eIF5A) containing a single-point mutation that prevents hypusination, an siRNA that inhibits expression of the pro-survival hypusine-eIF5A protein, and a polymer that serves to assemble the nucleic acids into a nanoparticle. SNS01-T is currently being investigated in a multi-site, open-label Phase1b/2a dose escalation study in subjects with relapsed or refractory multiple myeloma (MM). SNS01-T and its preclinical precursors have been studied extensively in multiple myeloma and B cell lymphoma tumor models. In this study we tested the in vitro and in vivo anti-cancer activity of SNS01-T in combination with the immunomodulatory drug lenalidomide. The combination of low doses of SNS01-T and lenalidomide synergistically reduced viability of RPMI 8226 MM cells and induced apoptosis to a greater degree than either drug alone. To determine whether SNS01-T treatment increases the anti-myeloma activity of lenalidomide in vivo, 0.375 mg/kg SNS01-T was combined with either 15 or 50 mg/kg lenalidomide in a RPMI 8226 xenograft model of multiple myeloma. Mice were dosed for two cycles of treatment for a total of 11 weeks of dosing. Mice with no measurable tumor at the end of the first cycle of treatment did not receive treatment in the second cycle but were monitored closely for tumor recurrence. A two-week observation period at the end of the study allowed monitoring of tumor growth after the cessation of the second cycle of treatment. At the end of the second cycle of dosing, tumor growth was inhibited by 84 % (p < 0.0001), 34 % (p = 0.05), and 98.1 % (p << 0.0001) in animals treated with SNS01-T, 50 mg/kg lenalidomide, and SNS01-T plus 50 mg/kg lenalidomide, respectively. Complete tumor regression (undetectable tumor) was achieved in 40% of mice treated with SNS01-T, 0% of mice treated with 50 mg/kg lenalidomide, and 83% of mice treated with the combination therapy of SNS01-T and 50 mg/kg lenalidomide. Complete regression of tumors treated with the combination therapy was maintained for more than 8 weeks without treatment until the end of the study in 4 of 6 (67%) of treated mice. Combining SNS01-T treatment with 50 mg/kg lenalidomide inhibited tumor growth more effectively than either drug alone and prolonged survival with 100% of mice surviving to the end of the 102-day study. Combination therapy with SNS01-T and 15 mg/kg lenalidomide also demonstrated significant activity in a murine JMV-2 mantle cell lymphoma (MCL) xenograft model. Treatment of mice with the drug combination of SNS01-T and lenalidomide resulted in a statistically significant increase in survival compared to either SNS01-T (p = 0.002; logrank test) or lenalidomide (p = 0.007) alone. Collectively, these preclinical studies indicate that the combination therapy of SNS01-T and lenalidomide is well tolerated, has significant activity against MM and MCL, and provides a strong rationale to evaluate SNS01-T and lenalidomide combination therapy to improve patient outcome in MM and B cell lymphomas. Disclosures: Taylor: Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Darbepoetin alfa Radiosensitizes Tumors Independent of Anemia or the Correction of Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1637-1637
Author(s):  
Shoucheng Ning ◽  
Sinclair Angus ◽  
Hartley Cynthia ◽  
Knox Susan4
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Fold Increase ◽  
Growth Delay ◽  
Local Tumor ◽  
Tumor Growth Delay ◽  
Tumor Bearing ◽  
Tumor Irradiation

