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5. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity.

Author

Pai, Chien-Chun Steven, Simons, Donald M, Lu, Xiaoqing, Evans, Michael, Wei, Junnian, Wang, Yung-Hua, Chen, Mingyi, Huang, John, Park, Chanhyuk, Chang, Anthony, Wang, Jiaxi, Westmoreland, Susan, Beam, Christine, Banach, Dave, Bowley, Diana, Dong, Feng, Seagal, Jane, Ritacco, Wendy, Richardson, Paul L, Mitra, Soumya, Lynch, Grace, Bousquet, Pete, Mankovich, John, Kingsbury, Gillian, and Fong, Lawrence

Subjects
Cell Line, Tumor, Animals, Mice, Knockout, Humans, Mice, Neoplasms, Immunotherapy, Immunity, Cellular, Male, T-Lymphocytes, Regulatory, Single-Chain Antibodies, HEK293 Cells, Tumor Microenvironment, CTLA-4 Antigen, Antineoplastic Agents, Immunological, Cancer immunotherapy, Immunology, Oncology, Immunization, Digestive Diseases, Vaccine Related, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Inflammatory and immune system, Medical and Health Sciences
Abstract

While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.

Published
2019

10. Near infrared readouts offer sensitive and rapid assessments of intestinal permeability and disease severity in inflammatory bowel disease models

Author

Zhang, Liang, Wallace, Craig D., Erickson, Jamie E., Nelson, Christine M., Gaudette, Stephanie M., Pohl, Calvin S., Karsen, Samuel D., Simler, Gricelda H., Peng, Ruoqi, Stedman, Christopher A., Laroux, F. Stephen, Wurbel, Marc A., Kamath, Rajesh V., McRae, Bradford L., Schwartz Sterman, Annette J., and Mitra, Soumya

Published
2020
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12. FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GvHD after Two or More Prior Lines of Systemic Therapy

Author

Przepiorka, Donna, primary, Le, Robert Q., additional, Ionan, Alexei, additional, Li, Ruo-Jing, additional, Wang, Ying-Hong, additional, Gudi, Ramadevi, additional, Mitra, Soumya, additional, Vallejo, Jonathon, additional, Okusanya, Olanrewaju O., additional, Ma, Lian, additional, Yang, Yuching, additional, Patel, Paresma, additional, Mezaache, Djelila, additional, Shah, Rakhi, additional, Banerjee, Anamitro, additional, McLamore, Sherita, additional, Maung, Adam N., additional, Goldberg, Kirsten B., additional, Pazdur, Richard, additional, Theoret, Marc R., additional, and De Claro, R. Angelo, additional

Published
2022
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15. Asymmetric total synthesis of dibenzocylooctadiene lignan natural products

Author

Coleman, Robert S., Gurrala, Srinivas Reddy, Mitra, Soumya, and Raao, Amresh

Subjects
Aromatic compounds -- Chemical properties, Biological sciences, Chemistry
Abstract

Full details of the asymmetric total synthesis of the dibenzocyclooctadiene lignans interiotherin A, angeloygomision R, gomison O, and gomisin E are presented. The synthesis is achieved in six to eight steps from simple aromatic precursors.

Published
2005

16. Su2050 – Near Infrared (NIR) Fluorescence Readouts of Intestinal Permeability and Disease Severity in Murine IBD Models

Author

Mitra, Soumya, primary, Zhang, Liang, additional, Wallace, Craig, additional, Erickson, Jamie, additional, Nelson, Christine, additional, Gaudette, Stephanie, additional, Karsen, Sam, additional, Stedman, Christopher, additional, Laroux, Stephen, additional, Simler, Gricelda, additional, Peng, Ruoqi, additional, Wurbel, Marc-Andre, additional, Kamath, Rajesh, additional, McRae, Bradford L., additional, Slavin, Anthony, additional, and Sterman, Annette Schwartz, additional

Published
2019
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17. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity

