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Immunological response and overall survival in a subset of advanced renal cell carcinoma patients from a randomized phase 2/3 study of naptumomab estafenatox plus IFN-α versus IFN-α.

Elkord E, Burt DJ, Sundstedt A, Nordle Ö, Hedlund G, Hawkins RE - Oncotarget (2015)

Bottom Line: We found that Nap-specific T cells were reduced after 3 treatment days in patients' peripheral blood.The patients in the UK subset showed a tendency of OS benefit after Nap treatment.In conclusion, patients with low baseline IL-6 and normal anti-SEA/E-120 may respond well to Nap by T cell activation and expansion paving the way for anti-tumour effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Institute of Cancer Sciences, The University of Manchester, Manchester, UK.

ABSTRACT
Naptumomab estafenatox/ABR-217620/ANYARA (Nap) has been evaluated in clinical phase 1 and 2/3 studies. RCC patients in the phase 2/3 trial were randomized 1:1 in an open label study to receive Nap+IFN-α or IFN-α. In this study, we analyzed the UK patients for their immunological response in relation to prolonged overall survival (OS). We found that Nap-specific T cells were reduced after 3 treatment days in patients' peripheral blood. Levels of both Nap-specific CD4+ and CD8+ T cells were significantly higher 8 days after the first treatment. Patients with such pattern of reduction and expansion of Nap-binding T cells also showed increased levels of IL-2 and IFN-γ in plasma 3 hours after the first Nap treatment. In addition, Nap caused an increase of IL-6, IL-10 and TNF-α. The patients in the UK subset showed a tendency of OS benefit after Nap treatment. Most Nap treated patients with long OS had low baseline IL-6 and normal levels of anti-SEA/E-120 antibodies. Furthermore, patients with pronounced Nap induced IL-2 and T cell expansion had long OS. In conclusion, patients with low baseline IL-6 and normal anti-SEA/E-120 may respond well to Nap by T cell activation and expansion paving the way for anti-tumour effects.

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The overall percentages of Nap-specific T cells for the four patients with the most pronounced changes in these subsets are shown before and during/after the first cycle of treatmentThe flow cytometric plots show the levels of Nap-specific T cells of patient 101–01 before and three time points after treatment. Prognosis and clinical responses for these patients are depicted.
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Figure 2: The overall percentages of Nap-specific T cells for the four patients with the most pronounced changes in these subsets are shown before and during/after the first cycle of treatmentThe flow cytometric plots show the levels of Nap-specific T cells of patient 101–01 before and three time points after treatment. Prognosis and clinical responses for these patients are depicted.

Mentions: Nine patients donated blood for lymphocyte subset analysis during Nap treatment. Four-color flow cytometric assays were performed to measure the level of Nap-specific T cells in the peripheral blood of patients prior to and after treatment with Nap. T lymphocytes expressing T cell receptors containing TRBV7–9 bind Nap and can be activated by Nap [11]. An example of flow cytometric analysis during the three Nap treatment cycles is shown in Figure 1A. Levels of Nap-specific CD4+ and CD8+ T cells for all patients at all analyzed time points are shown in Figures 1D and 1E, respectively. At baseline, Nap-specific CD4+ T cell level (0.86%) was significantly higher than Nap-specific CD8+ T cells (0.35%) (p = 0.001). The frequency of Nap-specific CD4+ T cells in peripheral blood was reduced after 3 treatment days in samples collected pre-dose on day 4 (C1D4, p = 0.09). However, levels of both Nap-specific CD4+ and CD8+ T cells were significantly higher 8 days after the first treatment (C1D8, p = 0.02 and 0.04), as shown in Figure 1. The total number of T lymphocytes, Nap-specific as well as non-specific (data not shown), were reduced in peripheral blood after 3 days of treatment and expanded on day 8, 4 days after the last Nap injection. The four patients (patients 101–01, 101–11, 101–13 and 106–01) with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 are depicted in Figure 2. The expansion of Nap-specific T cells at C1D8 was higher within the CD4+ T-cell subpopulation, compared to the CD8+ T cell subpopulation. In addition, patient 101–13 showed increased Nap-specific T cell frequencies at day 8 of cycle 2 (C2D8) as well (Figure 1B).