Abstract Darbepoetin alfa (DA) is a FDA approved long acting erythropoietic protein. We hypothesized that correction of anemia in tumor-bearing mice by DA would secondarily increase the tumor pO2 and potentiate radiation-induced cell killing of tumor cells. To test this hypothesis, we used total body irradiation (TBI) to induce anemia in C3H mice. Murine squamous cell carcinoma tumor (SCC VII) and fibrosarcoma (RIF-1) models were used to study tumor responses to radiation in vivo. DA (30μg/kg) was administered i.p. either every two weeks or weekly. EPO-R RNA levels were measured in tumors from normal, anemic and DA treated mice in both tumor models. Tumors were locally irradiated with daily fractions of 250 cGy for 5 days. Following 500 cGy TBI, hemoglobin levels decreased and reached a nadir of 7.0 ± 0.9 gm/dL 14 days post TBI. Administration of DA reduced the depth and duration of anemia and improved the general health condition of anemic animals as evidenced by accelerated recovery of body weight following the TBI and maintenance of normal levels of activity compared to similarly irradiated animals not treated with DA. Mice treated with DA on the same day as the TBI had elevated hemoglobin levels with a nadir of 11.1 gm/dL on day 14 after TBI. Systemic administration of DA alone did not stimulate tumor growth in TBI-induced anemic mice. When combined with fractionated local tumor irradiation, administration of DA at any of the time points studied (18, 11, 4 and 0 days before initiation of local tumor irradiation) delayed tumor growth and increased the tumor growth delay time from 2.7 days for irradiation alone to 7.3 – 10.6 days for DA treated animals (p < 0.01). There was no statistically significant difference between tumor growth delay times for groups of mice treated with DA at various times before tumor irradiation. Although DA effectively corrected anemia in tumor-bearing mice and significantly decreased the number of hypoxic cells in the tumors as shown by EF5 staining, radiosensitization by DA was independent of the correction of anemia. EPOR RNA expression was barely detectible in tumors cultured in vitro. There were no differences in EPO-R RNA levels in tumors from anemic or DA treated mice (1–2 fold increase), although EPO-R transcription was upregulated in tumors grown in vivo compared to control tumors lines grown in vitro (40–80 fold increase). This may be due to hypoxic induction of EPO-R by tumors in vivo or expression of EPO-R by endothelial cells or infiltrating macrophages. Results from an experiment in non-anemic mice with RIF-1 tumors suggest that DA can sensitize tumor cells in non-anemic mice to radiation as well. These results support the idea that radiosensitization by DA is independent of hemoglobin and tumor pO2. It has long been assumed that anemia causes decreased tumor oxygenation and increased tumor radioresistance, and that correction of anemia would therefore increase tumor pO2, and result in enhanced radiosensitivity. However, the data presented here challenge this presumed relationship. These findings are promising and may have relevance to the treatment of patients with a variety of tumor types with radiation therapy.

HCD122, an Antagonist Human Anti-CD40 Monoclonal Antibody, Inhibits Tumor Growth in Xenograft Models of Human Diffuse Large B-Cell Lymphoma, a Subset of Non-Hodgkins Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2519-2519 ◽  
Author(s):  
Ssucheng J. Hsu ◽  
Lin A. Esposito ◽  
Sharon L. Aukerman ◽  
Seema Kantak ◽  
Amer M. Mirza
Keyword(s):  
Tumor Growth ◽  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Non Hodgkins Lymphoma ◽  
Xenograft Models

Abstract CD40, a member of the tumor necrosis factor receptor family, is expressed in all human B-cell malignancies and engagement by the CD40 ligand (CD40L) is important for both cell proliferation and cell survival. CD40L has been shown to be co-expressed with CD40 in neoplastic B-cells from Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkins Lymphoma (NHL), suggesting the importance of an autocrine CD40/CD40L loop in these malignancies. HCD122 (formerly known as CHIR-12.12) is a fully human, highly potent, IgG1 antagonist anti-CD40 monoclonal antibody (mAb) that blocks CD40/CD40L interactions in vitro and also mediates ADCC. Previous studies showed that HCD122 can mediate ADCC in vitro and has anti-proliferative and anti-tumor activities as a single agent in CLL, MM, and Burkitts Lymphoma in vitro and in vivo. In this study, the activity of HCD122 on a subtype of NHL, Diffuse Large B-Cell Lymphoma (DLBCL) was examined. The DLBCL derived cell lines, RL and SU-DHL-4, were selected for this study based upon in vivo characterization as well as their sensitivity to Rituximab as reported in the literature. These cell lines were subsequently confirmed for the expression of CD40 and CD20 by flow cytometry. The in vivo anti-tumor effects of HCD122 as single agent was demonstrated in these two xenograft models and was compared to Rituximab, an anti-CD20 antibody therapeutic currently approved for the treatment of relapsed or refractory, low-grade or follicular, NHL. HCD122 when administered intraperitoneally weekly at 1 mg/kg significantly reduced tumor growth with a tumor growth inhibition (TGI) of 85.5% (P<0.01) in the RL model. At the same dose and schedule in the RL model, TGI achieved with Rituximab was 31.7% (P>0.05). In the SU-DHL-4 model, an 85% TGI (P<0.01) was observed at the 1 mg/kg dose of HCD122. In comparison, Rituximab at this dose elicited a 57.6% TGI (P<0.05). Additionally, the downstream CD40/CD40L signal transduction pathways were also examined in order to elucidate the molecular mechanism underlying the HCD122-mediated effects in DLBCL. Taken together, these results support the clinical development of HCD122 for the treatment of DLBCL. Currently HCD122 is in Phase I trials for treatment of CLL and MM.

