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31 results on '"Nguyen, Sang M."'

3. Tuning the Antigen Density Requirement for CAR T-cell Activity

Author

Majzner, Robbie G, Rietberg, Skyler P, Sotillo, Elena, Dong, Rui, Vachharajani, Vipul T, Labanieh, Louai, Myklebust, June H, Kadapakkam, Meena, Weber, Evan W, Tousley, Aidan M, Richards, Rebecca M, Heitzeneder, Sabine, Nguyen, Sang M, Wiebking, Volker, Theruvath, Johanna, Lynn, Rachel C, Xu, Peng, Dunn, Alexander R, Vale, Ronald D, and Mackall, Crystal L

Subjects
Cancer, Vaccine Related, Immunization, Animals, Humans, Mice, Receptors, Chimeric Antigen, Signal Transduction, Oncology and Carcinogenesis
Abstract

Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence. SIGNIFICANCE: Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.This article is highlighted in the In This Issue feature, p. 627.

Published
2020

7. A prospective 'test-and-treat' demonstration project among people who inject drugs in Vietnam

Author

Nguyen, Hai H., Bui, Duong D., Dinh, Thuy T.T., Pham, Loc Q., Nguyen, Van T.T., Tran, Tram H., Pham, Thang H., Nguyen, Sang M., Suthar, Amitabh B., Do, Nhan T., Ford, Nathan, Lo, Ying-Ru, Nguyen, Long Hoang, and Giang, Le M.

Subjects
HIV infections -- Risk factors -- Prevention -- Drug therapy, Disease transmission -- Control, Antiretroviral agents -- Dosage and administration, Health
Abstract

Introduction: Modelling suggests that early diagnosis and immediate antiretroviral therapy (ART) among key populations would have a substantial impact in reducing HIV transmission and mortality in Vietnam. An implementation research project of 'test-and-treat' among people who inject drugs (PWID) was developed to inform effective roll-out of such interventions. Methods: 'Test-and-treat' was offered to PWID in two high burden provinces, Thai Nguyen and Thanh Hoa. The interventions comprised the offer of biannual HIV testing and immediate ART, irrespective of CD4 count. PWID were enrolled between April 2014 and July 2015 and followed up for 12 months, and retention, HIV viral load (VL) and risk behaviours were assessed. Retention in care of this prospective cohort was compared with the retention among men enrolled in care in the preceding period (April 2012 to March 2013) at the same clinics when ART was initiated at CD4 cell count [less than or equal to]350 cells/[mm.sup.3]. Results: In total, 287 HIV positive PWID started immediate ART. The majority (98%) were men; median age was 34; and median (interquartile range) CD4 count was 199 (50 to 402) cells/[mm.sup.3]. After 12 months, 238 participants (83%) were retained on ART, and 205 achieved viral suppression ( Keywords: antiretroviral therapy; people who inject drugs; Vietnam; viral suppression; retention; test-and-treat; risk behaviour, 1 | INTRODUCTION Vietnam's HIV epidemic has been concentrated in key populations, with injection drug use being the dominant mode of transmission, like in many Asian and Eastern European countries [...]

Published
2018
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9. Supplementary Data from Tuning the Antigen Density Requirement for CAR T-cell Activity

Author

Majzner, Robbie G., primary, Rietberg, Skyler P., primary, Sotillo, Elena, primary, Dong, Rui, primary, Vachharajani, Vipul T., primary, Labanieh, Louai, primary, Myklebust, June H., primary, Kadapakkam, Meena, primary, Weber, Evan W., primary, Tousley, Aidan M., primary, Richards, Rebecca M., primary, Heitzeneder, Sabine, primary, Nguyen, Sang M., primary, Wiebking, Volker, primary, Theruvath, Johanna, primary, Lynn, Rachel C., primary, Xu, Peng, primary, Dunn, Alexander R., primary, Vale, Ronald D., primary, and Mackall, Crystal L., primary

Published
2023
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10. Data from Tuning the Antigen Density Requirement for CAR T-cell Activity

