14 results on '"Arce Vargas, Frederick"'
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2. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity
- Author
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Solomon, Isabelle, Amann, Maria, Goubier, Anne, Arce Vargas, Frederick, Zervas, Dimitrios, Qing, Chen, Henry, Jake Y., Ghorani, Ehsan, Akarca, Ayse U., Marafioti, Teresa, Śledzińska, Anna, Werner Sunderland, Mariana, Franz Demane, Dafne, Clancy, Joanne Ruth, Georgiou, Andrew, Salimu, Josephine, Merchiers, Pascal, Brown, Mark Adrian, Flury, Reto, Eckmann, Jan, Murgia, Claudio, Sam, Johannes, Jacobsen, Bjoern, Marrer-Berger, Estelle, Boetsch, Christophe, Belli, Sara, Leibrock, Lea, Benz, Joerg, Koll, Hans, Sutmuller, Roger, Peggs, Karl S., and Quezada, Sergio A.
- Published
- 2020
- Full Text
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3. Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma
- Author
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Roddie, Claire, primary, Lekakis, Lazaros J., additional, Marzolini, Maria A. V., additional, Ramakrishnan, Aravind, additional, Zhang, Yiyun, additional, Hu, Yanqing, additional, Peddareddigari, Vijay G R, additional, Khokhar, Nushmia Z, additional, Chen, Robert W, additional, Basilico, Silvia, additional, Raymond, Meera, additional, Arce Vargas, Frederick, additional, Duffy, Kevin, additional, Brugger, Wolfram, additional, O'Reilly, Maeve, additional, Wood, Leigh, additional, Linch, David, additional, Peggs, Karl S, additional, Bachier, Carlos, additional, Budde, Elizabeth Lihua, additional, Batlevi, Connie Lee, additional, Bartlett, Nancy L., additional, Irvine, David, additional, Tholouli, Eleni, additional, Osborne, Wendy, additional, Ardeshna, Kirit M, additional, and Pule, Martin, additional
- Published
- 2023
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4. Resolution of acute inflammation bridges the gap between innate and adaptive immunity
- Author
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Newson, Justine, Stables, Melanie, Karra, Efthimia, Arce-Vargas, Frederick, Quezada, Sergio, Motwani, Madhur, Mack, Matthias, Yona, Simon, Audzevich, Tatsiana, and Gilroy, Derek W.
- Published
- 2014
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5. Industrialization of an Academic Miltenyi Prodigy-Based CAR T Process
- Author
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Culshaw, Abigail, primary, Arce Vargas, Frederick, additional, Santiago Toledo, Gerardo, additional, Roddie, Claire, additional, Shaughnessy, Paul, additional, Cerec, Virginie, additional, Duffy, Kevin, additional, Perna, Serena, additional, Brugger, Wolfram, additional, Merges, Michael, additional, and Pule, Martin, additional
- Published
- 2021
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6. Fcγ-receptor tag team boosts anti-tumor immunity
- Author
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Arce Vargas, Frederick and Quezada, Sergio A.
- Published
- 2015
- Full Text
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7. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies
- Author
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Arce Vargas, Frederick, Furness, Andrew J.S., Litchfield, Kevin, Joshi, Kroopa, Rosenthal, Rachel, Ghorani, Ehsan, Solomon, Isabelle, Lesko, Marta H., Ruef, Nora, Roddie, Claire, Henry, Jake Y., Spain, Lavinia, Ben Aissa, Assma, Georgiou, Andrew, Wong, Yien Ning Sophia, Smith, Myles, Strauss, Dirk, Hayes, Andrew, Nicol, David, O'Brien, Tim, Mårtensson, Linda, Ljungars, Anne, Teige, Ingrid, Frendéus, Björn, Pule, Martin, Marafioti, Teresa, Gore, Martin, Larkin, James, Turajlic, Samra, Swanton, Charles, Peggs, Karl S., Quezada, Sergio A., Harrington, Kevin, Melcher, Alan, Wotherspoon, Andrew, Francis, Nicholas, Challacombe, Ben, Fernando, Archana, Hazell, Steve, Chandra, Ashish, Pickering, Lisa, Lynch, Joanna, Rudman, Sarah, Chowdhury, Simon, Harrison-Phipps, Karen, Varia, Mary, Horsfield, Catherine, Polson, Alexander, Stamp, Gordon, O'Donnell, Marie, Drake, William, Hill, Peter, Hrouda, David, Mayer, Eric, Olsburgh, Jonathan, Kooiman, Gordon, O'Connor, Kevin, Stewart, Grant, Aitchison, Michael, Tran, Maxine, Fotiadis, Nicos, Verma, Hema, Lopez, Jose, Lester, Jason, Morgan, Fiona, Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Fennell, Dean, Shaw, Jacqui, Le