التفاصيل البيبلوغرافية
| العنوان: |
Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy. |
| المؤلفون: |
Chacon, Jessica Ann, Wu, Richard C., Sukhumalchandra, Pariya, Molldrem, Jeffrey J., Sarnaik, Amod, Pilon-Thomas, Shari, Weber, Jeffrey, Hwu, Patrick, Radvanyi, Laszlo |
| المصدر: |
PLoS ONE; Apr2013, Vol. 8 Issue 4, p1-14, 14p |
| مصطلحات موضوعية: |
MELANOMA treatment, T cells, CELL physiology, LYMPHOCYTES, GENE expression, ANTINEOPLASTIC agents, MEDICAL statistics, IMMUNOLOGY |
| مستخلص: |
Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the “rapid expansion protocol” (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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