Author

Majzner, Robbie G., primary, Rietberg, Skyler P., primary, Sotillo, Elena, primary, Dong, Rui, primary, Vachharajani, Vipul T., primary, Labanieh, Louai, primary, Myklebust, June H., primary, Kadapakkam, Meena, primary, Weber, Evan W., primary, Tousley, Aidan M., primary, Richards, Rebecca M., primary, Heitzeneder, Sabine, primary, Nguyen, Sang M., primary, Wiebking, Volker, primary, Theruvath, Johanna, primary, Lynn, Rachel C., primary, Xu, Peng, primary, Dunn, Alexander R., primary, Vale, Ronald D., primary, and Mackall, Crystal L., primary

Published
2023
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11. Supplementary Figures and Table from Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence

Author

Ramakrishna, Sneha, primary, Highfill, Steven L., primary, Walsh, Zachary, primary, Nguyen, Sang M., primary, Lei, Haiyan, primary, Shern, Jack F., primary, Qin, Haiying, primary, Kraft, Ira L., primary, Stetler-Stevenson, Maryalice, primary, Yuan, Constance M., primary, Hwang, Jennifer D., primary, Feng, Yang, primary, Zhu, Zhongyu, primary, Dimitrov, Dimiter, primary, Shah, Nirali N., primary, and Fry, Terry J., primary

Published
2023
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15. Association of Fruit, Vegetable, and Animal Food Intakes with Breast Cancer Risk Overall and by Molecular Subtype among Vietnamese Women

Author

Nguyen, Sang M., primary, Tran, Huong T.T., additional, Nguyen, Lan M., additional, Bui, Oanh Thi, additional, Hoang, Dong V., additional, Shrubsole, Martha J., additional, Cai, Qiuyin, additional, Ye, Fei, additional, Zheng, Wei, additional, Luu, Hung N., additional, Tran, Thuan V., additional, and Shu, Xiao-Ou, additional

Published
2022
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16. Sharing Best Practice: Establishing a National Vietnamese Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Consortium

Author

Nguyen, Sang M., primary, Huynh, Phu D.V., additional, Abramovitz, Linda, additional, Agrawal, Anu, additional, Assanasen, Chatchawin, additional, Blair, Sally, additional, Chu, Minh H., additional, Faulkner, Lawrence, additional, Hoang, Tram T.A., additional, Ho, Hang T.K., additional, Horn, Biljana, additional, Huynh, Chau T.B., additional, Le, Anh H., additional, Le, Phuong B., additional, Le, Son T., additional, Noonan, Nancy, additional, Nguyen, Dinh V., additional, Nguyen, Hang T.T., additional, Nguyen, Hoa T.K., additional, Nguyen, Nam H., additional, Nguyen, Nhai T., additional, Nguyen, Tho T., additional, Oh, Jess, additional, Palma, Julia, additional, Phan, Trang T.T., additional, Pham, Anh T.N., additional, Pham, Tuan M., additional, Rees, Hannah, additional, Tan, Poh-Lin, additional, Tran, My, additional, Vo, Binh T.T., additional, Watanabe, Kazuyo, additional, Yi, Hyeon Gyu, additional, Bui, Lan N., additional, and Hermiston, Michelle, additional

Published
2022
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22. 444 - Sharing Best Practice: Establishing a National Vietnamese Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy Consortium

Author

Nguyen, Sang M., Huynh, Phu D.V., Abramovitz, Linda, Agrawal, Anu, Assanasen, Chatchawin, Blair, Sally, Chu, Minh H., Faulkner, Lawrence, Hoang, Tram T.A., Ho, Hang T.K., Horn, Biljana, Huynh, Chau T.B., Le, Anh H., Le, Phuong B., Le, Son T., Noonan, Nancy, Nguyen, Dinh V., Nguyen, Hang T.T., Nguyen, Hoa T.K., Nguyen, Nam H., Nguyen, Nhai T., Nguyen, Tho T., Oh, Jess, Palma, Julia, Phan, Trang T.T., Pham, Anh T.N., Pham, Tuan M., Rees, Hannah, Tan, Poh-Lin, Tran, My, Vo, Binh T.T., Watanabe, Kazuyo, Yi, Hyeon Gyu, Bui, Lan N., and Hermiston, Michelle