Quesne, John, Nakas, Apostolos, Rathinam, Sridhar, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Riley, Joan, Primrose, Lindsay, Martinson, Luke, Anand, Girija, Khan, Sajid, Nicolson, Marianne, Kerr, Keith, Palmer, Shirley, Remmen, Hardy, Miller, Joy, Buchan, Keith, Chetty, Mahendran, Gomersall, Lesley, Lock, Sara, Naidu, Babu, Langman, Gerald, Trotter, Simon, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Middleton, Gary, Djearaman, Madava, Summers, Yvonne, Califano, Raffaele, Taylor, Paul, Shah, Rajesh, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Crosbie, Phil, Moss, Stuart, Idries, Faiza, Novasio, Juliette, Joseph, Leena, Bishop, Paul, Chaturvedi, Anshuman, Marie Quinn, Anne, Doran, Helen, leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Blackhall, Fiona, Rogan, Jane, Smith, Elaine, Dive, Caroline, Brady, Ged, Rothwell, Dominic, Gulati, Sakshi, Chemie, Francesca, Tugwood, Jonathan, Pierce, Jackie, Lawrence, David, Hayward, Martin, Panagiotopoulos, Nikolaos, George, Robert, Patrini, Davide, Falzon, Mary, Borg, Elaine, Khiroya, Reena, Jamal-Hanjani, Mariam, Wilson, Gareth, Juul Birkbak, Nicolai, Watkins, Thomas, McGranahan, Nicholas, Abbosh, Christopher, Horswell, Stuart, Mitter, Richard, Escudero, Mickael, Stewart, Aengus, Rowan, Andrew, Hiley, Crispin, Goldman, Jacki, Ahmed, Asia, Taylor, Magali, Choudhary, Junaid, Shaw, Penny, Veeriah, Raju, Czyzewska-Khan, Justyna, Johnson, Diana, Laycock, Joanne, Hynds, Robert, Werner Sunderland, Mariana, Reading, James, Novelli, Marco, Oukrif, Dahmane, Janes, Sam, Forster, Martin, Ahmad, Tanya, Ming Lee, Siow, van Loo, Peter, Herrero, Javier, Hartley, John, Kevin Stone, Richard, Denner, Tamara, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Chambers, Tim, Nye, Emma, Ward, Sophie, Elgar, Greg, Al-Bakir, Maise, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Papadatos-Pastos, Dionysis, Scarci, Marco, Gorman, Pat, Lowe, Helen, Ensell, Leah, Moore, David, MacKenzie, Mairead, Wilcox, Maggie, Bell, Harriet, Hackshaw, Allan, Ngai, Yenting, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Tavares Barbosa, Monica, Nicholson, Andrew, Bowman, Alex, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Elena Cufari, Maria, Carlo Ronquillo, John, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Ezhil, Veni, Prakash, Vineet, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, Asante-Siaw, Julius, Russell, Peter, Light, Teresa, Horey, Tracey, Blyth, Kevin, Dick, Craig, and Kirk, Alan
- Abstract
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
- Published
- 2018
8. Fc-Optimized Anti-CD25 depletes tumor-infiltrating regulatory T Cells and synergizes with PD-1 Blockade to eradicate established tumors
- Author
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Arce Vargas, Frederick, Furness, Andrew J.S., Solomon, Isabelle, Joshi, Kroopa, Mekkaoui, Leila, Lesko, Marta H., Miranda Rota, Enrique, Dahan, Rony, Georgiou, Andrew, Sledzinska, Anna, Ben Aissa, Assma, Franz, Dafne, Werner Sunderland, Mariana, Wong, Yien Ning Sophia, Henry, Jake Y., O’Brien, Tim, Nicol, David, Challacombe, Ben, Beers, Stephen A., Turajlic, Samra, Gore, Martin, Larkin, James, Swanton, Charles, Chester, Kerry A., Pule, Martin, Ravetch, Jeffrey V., Marafioti, Teresa, Peggs, Karl S., Quezada, Sergio A., Spain, Lavinia, Wotherspoon, Andrew, Francis, Nicholas, Smith, Myles, Strauss, Dirk, Hayes, Andrew, Soultati, Aspasia, Stares, Mark, Lynch, Joanna, Fotiadis, Nicos, Fernando, Archana, Hazell, Steve, Chandra, Ashish, Pickering, Lisa, Rudman, Sarah, Chowdhury, Simon, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Shafi, Seema, Czyzewska-Khan, Justyna, Johnson, Diana, Laycock, Joanne, Bosshard-Carter, Leticia, Goh, Gerald, Rosenthal, Rachel, Gorman, Pat, Murugaesu, Nirupa, Hynds, Robert E., Wilson, Gareth, Birkbak, Nicolai J., Watkins, Thomas B.K., McGranahan, Nicholas, Horswell, Stuart, Mitter, Richard, Escudero, Mickael, Stewart, Aengus, Van