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2. Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

Author

Zhou, Xueyuan, Geyer, Felix Klaus, Happel, Dominic, Takimoto, Jeffrey, Kolmar, Harald, Rabinovich, Brian, Zhou, Xueyuan, Geyer, Felix Klaus, Happel, Dominic, Takimoto, Jeffrey, Kolmar, Harald, and Rabinovich, Brian

Abstract

T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a “cytokine window” defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed.

Published
2024

4. Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers

Author

Boje, Ammelie Svea, primary, Pekar, Lukas, additional, Koep, Katharina, additional, Lipinski, Britta, additional, Rabinovich, Brian, additional, Evers, Andreas, additional, Gehlert, Carina Lynn, additional, Krohn, Steffen, additional, Xiao, Yanping, additional, Krah, Simon, additional, Zaynagetdinov, Rinat, additional, Toleikis, Lars, additional, Poetzsch, Sven, additional, Peipp, Matthias, additional, Zielonka, Stefan, additional, and Klausz, Katja, additional

Published
2024
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5. Figure S4 from M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation

Author

Xu, Chunxiao, primary, Zhou, Xueyuan, primary, Webb, Lindsay, primary, Yalavarthi, Sireesha, primary, Zheng, Wenxin, primary, Saha, Somdutta, primary, Schweickhardt, Rene, primary, Soloviev, Maria, primary, Jenkins, Molly H., primary, Brandstetter, Susanne, primary, Belousova, Natalya, primary, Alimzhanov, Marat, primary, Rabinovich, Brian, primary, Deshpande, Amit M., primary, Brewis, Neil, primary, and Helming, Laura, primary

Published
2024
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6. Supplementary Tables from M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation

Author

Xu, Chunxiao, primary, Zhou, Xueyuan, primary, Webb, Lindsay, primary, Yalavarthi, Sireesha, primary, Zheng, Wenxin, primary, Saha, Somdutta, primary, Schweickhardt, Rene, primary, Soloviev, Maria, primary, Jenkins, Molly H., primary, Brandstetter, Susanne, primary, Belousova, Natalya, primary, Alimzhanov, Marat, primary, Rabinovich, Brian, primary, Deshpande, Amit M., primary, Brewis, Neil, primary, and Helming, Laura, primary

Published
2024
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7. Data from M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation

Author

Xu, Chunxiao, primary, Zhou, Xueyuan, primary, Webb, Lindsay, primary, Yalavarthi, Sireesha, primary, Zheng, Wenxin, primary, Saha, Somdutta, primary, Schweickhardt, Rene, primary, Soloviev, Maria, primary, Jenkins, Molly H., primary, Brandstetter, Susanne, primary, Belousova, Natalya, primary, Alimzhanov, Marat, primary, Rabinovich, Brian, primary, Deshpande, Amit M., primary, Brewis, Neil, primary, and Helming, Laura, primary

Published
2024
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8. M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation

Author

Xu, Chunxiao, primary, Zhou, Xueyuan, additional, Webb, Lindsay, additional, Yalavarthi, Sireesha, additional, Zheng, Wenxin, additional, Saha, Somdutta, additional, Schweickhardt, Rene, additional, Soloviev, Maria, additional, Jenkins, Molly H., additional, Brandstetter, Susanne, additional, Belousova, Natalya, additional, Alimzhanov, Marat, additional, Rabinovich, Brian, additional, Deshpande, Amit M., additional, Brewis, Neil, additional, and Helming, Laura, additional

Published
2023
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9. A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A, Trejo, Christy L, Silva, Jillian M, Gu, Shenda, Korkola, James E, Heiser, Laura M, Charles, Roch-Philippe, Rabinovich, Brian A, Hann, Byron, Dankort, David, Spellman, Paul T, Phillips, Wayne A, Gray, Joe W, and McMahon, Martin

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Rare Diseases, Pancreatic Cancer, Cancer, Genetics, Digestive Diseases, Good Health and Well Being, Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Transformation, Neoplastic, Extracellular Signal-Regulated MAP Kinases, Genes, ras, Humans, Immunoblotting, Immunohistochemistry, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Pancreatic Neoplasms, Proto-Oncogene Proteins B-raf, Oncology and Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledKRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAF(V600E), but not PIK3CA(H1047R), in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAF(V600E) and TP53(R270H) result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.SignificancePDA is diffi cult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we defi ne rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3'K)→AKT.

Published
2012

10. Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager.

