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202. Supplementary Figures S1-S4 and Tables S1-S2 from Protein Kinase Inhibitor H89 Enhances the Activity of Pseudomonas Exotoxin A–Based Immunotoxins

Author

Ira Pastan, Alan S. Wayne, Fabian Müller, and Xiufen Liu

Abstract

Fig S1. H89 increased ADP-ribosylation and MCL-1 degradation in SEM cells Fig S2. Combination of RIT and H89 lowers MCL1 and induces PARP-cleavage Fig S3. PKA regulator, S6K1-, or ROCK2-inhibitor show little change in LMB-11 activity Fig S4. Combination of LMB-11 and S6K1 inhibitor PF4708671 enhances MCL1 degradation but not ADP-ribosylation Table S1. Cytotoxic activity (IC50) of immunotoxins with and without H89 Table S2. In vitro screening for H89 inhibited kinases

Published
2023

204. Data from Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity

Author

Ira Pastan, Yoram Reiter, Chin-Hsien Tai, Gerhard Niederfellner, Birgit Bossenmaier, Jay A. Berzofsky, Masaki Terabe, Tapan K. Bera, Xiufen Liu, James O'Brien, and Yasmin Leshem

Abstract

Immune checkpoint blockade using antibodies to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) benefits a limited number of cancer patients. SS1P and LMB-100 are immunotoxins that target mesothelin. We observed delayed responses to SS1P in patients with mesothelioma suggesting that antitumor immunity was induced. Our goal was to stimulate antitumor immunity by combining SS1P or LMB-100 with anti–CTLA-4. We constructed a BALB/c breast cancer cell line expressing human mesothelin (66C14-M), which was implanted in one or two locations. SS1P or LMB-100 was injected directly into established tumors and anti–CTLA-4 administered i.p. In mice with two tumors, one tumor was injected with immunotoxin and the other was not. The complete regression rate was 86% for the injected tumors and 53% for the uninjetced tumors. No complete regressions occurred when drugs were given separately. In regressing tumors, dying and dead tumor cells were intermingled with PMNs and surrounded by a collar of admixed eosinophils and mononuclear cells. Tumor regression was associated with increased numbers of tumor-infiltrating CD8+ cells and blocked by administration of antibodies to CD8. Surviving mice were protected from tumor rechallenge by 66C14 cells not expressing mesothelin, indicating the development of antitumor immunity. The antitumor effect was abolished when a mutant noncytotoxic variant was used instead of LMB-100, showing that the antitumor response is not mediated by recognition of a foreign bacterial protein. Our findings support developing a therapy composed of immunotoxins and checkpoint inhibitors for patients. Cancer Immunol Res; 5(8); 685–94. ©2017 AACR.

Published
2023

212. IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

Author

Joshi, BH, Leland, P, Silber, J, Kreitman, RJ, Pastan, I, Berger, M, and Puri, RK

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Brain Disorders, Pediatric, Neurosciences, Brain Cancer, Cancer, Rare Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, ADP Ribose Transferases, Bacterial Toxins, Brain Neoplasms, Exotoxins, Fluorescent Antibody Technique, Humans, Immunoconjugates, Medulloblastoma, RNA, Messenger, Receptors, Interleukin-4, Recombinant Fusion Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Virulence Factors, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT--PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha') chains, however common gamma(c), a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.

Published
2002

214. The ASCENT (Allocation System Changes for Equity in Kidney Transplantation) Study: A Randomized Effectiveness-Implementation Study to Improve Kidney Transplant Waitlisting and Reduce Racial Disparity

Author

Rachel E. Patzer, Kayla Smith, Mohua Basu, Jennifer Gander, Sumit Mohan, Cam Escoffery, Laura Plantinga, Taylor Melanson, Sean Kalloo, Gary Green, Alex Berlin, Gary Renville, Teri Browne, Nicole Turgeon, Susan Caponi, Rebecca Zhang, and Stephen Pastan

Subjects
education, ESRD Networks, Kidney Allocation System, kidney transplantation, multicomponent intervention, waitlisting, Diseases of the genitourinary system. Urology, RC870-923
Abstract