Loo, Peter, Rowan, Andrew, Xu, Hang, Hiley, Crispin, Abbosh, Christopher, Goldman, Jacki, Stone, Richard Kevin, Denner, Tamara, Matthews, Nik, Elgar, Greg, Ward, Sophia, Biggs, Jennifer, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Chambers, Tim, Nye, Emma, Graca, Sofia, Al Bakir, Maise, Hartley, John A., Lowe, Helen L., Herrero, Javier, Lawrence, David, Hayward, Martin, Panagiotopoulos, Nikolaos, Kolvekar, Shyam, Falzon, Mary, Borg, Elaine, Simeon, Celia, Hector, Gemma, Smith, Amy, Aranda, Marie, Novelli, Marco, Oukrif, Dahmane, Janes, Sam M., Thakrar, Ricky, Forster, Martin, Ahmad, Tanya, Lee, Siow Ming, Papadatos-Pastos, Dionysis, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Ahmed, Asia, Taylor, Magali, Choudhary, Junaid, Summers, Yvonne, Califano, Raffaele, Taylor, Paul, Shah, Rajesh, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Crosbie, Phil, Moss, Stuart, Idries, Faiza, Joseph, Leena, Bishop, Paul, Chaturved, Anshuman, Quinn, Anne Marie, Doran, Helen, Leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Novasio, Juliette, Blackhall, Fiona, Rogan, Jane, Smith, Elaine, Dive, Caroline, Tugwood, Jonathan, Brady, Ged, Rothwell, Dominic G., Chemi, Francesca, Pierce, Jackie, Gulati, Sakshi, Naidu, Babu, Langman, Gerald, Trotter, Simon, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Middleton, Gary, Djearaman, Madava, Fennell, Dean, Shaw, Jacqui A., Le Quesne, John, Moore, David, Nakas, Apostolos, Rathinam, Sridhar, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Riley, Joan, Primrose, Lindsay, Martinson, Luke, Anand, Girija, Khan, Sajid, Amadi, Anita, Nicolson, Marianne, Kerr, Keith, Palmer, Shirley, Remmen, Hardy, Miller, Joy, Buchan, Keith, Chetty, Mahendran, Gomersall, Lesley, Lester, Jason, Edwards, Alison, Morgan, Fiona, Adams, Haydn, Davies, Helen, Kornaszewska, Malgorzata, Attanoos, Richard, Lock, Sara, Verjee, Azmina, MacKenzie, Mairead, Wilcox, Maggie, Bell, Harriet, Iles, Natasha, Hackshaw, Allan, Ngai, Yenting, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Barbosa, Monica Tavares, Bowman, Alex, Jorda, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Cufari, Maria Elena, Ronquillo, John Carlo, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Nicholson, Andrew G., Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Ezhil, Veni, Ismail, Babikir, Irvin-sellers, Melanie, Prakash, Vineet, Russell, Peter, Light, Teresa, Horey, Tracey, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Fisher, Patricia, Keerio, Allah Dino, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, and Asante-Siaw, Julius
- Subjects
hemic and immune systems ,chemical and pharmacologic phenomena ,R1 - Abstract
Summary\ud \ud CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
- Published
- 2017
9. The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2
- Author
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Hartwig, Torsten, Montinaro, Antonella, von Karstedt, Silvia, Sevko, Alexandra, Surinova, Silvia, Chakravarthy, Ankur, Taraborrelli, Lucia, Draber, Peter, Lafont, Elodie, Arce Vargas, Frederick, El-Bahrawy, Mona A., Quezada, Sergio A., Walczak, Henning, and Biotechnology and Biological Sciences Research Council (BBSRC)
- Subjects
Lung Neoplasms ,Time Factors ,TRAIL-R ,Fas-Associated Death Domain Protein ,NF-KAPPA-B ,MDSC ,TRAIL ,Mice, SCID ,TNF-Related Apoptosis-Inducing Ligand ,HEPATOCELLULAR-CARCINOMA ,Carcinoma, Non-Small-Cell Lung ,cytokine ,Tumor Microenvironment ,SUPPRESSOR-CELLS ,IN-VIVO ,Chemokine CCL2 ,Caspase 8 ,11 Medical And Health Sciences ,APOPTOSIS ,Tumor Burden ,Phenotype ,LIGAND TRAIL ,Cytokines ,Female ,RNA Interference ,Life Sciences & Biomedicine ,CCL2 ,Signal Transduction ,EXPRESSION ,Biochemistry & Molecular Biology ,CHEMOTHERAPEUTIC DRUGS ,tumor ,Receptors, CCR2 ,CELL LUNG-CANCER ,Adenocarcinoma ,Transfection ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,Science & Technology ,Macrophages ,Cell Biology ,06 Biological Sciences ,HCT116 Cells ,microenvironment ,Mice, Inbred C57BL ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,A549 Cells ,Hela Cells ,FADD ,CCR2 ,TUMORICIDAL ACTIVITY ,Developmental Biology - Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology.
