title: Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy.
abstract: 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.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jessica Ann
authors.initials: JA
authors.lastname: Chacon
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wu
authors.forename: Pariya
authors.initials: P
authors.lastname: Sukhumalchandra
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.forename: Amod
authors.initials: A
authors.lastname: Sarnaik
authors.forename: Shari
authors.initials: S
authors.lastname: Pilon-Thomas
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
mesh_terms: D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects; D016219:Immunotherapy, Adoptive; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000077022:Survivin; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000235:genetics* / Q000276:immunology
chemical_list: C107489:BIRC5 protein, human; D018106:CD28 Antigens; D007074:Immunoglobulin G; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
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