Immunological response and overall survival in a subset of advanced renal cell carcinoma patients from a randomized phase 2/3 study of naptumomab estafenatox plus IFN-α versus IFN-α.

Elkord E, Burt DJ, Sundstedt A, Nordle Ö, Hedlund G, Hawkins RE - Oncotarget (2015)

The overall percentages of Nap-specific T cells for the four patients with the most pronounced changes in these subsets are shown before and during/after the first cycle of treatmentThe flow cytometric plots show the levels of Nap-specific T cells of patient 101–01 before and three time points after treatment. Prognosis and clinical responses for these patients are depicted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414201&req=5

Figure 2: The overall percentages of Nap-specific T cells for the four patients with the most pronounced changes in these subsets are shown before and during/after the first cycle of treatmentThe flow cytometric plots show the levels of Nap-specific T cells of patient 101–01 before and three time points after treatment. Prognosis and clinical responses for these patients are depicted.
Mentions: Nine patients donated blood for lymphocyte subset analysis during Nap treatment. Four-color flow cytometric assays were performed to measure the level of Nap-specific T cells in the peripheral blood of patients prior to and after treatment with Nap. T lymphocytes expressing T cell receptors containing TRBV7–9 bind Nap and can be activated by Nap [11]. An example of flow cytometric analysis during the three Nap treatment cycles is shown in Figure 1A. Levels of Nap-specific CD4+ and CD8+ T cells for all patients at all analyzed time points are shown in Figures 1D and 1E, respectively. At baseline, Nap-specific CD4+ T cell level (0.86%) was significantly higher than Nap-specific CD8+ T cells (0.35%) (p = 0.001). The frequency of Nap-specific CD4+ T cells in peripheral blood was reduced after 3 treatment days in samples collected pre-dose on day 4 (C1D4, p = 0.09). However, levels of both Nap-specific CD4+ and CD8+ T cells were significantly higher 8 days after the first treatment (C1D8, p = 0.02 and 0.04), as shown in Figure 1. The total number of T lymphocytes, Nap-specific as well as non-specific (data not shown), were reduced in peripheral blood after 3 days of treatment and expanded on day 8, 4 days after the last Nap injection. The four patients (patients 101–01, 101–11, 101–13 and 106–01) with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 are depicted in Figure 2. The expansion of Nap-specific T cells at C1D8 was higher within the CD4+ T-cell subpopulation, compared to the CD8+ T cell subpopulation. In addition, patient 101–13 showed increased Nap-specific T cell frequencies at day 8 of cycle 2 (C2D8) as well (Figure 1B).

Bottom Line: We found that Nap-specific T cells were reduced after 3 treatment days in patients' peripheral blood.The patients in the UK subset showed a tendency of OS benefit after Nap treatment.In conclusion, patients with low baseline IL-6 and normal anti-SEA/E-120 may respond well to Nap by T cell activation and expansion paving the way for anti-tumour effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Institute of Cancer Sciences, The University of Manchester, Manchester, UK.

ABSTRACT
Naptumomab estafenatox/ABR-217620/ANYARA (Nap) has been evaluated in clinical phase 1 and 2/3 studies. RCC patients in the phase 2/3 trial were randomized 1:1 in an open label study to receive Nap+IFN-α or IFN-α. In this study, we analyzed the UK patients for their immunological response in relation to prolonged overall survival (OS). We found that Nap-specific T cells were reduced after 3 treatment days in patients' peripheral blood. Levels of both Nap-specific CD4+ and CD8+ T cells were significantly higher 8 days after the first treatment. Patients with such pattern of reduction and expansion of Nap-binding T cells also showed increased levels of IL-2 and IFN-γ in plasma 3 hours after the first Nap treatment. In addition, Nap caused an increase of IL-6, IL-10 and TNF-α. The patients in the UK subset showed a tendency of OS benefit after Nap treatment. Most Nap treated patients with long OS had low baseline IL-6 and normal levels of anti-SEA/E-120 antibodies. Furthermore, patients with pronounced Nap induced IL-2 and T cell expansion had long OS. In conclusion, patients with low baseline IL-6 and normal anti-SEA/E-120 may respond well to Nap by T cell activation and expansion paving the way for anti-tumour effects.

Show MeSH