- Published
- 2017
10. The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2
- Author
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Hartwig, Torsten, primary, Montinaro, Antonella, additional, von Karstedt, Silvia, additional, Sevko, Alexandra, additional, Surinova, Silvia, additional, Chakravarthy, Ankur, additional, Taraborrelli, Lucia, additional, Draber, Peter, additional, Lafont, Elodie, additional, Arce Vargas, Frederick, additional, El-Bahrawy, Mona A., additional, Quezada, Sergio A., additional, and Walczak, Henning, additional
- Published
- 2017
- Full Text
- View/download PDF
11. Immunomodulatory antibodies for the treatment of lymphoma: Report on the CALYM Workshop.
- Author
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UCL - SSS/DDUV - Institut de Duve, Houot, Roch, Gaulard, Philippe, Schreiber, Robert, Mellman, Ira, Lambotte, Olivier, Coulie, Pierre, Fest, Thierry, Korman, Alan, Levy, Ronald, Shipp, Margaret, Tarte, Karin, Kohrt, Holbrook, Marabelle, Aurélien, Ansell, Stephen, Watier, Hervé, van Elsas, Andrea, Balakumaran, Arun, Arce Vargas, Frederick, Quezada, Sergio A, Salles, Gilles, Olive, Daniel, UCL - SSS/DDUV - Institut de Duve, Houot, Roch, Gaulard, Philippe, Schreiber, Robert, Mellman, Ira, Lambotte, Olivier, Coulie, Pierre, Fest, Thierry, Korman, Alan, Levy, Ronald, Shipp, Margaret, Tarte, Karin, Kohrt, Holbrook, Marabelle, Aurélien, Ansell, Stephen, Watier, Hervé, van Elsas, Andrea, Balakumaran, Arun, Arce Vargas, Frederick, Quezada, Sergio A, Salles, Gilles, and Olive, Daniel
- Abstract
In November 2015, the CALYM Carnot Institute held a 2-d workshop to discuss the current and future development of immunomodulatory antibodies for the treatment of lymphoma. Highlights from the workshop are presented in this article.
- Published
- 2016
12. Immunomodulatory antibodies for the treatment of lymphoma: Report on the CALYM Workshop
- Author
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Houot, Roch, primary, Gaulard, Philippe, additional, Schreiber, Robert, additional, Mellman, Ira, additional, Lambotte, Olivier, additional, Coulie, Pierre G., additional, Fest, Thierry, additional, Korman, Alan, additional, Levy, Ronald, additional, Shipp, Margaret, additional, Tarte, Karin, additional, Kohrt, Holbrook, additional, Marabelle, Aurélien, additional, Ansell, Stephen, additional, Watier, Hervé, additional, van Elsas, Andrea, additional, Balakumaran, Arun, additional, Arce Vargas, Frederick, additional, Quezada, Sergio A., additional, Salles, Gilles, additional, and Olive, Daniel, additional
- Published
- 2016
- Full Text
- View/download PDF
13. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
- Author
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Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, and Quezada SA
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological pharmacology, CTLA-4 Antigen antagonists & inhibitors, Cell Line, Tumor, Female, Humans, Ipilimumab administration & dosage, Ipilimumab pharmacology, Melanoma genetics, Melanoma immunology, Mice, Receptors, IgG metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological administration & dosage, Melanoma drug therapy, Polymorphism, Single Nucleotide, Receptors, IgG genetics, T-Lymphocytes, Regulatory immunology
- Abstract
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8
+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
14. Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
- Author
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Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Miranda Rota E, Dahan R, Georgiou A, Sledzinska A, Ben Aissa A, Franz D, Werner Sunderland M, Wong YNS, Henry JY, O'Brien T, Nicol D, Challacombe B, Beers SA, Turajlic S, Gore M, Larkin J, Swanton C, Chester KA, Pule M, Ravetch JV, Marafioti T, Peggs KS, and Quezada SA
- Subjects
- Animals, Antibodies, Monoclonal metabolism, Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Flow Cytometry, Humans, Immunotherapy methods, K562 Cells, Kaplan-Meier Estimate, Lymphocyte Depletion, Mice, Neoplasms pathology, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Protein Binding immunology, Receptors, IgG immunology, Receptors, IgG metabolism, T-Lymphocytes, Regulatory metabolism, Antibodies, Monoclonal immunology, Immunoglobulin Fc Fragments immunology, Interleukin-2 Receptor alpha Subunit immunology, Neoplasms immunology, Programmed Cell Death 1 Receptor immunology, T-Lymphocytes, Regulatory immunology
- Abstract
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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