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.
Highlights
Adoptive transfer of ex vivo expanded autologous tumorinfiltrating lymphocytes together followed by one to two cycles of high-dose IL-2 therapy has emerged in multiple Phase II clinical trials to be one of the most powerful therapies for unresectable metastatic melanoma [1,2,3,4]
For these experiments tumor-infiltrating lymphocytes (TIL) were labeled with CFSE to distinguish them from the feeder cells before being activated by anti-CD3 in the rapid expansion protocol’’ (REP). 4-1BB is upregulated on T cells 24–48 hours after activation [14,17]
We have found that both the total number of TIL and CD8+ T cells within the infused TIL are critical in mediating tumor regression associated with improved overall survival in melanoma patients receiving TIL therapy [3]
Summary
Adoptive transfer of ex vivo expanded autologous tumorinfiltrating lymphocytes together followed by one to two cycles of high-dose IL-2 therapy has emerged in multiple Phase II clinical trials to be one of the most powerful therapies for unresectable metastatic melanoma [1,2,3,4]. Our group at MD Anderson Cancer Center (MDACC) has recently completed a study on 31 metastatic patients that have failed multiple first- and second- line therapies using this regimen and reported a 48% clinical response rate [3]. One of the key issues in TIL therapy when determining whether objective tumor regression will occur is the phenotype of the T cells infused and their persistence in vivo following adoptive transfer. Recent data from our group and others has found that higher frequencies and total numbers of infused effector-memory CD8+ T cells correlated highly with clinical response suggesting that CD8+ T cells in the TIL infusion product are the most critical T cells mediating objective tumor regression [1,3,10]. Other studies have found that expanded CD8+ TIL maintaining CD28 expression and other effector-memory phenotypic markers, such as CD27, are associated with longer telomere
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