Author

Xueyuan Zhou, Geyer, Felix Klaus, Happel, Dominic, Takimoto, Jeffrey, Kolmar, Harald, and Rabinovich, Brian

Subjects
CYTOTOXINS, T cells, CYTOKINE release syndrome, BISPECIFIC antibodies, CYTOKINES
Abstract

T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a "cytokine window" defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Supplementary Table 1 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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12. Data from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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13. Supplementary Table 2 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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14. Supplementary Figure Legends 1-5, Table Legends 1-2 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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15. Supplementary Figure 4 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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16. Supplementary Materials and Methods from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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17. Supplementary Figure 5 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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18. Supplementary Figure 1 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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19. Supplementary Figure 2 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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20. Supplementary Figure 3 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Author

Collisson, Eric A., primary, Trejo, Christy L., primary, Silva, Jillian M., primary, Gu, Shenda, primary, Korkola, James E., primary, Heiser, Laura M., primary, Charles, Roch-Philippe, primary, Rabinovich, Brian A., primary, Hann, Byron, primary, Dankort, David, primary, Spellman, Paul T., primary, Phillips, Wayne A., primary, Gray, Joe W., primary, and McMahon, Martin, primary

Published
2023
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22. Supplementary Figures 1 and 2 from Src Inhibition with Saracatinib Reverses Fulvestrant Resistance in ER-Positive Ovarian Cancer Models In Vitro and In Vivo

Author

Simpkins, Fiona, primary, Hevia-Paez, Pedro, primary, Sun, Jun, primary, Ullmer, Wendy, primary, Gilbert, Candace A., primary, da Silva, Thiago, primary, Pedram, Ali, primary, Levin, Ellis R., primary, Reis, Isildinha M., primary, Rabinovich, Brian, primary, Azzam, Diana, primary, Xu, Xiang-Xi, primary, Ince, Tan A., primary, Yang, Ji-Yeon, primary, Verhaak, Roel G.W., primary, Lu, Yiling, primary, Mills, Gordon B., primary, and Slingerland, Joyce M., primary

Published
2023
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23. Supplementary Table 1 from Src Inhibition with Saracatinib Reverses Fulvestrant Resistance in ER-Positive Ovarian Cancer Models In Vitro and In Vivo

Author

Simpkins, Fiona, primary, Hevia-Paez, Pedro, primary, Sun, Jun, primary, Ullmer, Wendy, primary, Gilbert, Candace A., primary, da Silva, Thiago, primary, Pedram, Ali, primary, Levin, Ellis R., primary, Reis, Isildinha M., primary, Rabinovich, Brian, primary, Azzam, Diana, primary, Xu, Xiang-Xi, primary, Ince, Tan A., primary, Yang, Ji-Yeon, primary, Verhaak, Roel G.W., primary, Lu, Yiling, primary, Mills, Gordon B., primary, and Slingerland, Joyce M., primary

Published
2023
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24. Supplementary Video D from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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26. Supplementary figure 5 from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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27. Tables 1 and 2 from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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28. Supplementary Video E from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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29. Supplementary figure 1 and 2 from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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30. Supplementary Materials and Methods, Figures 1 - 13, Table 1 from Activating and Propagating Polyclonal Gamma Delta T Cells with Broad Specificity for Malignancies

Author

Deniger, Drew C., primary, Maiti, Sourindra N., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Ramachandran, Vijaya, primary, Hurton, Lenka V., primary, Ang, Sonny, primary, Olivares, Simon, primary, Rabinovich, Brian A., primary, Huls, M. Helen, primary, Lee, Dean A., primary, Bast, Robert C., primary, Champlin, Richard E., primary, and Cooper, Laurence J.N., primary

Published
2023
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31. Supplementary materials from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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32. Supplementary Video A from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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33. Supplementary figure 3 and 4 from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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35. Supplementary Video C from Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma

Author

Krishnamurthy, Janani, primary, Rabinovich, Brian A., primary, Mi, Tiejuan, primary, Switzer, Kirsten C., primary, Olivares, Simon, primary, Maiti, Sourindra N., primary, Plummer, Joshua B., primary, Singh, Harjeet, primary, Kumaresan, Pappanaicken R., primary, Huls, Helen M., primary, Wang-Johanning, Feng, primary, and Cooper, Laurence J.N., primary

Published
2023
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36. Supplementary Methods, Tables 1-3, Figures 1-4 from Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Author

O'Toole, Sandra A., primary, Machalek, Dorothy A., primary, Shearer, Robert F., primary, Millar, Ewan K.A., primary, Nair, Radhika, primary, Schofield, Peter, primary, McLeod, Duncan, primary, Cooper, Caroline L., primary, McNeil, Catriona M., primary, McFarland, Andrea, primary, Nguyen, Akira, primary, Ormandy, Christopher J., primary, Qiu, Min Ru, primary, Rabinovich, Brian, primary, Martelotto, Luciano G., primary, Vu, Duc, primary, Hannigan, Gregory E., primary, Musgrove, Elizabeth A., primary, Christ, Daniel, primary, Sutherland, Robert L., primary, Watkins, D. Neil, primary, and Swarbrick, Alexander, primary