Author

Pai, Chien-Chun Steven, primary, Simons, Donald M., additional, Lu, Xiaoqing, additional, Evans, Michael, additional, Wei, Junnian, additional, Wang, Yung-hua, additional, Chen, Mingyi, additional, Huang, John, additional, Park, Chanhyuk, additional, Chang, Anthony, additional, Wang, Jiaxi, additional, Westmoreland, Susan, additional, Beam, Christine, additional, Banach, Dave, additional, Bowley, Diana, additional, Dong, Feng, additional, Seagal, Jane, additional, Ritacco, Wendy, additional, Richardson, Paul L., additional, Mitra, Soumya, additional, Lynch, Grace, additional, Bousquet, Pete, additional, Mankovich, John, additional, Kingsbury, Gillian, additional, and Fong, Lawrence, additional

Published
2018
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18. Total synthesis of the eupomatilones

Author

Mitra, Soumya, Gurrala, Srinivas Reddy, and Coleman, Robert S.

Subjects
Diastereomers -- Research, Lactones -- Chemical properties, Organoboranes -- Usage, Photosensitivity disorders -- Causes of, Biological sciences, Chemistry
Abstract

The total syntheses of five members of the eupomatilone family of lignans are described. Suzuki-Miyuara biaryl cross-coupling reaction and an efficient asymmetric carbomethoxycrotylboration reaction have contributed towards the success of the sequence.

Published
2007

19. Enhydra fluctuansLour. aqueous extract inhibited the growth of calcium phosphate crystals: An in vitrostudy

Author

Chattaraj, Bornika, Nandi, Arijit, Das, Anwesha, Baidya, Arun, Mahata, Sourav, Chowdhury, Aritra, Mitra, Soumya, Roy, Sumon, Chakraborty, Subrata, and Dey, Yadu Nandan

Abstract

•Aqueous extract of E. fluctuans(AEEF) is traditionally used in relieving kidney stones.•The study investigated the effect of AEEF on growth of brushite crystals.•AEEF exhibited an inhibitory role on brushite crystal growth.•AEEF showed antimicrobial and antioxidant activities.

Published
2023
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21. Tumor Response to mTHPC-Mediated Photodynamic Therapy Exhibits Strong Correlation With Extracellular Release of HSP70

Author

Mitra, Soumya, Giesselman, Benjamin R., De Jesús-Andino, Francisco J., and Foster, Thomas H.

Subjects
Mice, Inbred BALB C, Luminescent Agents, Photosensitizing Agents, Dose-Response Relationship, Drug, Blotting, Western, Green Fluorescent Proteins, Mammary Neoplasms, Experimental, Apoptosis, Sarcoma, Article, Mice, Oxidative Stress, Mesoporphyrins, Microscopy, Fluorescence, Photochemotherapy, Cell Line, Tumor, Animals, Female, HSP70 Heat-Shock Proteins
Abstract

We investigated the relationship among heat shock protein 70 (hsp70) promoter activation, extracellular HSP70 protein levels, and tumor cure in an animal model of meso-tetrahydroxyphenyl chlorin (mTHPC; Foscan®)-mediated photodynamic therapy (PDT).Using Western blot analysis, we compared HSP70 protein levels in control and PDT-treated EMT6 cells with the amplitude of hsp70-promoter driven green fluorescent protein (GFP) expression in identically treated, stably transfected hsp70-GFP/EMT6 cells. A clonogenic survival assay was performed to assess the relationship among promoter activation, HSP70 levels, and cell survival in vitro. Tumor growth studies with this transfected cell line were performed to examine responses to fluences from 0.1 to 10 J cm(-2) , which ranged from sub-curative to curative. In vivo stereofluorescence and confocal fluorescence imaging were used to assess the temporal kinetics in hsp70 activation in tumors subjected to these fluences and the intratumor spatial correlation between hsp70 induction and extracellular levels of HSP70, respectively.Maximum GFP expression and HSP protein levels in cells were observed at PDT doses that corresponded to 30% cell survival. The relative changes in GFP and HSP70 protein accumulation as analyzed using Western immunoblots agreed very well, thereby confirming the validity of fluorescent reporter assessment of gene expression in our studies. In vivo imaging revealed that hsp70 promoter-driven GFP expression and accumulation of extracellular HSP70 in PDT-treated tumors subjected to non-curative doses exhibit minimal spatial correlation. There is a strong correlation between mTHPC-PDT doses that result in long-term tumor cure and those that cause high levels of surface exposed or extracellularly released HSP70s.Treatment conditions that induce strong promoter activation do not correspond to tumor cure. PDT doses that result in long-term tumor growth control also produce significant accumulation of extracellular HSP70.