Published
2022
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23. Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence

Author

Ramakrishna, Sneha, primary, Highfill, Steven L., additional, Walsh, Zachary, additional, Nguyen, Sang M., additional, Lei, Haiyan, additional, Shern, Jack F., additional, Qin, Haiying, additional, Kraft, Ira L., additional, Stetler-Stevenson, Maryalice, additional, Yuan, Constance M., additional, Hwang, Jennifer D., additional, Feng, Yang, additional, Zhu, Zhongyu, additional, Dimitrov, Dimiter, additional, Shah, Nirali N., additional, and Fry, Terry J., additional

Published
2019
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24. Low CD19 Antigen Density Diminishes Efficacy of CD19 CAR T Cells and Can be Overcome By Rational Redesign of CAR Signaling Domains

Author

Majzner, Robbie G., primary, Rietberg, Skyler P., additional, Labanieh, Louai, additional, Sotillo, Elena, additional, Weber, Evan W., additional, Lynn, Rachel C., additional, Theruvath, Johanna L., additional, Yuan, Constance M., additional, Xu, Peng, additional, Nguyen, Sang M., additional, Shah, Nirali N., additional, Stetler-Stevenson, Maryalice, additional, Fry, Terry J., additional, Lee, Daniel W., additional, and Mackall, Crystal L., additional

Published
2018
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28. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Author

Jacoby, Elad, primary, Nguyen, Sang M., additional, Fountaine, Thomas J., additional, Welp, Kathryn, additional, Gryder, Berkley, additional, Qin, Haiying, additional, Yang, Yinmeng, additional, Chien, Christopher D., additional, Seif, Alix E., additional, Lei, Haiyan, additional, Song, Young K., additional, Khan, Javed, additional, Lee, Daniel W., additional, Mackall, Crystal L., additional, Gardner, Rebecca A., additional, Jensen, Michael C., additional, Shern, Jack F., additional, and Fry, Terry J., additional

Published
2016
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29. The use of technology to find sexual health information online among men who have sex with men in Hanoi, Vietnam, 2016.

Author

Nguyen, Minh X., Krishnan, Aparna, Le, Giang M., Nguyen, Quynh T., Bhadra, Nia M., Nguyen, Sang M., Miller, William C., and Go, Vivian F.

Subjects
SEXUAL health, MEDICAL informatics, MEN who have sex with men, DISEASE prevalence, PUBLIC health
Abstract

In an era where mobile phones and computers are ubiquitous, technology-based interventions to reduce HIV and other sexually transmitted infections (STIs) have great potential to reach high-risk groups, including men who have sex with men (MSM). This study aimed to examine technology usage to find sexual health information online among MSM in Hanoi, Vietnam. A cross-sectional study of 205 MSM in Hanoi was conducted from February to May 2016. Overall, 50.7% of participants reported having used a smartphone, computer, or tablet to find HIV/STI testing locations in the past year, and 75.1% reported having used such devices to find other HIV/STI information online. Unemployment (adjusted prevalence ratio [aPR]: 1.13, 95%CI: 1.00-1.28) and having been tested for HIV (aPR: 1.27, 95%CI: 1.07-1.51) were significantly associated with using technology to find online sexual health information. MSM who had ever exchanged sex for money or drugs (aPR: 0.80; 95%CI: 0.68-0.94) were less likely to use technology to find sexual health information online. Technology is a promising platform for HIV/STI prevention programs among MSM, with the potential to reach different subgroups. Further efforts to develop technology-based interventions tailored to the needs of the MSM communities in Hanoi and to encourage MSM who were not currently seeking sexual health information and testing services online to do so are necessary. [ABSTRACT FROM AUTHOR]