Published
2023
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37. Data from Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Author

O'Toole, Sandra A., primary, Machalek, Dorothy A., primary, Shearer, Robert F., primary, Millar, Ewan K.A., primary, Nair, Radhika, primary, Schofield, Peter, primary, McLeod, Duncan, primary, Cooper, Caroline L., primary, McNeil, Catriona M., primary, McFarland, Andrea, primary, Nguyen, Akira, primary, Ormandy, Christopher J., primary, Qiu, Min Ru, primary, Rabinovich, Brian, primary, Martelotto, Luciano G., primary, Vu, Duc, primary, Hannigan, Gregory E., primary, Musgrove, Elizabeth A., primary, Christ, Daniel, primary, Sutherland, Robert L., primary, Watkins, D. Neil, primary, and Swarbrick, Alexander, primary

Published
2023
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41. Multifunctional NK Cell–Engaging Antibodies Targeting EGFR and NKp30 Elicit Efficient Tumor Cell Killing and Proinflammatory Cytokine Release

Author

Klausz, Katja, primary, Pekar, Lukas, additional, Boje, Ammelie Svea, additional, Gehlert, Carina Lynn, additional, Krohn, Steffen, additional, Gupta, Tushar, additional, Xiao, Yanping, additional, Krah, Simon, additional, Zaynagetdinov, Rinat, additional, Lipinski, Britta, additional, Toleikis, Lars, additional, Poetzsch, Sven, additional, Rabinovich, Brian, additional, Peipp, Matthias, additional, and Zielonka, Stefan, additional

Published
2022
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42. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Author

Kumaresan, Pappanaicken R., Manuri, Pallavi R., Albert, Nathaniel D., Maiti, Sourindra, Singh, Harjeet, Mi, Tiejuan, Roszik, Jason, Rabinovich, Brian, Olivares, Simon, Krishnamurthy, Janani, Zhang, Ling, Najjar, Amer M., Huls, M. Helen, Lee, Dean A., Champlin, Richard E., Kontoyiannis, Dimitrios P., and Cooper, Laurence J. N.

Published
2014

48. Persistent antigen at vaccination sites induces tumor-specific [CD8.sup.+] T cell sequestration, dysfunction and deletion

Author

Hailemichael, Yared, Dai, Zhimin, Jaffarzad, Nina, Ye, Yang, Medina, Miguel A., Huang, Xue-Fei, Dorta-Estremera, Stephanie M., Greeley, Nathaniel R., Nitti, Giovanni, Peng, Weiyi, Liu, Chengwen, Lou, Yanyan, Wang, Zhiqiang, Ma, Wencai, Rabinovich, Brian, Schluns, Kimberly S., Davis, Richard E., Hwu, Patrick, and Overwijk, Willem W.

Subjects
Vaccination -- Health aspects -- Analysis -- Research, T cells -- Physiological aspects -- Analysis -- Research, Melanoma -- Research, Biological sciences, Health
Abstract

To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific [CD8.sup.+] T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines., Cancer vaccines have shown objective therapeutic benefit in several recent randomized clinical trials (1-5), but a pressing question remains why many vaccinated patients show increased numbers of circulating tumor-specific T [...]

Published
2013
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50. Plasmacytoid dendritic cells induce NK cell--dependent, tumor antigen--specific T cell cross-priming and tumor regression in mice

Author

Liu, Chengwen, Lou, Yanyan, Lizee, Gregory, Qin, Hong, Liu, Shujuan, Rabinovich, Brian, Kim, Grace J., Wang, Yi-Hong, Ye, Yang, Sikora, Andrew G., Overwijk, Willem W., Liu, Yong-Jun, Wang, Gang, and Hwu, Patrick

Subjects
Cellular immunity -- Health aspects, Cellular immunity -- Research, Dendritic cells -- Physiological aspects, Dendritic cells -- Health aspects, Dendritic cells -- Research, Immunohistochemistry -- Health aspects, Immunohistochemistry -- Research
Abstract

A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-[gamma] production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and [CD8.sup.+] T cells., Introduction Accumulating evidence suggests that the generation of potent adaptive immunity is dependent on the initial stimulation of a strong innate immune response (1), (2). Pathogen exposure generates robust T [...]

Published
2008

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