Published
2011

29. Spatial And Temporal Expression of Herpes Simplex Virus Type 1 Amplicon-Encoded Genes: Implications for Their Use As Immunization Vectors

Author

Santos, Kathlyn, primary, Simon, David A.L., additional, Conway, Erin, additional, Bowers, William J., additional, Mitra, Soumya, additional, Foster, Thomas H., additional, Lugade, Amit, additional, Lord, Edith M., additional, Federoff, Howard J., additional, Dewhurst, Stephen, additional, and Frelinger, John G., additional

Published
2007
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33. Sensitivity of Candida albicansGerm Tubes and Biofilms to Photofrin-Mediated Phototoxicity

Author

Chabrier-Roselló, Yeissa, Foster, Thomas H., Pérez-Nazario, Nelissa, Mitra, Soumya, and Haidaris, Constantine G.

Abstract

ABSTRACTTreatment of mucocutaneous and cutaneous Candida albicansinfections with photosensitizing agents and light, termed photodynamic therapy (PDT), offers an alternative to conventional treatments. Initial studies using the clinically approved photosensitizer Photofrin demonstrated the susceptibility of C. albicansto its photodynamic effects. In the present study, we have further refined parameters for Photofrin-mediated photodynamic action against C. albicansand examined whether mechanisms commonly used by microorganisms to subvert either antimicrobial oxidative defenses or antimicrobial therapy, including biofilm formation, were operative. In buffer and defined medium, germ tubes preloaded with Photofrin retained their photosensitivity for up to 2 hours, indicating the absence of degradation or export of Photofrin by the organism. The addition of serum resulted in a gradual loss of photosensitivity over 2 hours. In contrast to an adaptive response by germ tubes to oxidative stress by hydrogen peroxide, there was no adaptive response to singlet oxygen-mediated stress by photodynamic action. C. albicansbiofilms were sensitive to Photofrin-mediated phototoxicity in a dose-dependent manner. Finally, the metabolic activity of C. albicansbiofilms following photodynamic insult was significantly lower than that of biofilms treated with amphotericin B for the same time period. These results demonstrate that several of the mechanisms microorganisms use to subvert either antimicrobial oxidative defenses or antimicrobial therapy are apparently not operative during Photofrin-mediated photodynamic treatment of C. albicans. These observations provide support and rationale for the continued investigation of PDT as an adjunctive, or possibly alternative, mode of therapy against cutaneous and mucocutaneous candidiasis.

Published
2005
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34. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity.

Author

Chien-Chun Steven Pai, Simons, Donald M., Xiaoqing Lu, Evans, Michael, Junnian Wei, Yung-hua Wang, Mingyi Chen, Huang, John, Chanhyuk Park, Chang, Anthony, Jiaxi Wang, Westmoreland, Susan, Beam, Christine, Banach, Dave, Bowley, Diana, Feng Dong, Seaga, Jane, Ritacco, Wendy, Richardson, Paul L., and Mitra, Soumya

Subjects
*IMMUNOTHERAPY, *TUMOR treatment, *CANCER treatment, *LYMPHOCYTES, *IPILIMUMAB
Abstract

While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities. [ABSTRACT FROM AUTHOR]

Published
2019
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