The United Network for Organ Sharing (UNOS) implemented a new Kidney Allocation System (KAS) in December 2014 that is expected to substantially reduce racial disparities in kidney transplantation among waitlisted patients. However, not all dialysis facility clinical providers and end-stage renal disease (ESRD) patients are aware of how the policy change could improve access to transplantation. Methods: We describe the ASCENT (Allocation System Changes for Equity in Kidney Transplantation) study, a randomized, controlled effectiveness-implementation study designed to test the effectiveness of a multicomponent intervention to improve access to the early steps of kidney transplantation among dialysis facilities across the United States. The multicomponent intervention consists of an educational webinar for dialysis medical directors, an educational video for patients and an educational video for dialysis staff, and a dialysis facility−specific transplantation performance feedback report. Materials will be developed by a multidisciplinary dissemination advisory board and will undergo formative testing in dialysis facilities across the United States. Results: This study is estimated to enroll ∼600 US dialysis facilities with low waitlisting in all 18 ESRD networks. The co-primary outcomes include change in waitlisting and waitlist disparity at 1 year; secondary outcomes include changes in facility medical director knowledge about KAS, staff training regarding KAS, patient education regarding transplantation, and the intent of the medical director to refer patients for transplantation evaluation. Discussion: The results from the ASCENT study will demonstrate the feasibility and effectiveness of a multicomponent intervention designed to increase access to the deceased donor kidney waitlist and to reduce racial disparities in waitlisting.

Published
2017
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215. 5’UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia

Author

Caterina Marconi, Ilaria Canobbio, Valeria Bozzi, Tommaso Pippucci, Giorgia Simonetti, Federica Melazzini, Silvia Angori, Giovanni Martinelli, Giuseppe Saglio, Mauro Torti, Ira Pastan, Marco Seri, and Alessandro Pecci

Subjects
ANKRD26 gene, Acute myeloid leukemia, Inherited predisposition to leukemia, Inherited thrombocytopenia, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5’UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5’UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5’UTR. We found variants in four patients. One patient had the c.−125T>G substitution in the 5’UTR, while three patients carried two different variants in the 5’ end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c.−125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well-characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation.

Published
2017
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217. Supplemental Appendix 1 from Phase II Clinical Trial of Amatuximab, a Chimeric Antimesothelin Antibody with Pemetrexed and Cisplatin in Advanced Unresectable Pleural Mesothelioma

Author

Hassan, Raffit, primary, Kindler, Hedy L., primary, Jahan, Thierry, primary, Bazhenova, Lyudmila, primary, Reck, Martin, primary, Thomas, Anish, primary, Pastan, Ira, primary, Parno, Jeff, primary, O'Shannessy, Daniel J., primary, Fatato, Penny, primary, Maltzman, Julia D., primary, and Wallin, Bruce A., primary

Published
2023
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219. Supplemental Figure 2 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
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220. Supplementary Figures 1-9 from Construction of an Immunotoxin, D2C7-(scdsFv)-PE38KDEL, Targeting EGFRwt and EGFRvIII for Brain Tumor Therapy

Author

Chandramohan, Vidyalakshmi, primary, Bao, Xuhui, primary, Keir, Stephen T., primary, Pegram, Charles N., primary, Szafranski, Scott E., primary, Piao, Hailan, primary, Wikstrand, Carol J., primary, McLendon, Roger E., primary, Kuan, Chien-Tsun, primary, Pastan, Ira H., primary, and Bigner, Darell D., primary

Published
2023
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222. Supplemental Figure 1 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
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225. Supplementary Figure Legends from Construction of an Immunotoxin, D2C7-(scdsFv)-PE38KDEL, Targeting EGFRwt and EGFRvIII for Brain Tumor Therapy

Author

Chandramohan, Vidyalakshmi, primary, Bao, Xuhui, primary, Keir, Stephen T., primary, Pegram, Charles N., primary, Szafranski, Scott E., primary, Piao, Hailan, primary, Wikstrand, Carol J., primary, McLendon, Roger E., primary, Kuan, Chien-Tsun, primary, Pastan, Ira H., primary, and Bigner, Darell D., primary

Published
2023
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229. Supplemental Figure 3 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
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230. Supplementary Methods from Construction of an Immunotoxin, D2C7-(scdsFv)-PE38KDEL, Targeting EGFRwt and EGFRvIII for Brain Tumor Therapy

Author

Chandramohan, Vidyalakshmi, primary, Bao, Xuhui, primary, Keir, Stephen T., primary, Pegram, Charles N., primary, Szafranski, Scott E., primary, Piao, Hailan, primary, Wikstrand, Carol J., primary, McLendon, Roger E., primary, Kuan, Chien-Tsun, primary, Pastan, Ira H., primary, and Bigner, Darell D., primary

Published
2023
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232. Supplementary Data from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
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