The Bcl-2 Family Inhibitor ABT-263 Shows Significant Anti-Tumor Efficacy in Models of B Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 825-825
Author(s):  
Alex R. Shoemaker ◽  
Michael J. Mitten ◽  
Anatol Oleksijew ◽  
Jacqeuline M. O’Connor ◽  
Baole Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
B Cell ◽  
Cell Lymphoma ◽  
Cytotoxic Agents ◽  
Tumor Growth Inhibition ◽  
Complete Regression ◽  
Mantle Cell

Abstract ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Non-Hodgkin’s B-cell lymphomas represent clinically relevant disease targets for this molecule due, in part, to strong expression of Bcl-2 often associated with various types of NHL (frequently involving a t(14;18) translocation including the Bcl-2 locus). ABT-263 exhibits sub-micromolar in vitro activity against a variety of NHL cell lines. DoHH-2 and WSU-DLCL2 are two B-cell NHL lines harboring the t(14;18) translocation that exhibit differential in vitro sensitivity to ABT-263. Granta-519 is a mantle cell lymphoma line with the characteristic t(11;14)(q13:q32) translocation resulting in overexpression of cyclin D1. ABT-263 has an EC50 of approximately 150 nM in the Granta-519 cell line. Here we present efficacy data evaluating the activity of ABT-263 in several NHL xenograft models. ABT-263 has significant in vivo anti-tumor efficacy in established flank tumor models both as monotherapy and in combination with cytotoxic agents. The efficacy of ABT-263 at 100 mg/kg/day, p.o., q.d. ×21 was evaluated as monotherapy and in combination with etoposide, vincristine, modified CHOP, R-CHOP, bortezomib, rapamycin, and rituximab. Results show that ABT-263 significantly inhibits tumor growth as a monotherapy (~50–60% tumor growth inhibition) and enhances the efficacy of these cytotoxic agents in combination therapy. Statistically significant enhancement of tumor growth inhibition was observed for each combination relative to monotherapy treatment. Efficacy was maintained even when therapy was initiated on larger (~500 mm3) tumors. Combinations of ABT-263 + rapamycin and ABT-263 + rituximab result in complete regression of a significant percentage of established B cell lymphoma tumors for a sustained period of time in vivo. The combination of ABT-263 + R-CHOP resulted in complete regression of 100% of the tumors in the mantle cell lymphoma model. The strong in vitro potency and tumor regressions seen in vivo suggest that ABT-263 has great potential for the oral treatment of NHL B-cell lymphomas.

Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

2013 ◽  
Vol 189 (8) ◽  
pp. 684-692 ◽  
Author(s):  
F. Zwicker ◽  
A. Kirsner ◽  
P. Peschke ◽  
F. Roeder ◽  
J. Debus ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Delay ◽  
Tumor Growth Delay ◽  
Radiation Induced

A CD47xCD19 Bispecific Antibody That Remodels the Tumor Microenvironment for Improved Killing and Provokes a Memory Immune Response to Cancer B Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 44-44
Author(s):  
Walter G. Ferlin ◽  
Xavier Chauchet ◽  
Vanessa Buatois ◽  
Susana Salgado-Pires ◽  
Limin Shang ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
B Cell ◽  
Cell Lymphoma ◽  
Treatment Strategies ◽  
B Cell Lymphoma ◽  
Tumor Killing

