Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy - PubMed (original) (raw)

Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy

Juhua Zhou et al. J Immunol. 2005.

Abstract

Recent studies have indicated that adoptive immunotherapy with autologous antitumor tumor-infiltrating lymphocytes (TILs) following nonmyeloablative chemotherapy mediates tumor regression in approximately 50% of treated patients with metastatic melanoma, and that tumor regression is correlated with the degree of persistence of adoptively transferred T cells in peripheral blood. These findings, which suggested that the proliferative potential of transferred T cells may play a role in clinical responses, led to the current studies in which telomere length as well as phenotypic markers expressed on the administered TILs were examined. TILs that were associated with objective clinical responses following adoptive transfer possessed a mean telomere length of 6.3 kb, whereas TILs that were not associated with significant clinical responses were significantly shorter, averaging 4.9 kb (p < 0.01). Furthermore, individual TIL-derived T cell clonotypes that persisted in vivo following adoptive cell transfer possessed telomeres that were longer than telomeres of T cell clonotypes that failed to persist (6.2 vs 4.5 kb, respectively; p < 0.001). Expression of the costimulatory molecule CD28 also appeared to be associated with long telomeres and T cell persistence. These results, indicating that the telomere length of transferred lymphocytes correlated with in vivo T cell persistence following adoptive transfer, and coupled with the previous observation that T cell persistence was associated with clinical responses in this adoptive immunotherapy trial, suggest that telomere length and the proliferative potential of the transferred T cells may play a significant role in mediating response to adoptive immunotherapy.

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Figures

Figure 1

Figure 1

Representative histograms of telomere flow-FISH assays of bulk administered TILs. Administered TIL samples were thawed and used in telomere flow-FISH assays without further culture. Shaded area represents the unstained control.

Figure 2

Figure 2

Telomere length of administered TIL is not correlated with age of TIL or patient age but is correlated with absolute lymphocyte count. The relationship was examined between telomere lengths of the administered TIL and patient age (A), or between the telomere lengths of the administered TILs and the TIL age (B). TIL age refers to the total number of days TIL were cultured in vitro. The association between the telomere lengths of the TIL prior to adoptive transfer and absolute lymphocyte counts in the peripheral blood obtained between 5 and 10 days following adoptive cell transfer (C) and between 19 and 37 days following adoptive cell transfer (D) was evaluated. All TIL samples were included if their corresponding data were available.

Figure 3

Figure 3

Correlation of telomere length of transferred lymphocytes with in vivo T cell persistence. The telomere lengths of transferred lymphocytes were compared with the total number of persistent T cells detected in patient peripheral blood samples obtained between 5 and 10 days following adoptive cell transfer (A) and between 19 and 37 days following adoptive transfer (B). In addition, the relative number of persistent T cells that were present in peripheral blood was calculated by determining the ratio of number of cells corresponding to individual persistent clonotypes that were originally present in the administered TIL to the number of those cells detected in peripheral blood at the two time points, assuming a total cell blood volume of 4 liters. A value of 1 indicates that the number of cells present in blood was equal to that present in the TIL. The relative cell numbers were calculated between 5 and 10 days (C) and between 19 and 37 days (D) following transfer. All clonotypes that were present in the administered TILs, as determined by sequencing the expressed TRBV gene products, and that were also detected in the peripheral blood at levels of 1% or greater in either sample, were included in this analysis.

Figure 4

Figure 4

Relationship between telomere lengths and CD28 expression of transferred T cell clonotypes. The percentage of CD28 expression on cells corresponding to individual clonotypes was determined by co-staining with anti-TCR Vbeta antibodies. Closed squares represented persistent clonotypes and closed circles represented non-persistent clonotypes.

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