Published
2018
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31. Modulation of CD22 Antigen Density Improves Efficacy of CD22 Chimeric Antigen Receptor (CAR) T Cells Against CD22loB-Lineage Leukemia and Lymphoma

Author

Ramakrishna, Sneha, Nguyen, Sang M, Qin, Haiying, Highfill, Steven L, Kraft, Ira, Shern, John, Walsh, Zachary, Dimitrov, Dimiter, and Fry, Terry J

Abstract

While overall survival for acute lymphoblastic leukemia (ALL) in children treated with risk-adapted, multi-agent chemotherapeutic regimens is greater than 85%, relapsed ALL remains a major challenge. Chimeric antigen receptor (CAR) T cell therapy targeting CD19 provides these patients with a remission induction rate of 70-90% across multiple clinical trials, but loss of the targeted epitope results in relapse following CD19 CAR T cells. In the setting of these relapses, our group conducted a CD22 CAR T cell trial, which induces remission in approximately 70% percent of patients with relapsed/refractory CD22-positive pre-B cell ALL, including those relapsing after CD19 CAR therapy (NCT02315612). However, relapse associated with reduced CD22 site density has shortened remission duration in some patients. To test the impact of low CD22 site density on CD22 CAR T cell functionality, we modified Nalm6 ALL cell lines using CRISPR/Cas9 to eliminate the CD22 gene, followed by lentiviral transduction of full-length CD22 and single-cell cloning based on CD22 expression levels. CD22 site density was assessed with the Quantibrite-PE Assay Kit and four cell lines were identified for a spectrum of CD22 expression: CD22 negative (CD22neg); CD22 low (CD22lo) - site density comparable to that seen in ALL patients relapsing following CD22 CAR therapy; CD22 normal (Nalm6) - site density comparable to ALL CD22 expression; and CD22 high (CD22hi) - site density comparable to CD19 levels. As CD22 site density decreases, CD22 CAR T cells produce incrementally less interferon-gamma and do not produce IL-2 against CD22loALL. CD22 CAR delayed, but was unable to prevent, progression of CD22loALL in murine xenografts. We next evaluated two potential approaches to overcoming low site density antigen escape: improving CAR activity or increasing tumor sensitivity. To improve CAR activity, we generated a high-binding affinity CD22 CAR (CD22 CARH1) using an affinity-enhanced version of the scFv from the CD22 CAR construct in our ongoing trial. Despite higher affinity, the CD22 CARH1T cell did not improve in vitrokilling or in vivoclearance of CD22loALL. To increase tumor sensitivity, we sought to increase CD22 site density using the PKC inhibitor Bryostatin1, a drug previously shown to increase CD22 expression in CLL. Bryostatin1 increases CD22 site density on a panel of pre-B cell ALL and diffuse large B cell lymphoma (DLBCL) cell lines. Interestingly, the CD22 increase is durable for at least 1 week after exposure to Bryostatin1. Bryostatin1-mediated CD22 increased site density improves cytokine production by CD22 CAR T cells. To evaluate the mechanism of Bryostatin1-mediated upregulation of CD22 expression, RNAseq was performed on Bryostatin1-exposed ALL. Preliminary analysis demonstrates that Bryostatin1 does not directly affect CD22 mRNA expression levels, but modulates early transcription factors within the B-cell receptor pathway. Based on these results, we are further evaluating pathways affected by Bryostatin1 through protein expression analysis and assessing in vivofunction of Bryostatin1 in the setting of a patient-derived CD22 CAR-resistant xenograft model. In conclusion, these results demonstrate a clear threshold antigen site density, below which the CD22 CAR is unable to clear CD22-expressing ALL. We further demonstrate that increased CD22 CAR affinity does not seem to improve CD22 CAR activity against CD22loALL. Bryostatin1-mediated CD22 modulation can improve CD22 CAR response against leukemia and lymphoma providing a potential rational combination to rescue CD22 CAR activity and remission durability.

Published
2017
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