Abstract Up-regulation of CD47 in hematological and solid cancers correlates with poor clinical prognosis. CD47 interaction with SIRPα provides a ‘don't eat me’ signal that allows healthy cells to limit elimination by immune cells, in particular macrophages. Although tumor-associated macrophages (TAMs) are often considered pro-tumorigenic, several studies report a high phagocytic potential and tumoricidal function in the presence of therapeutic antibodies (Ab). Therefore, targeting the CD47-SIRPα pathway in the tumor microenvironment is an attractive approach to maximize the tumor killing potential of TAMs to boost tumor destruction. However, clinical development of monoclonal Abs to CD47 is likely to be hindered by the ubiquitous expression of CD47 leading to rapid drug elimination and toxicity including anemia. To address these concerns, we have created NI-1701, a bispecific Ab that drives efficacious binding only to CD19+B cells by pairing a high affinity anti-CD19 targeting arm to an anti-CD47 arm of optimized affinity.. In addition to in vitro data demonstrating that the bispecific Ab, NI-1701, effectively kills CD19+ human tumor B cells through ADCP (antibody-dependent cellular phagocytosis) and antibody-dependent cell-mediated cytotoxicity (ADCC), we have observed significant tumor killing in vivo, as either a monotherapy or in a combination approach. NI-1701 controlled sub-cutaneously implanted Raji cell tumor growth in NOD/SCID mice in a manner dependent on the co-ligation of both CD19 and CD47. Examination of the excised tumors revealed that NI-1701 reshaped the tumor microenvironment by enhancing the tumoricidal activity of macrophages (i.e., more macrophages engulfing tumor cells), by promoting an antitumor M1-like phenotype, and reducing the proportion of CD11b+Gr1+myeloid-derived suppressor cells (MDSCs). Extending these findings to a disseminated in vivo model, NI-1701 eliminated tumor cells from the peripheral blood, bone marrow and liver in mice transplanted either with the B-Acute Lymphocytic Leukemia (B-ALL) cell line NALM-6 or with primary cells from B-ALL patients. Furthermore, NI-1701 also abrogated tumor growth more efficiently than the BTK inhibitor ibrutinib in a Diffuse Large B-Cell Lymphoma (DLBCL) patient-derived xenograft (PDX) mouse model. As combination therapies are gaining traction as successful treatment strategies in the clinic, we next tested the effect of blocking CD47 biology in combination with clinically validated molecules. Interestingly, in NOD/SCID mice implanted with Raji cells, NI-1701 was shown to be more efficacious at controlling tumor cell growth than Rituximab. A combination of NI-1701 and Rituximab was shown to act synergistically at controlling tumor growth and leading to tumor regression in some mice. Finally, in a syngeneic re-challenge model, using bispecific reagents targeting CD47 blockade to the A20 murine B-cell lymphoma, we observed the induction of a durable and protective anti-tumor response when combined with a single administration of cyclophosphamide. Importantly, in vitro safety studies demonstrate a favorable binding profile of NI-1701 to B cells compared with erythrocytes, no evidence of platelet activation or aggregation and no haemagglutination at and above anticipated therapeutic concentrations. Single and multiple dose studies in non-human primates demonstrated favorable elimination kinetics and no effects on hematological parameters (e.g., red blood cell and platelet counts) up to 100mg/kg, the highest dose tested. Taken together, we describe a novel bispecific approach that balances a safe yet effective blockade of CD47 with a high selectivity for a B cell associated antigen resulting in impressive tumor cell killing in a range of preclinical models. The effects on both the reshaping of the tumor microenvironment and the induction of long term tumor immunity provide further evidence that manipulation of myeloid lineage cells (e.g., macrophages and dendritic cells) is a promising approach for the next frontier in immune-oncology treatment strategies. NI-1701 is in preclinical enabling studies in preparation for a Phase I clinical study in patients with CD19+ B cell malignancies, planned for early 2017. Disclosures Ferlin: Novimmune S.A.: Employment, Equity Ownership. Chauchet:Novimmune S.A.: Employment. Buatois:Novimmune S.A.: Employment. Salgado-Pires:Novimmune S.A.: Employment. Shang:Novimmune S.A.: Employment. Dheilly:Novimmune S.A.: Employment. Masternak:Novimmune S.A.: Employment. Johnson:Novimmune S.A.: Employment. DiPersio:Incyte Corporation: Research Funding. Kosco-Vilbois:Novimmune S.A.: Employment. Fischer:Novimmune S.A.: Employment.

scholarly journals Tumor dormancy and cell signaling. II. Antibody as an agonist in inducing dormancy of a B cell lymphoma in SCID mice.

1995 ◽  
Vol 181 (4) ◽  
pp. 1539-1550 ◽  
Author(s):  
E Racila ◽  
R H Scheuermann ◽  
L J Picker ◽  
E Yefenof ◽  
T Tucker ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Scid Mice ◽  
Tumor Dormancy ◽  
Cellular Mechanisms

Tumor dormancy can be induced in a murine B cell lymphoma (BCL1) by immunizing BALB/c mice with the tumor immunoglobulin (Ig) before tumor cell challenge. In this report, we have investigated the immunological and cellular mechanisms underlying the induction of dormancy. BCL1 tumor cells were injected into SCID mice passively immunized with antibody against different epitopes on IgM or IgD with or without idiotype (Id)-immune T lymphocytes. Results indicate that antibody to IgM is sufficient to induce a state of dormancy. Antibodies against other cell surface molecules including IgD and CD44 (Pgp1) had no effect on tumor growth. Id-immune T cells by themselves also had no effect on tumor growth in SCID mice. However, simultaneous transfer of anti-Id and Id-immune T cells enhanced both the induction and duration of the dormant state. In vitro studies indicated that antibody to IgM induced apoptosis within several hours and cell cycle arrest by 24 h. Hyper cross-linking increased apoptosis. The Fc gamma RII receptor played little or no role in the negative signaling. Antibodies that did not negatively signal in vitro did not induce dormancy in vivo. The results suggest that anti-IgM plays a decisive role in inducing tumor dormancy to BCL1 by acting as an agonist of IgM-mediated signal transduction pathways.

Sign in / Sign up

Export Citation Format

Share Document