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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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Foxp3 expression within CD4+Nap+/− T cellsExample of flow cytometric plots in PBMCs of patient 101–13 pre and two time points during cycle 1 of treatment is shown in (A). Cells were gated on lymphocytes and CD4+ T cells. The figure shows the mean percentage +/− SEM of cells having Foxp3 expression within CD4+Nap+ and CD4+Nap− T cells (B) for all patients before and at all investigated time points during/following treatment.
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Figure 4: Foxp3 expression within CD4+Nap+/− T cellsExample of flow cytometric plots in PBMCs of patient 101–13 pre and two time points during cycle 1 of treatment is shown in (A). Cells were gated on lymphocytes and CD4+ T cells. The figure shows the mean percentage +/− SEM of cells having Foxp3 expression within CD4+Nap+ and CD4+Nap− T cells (B) for all patients before and at all investigated time points during/following treatment.

Mentions: We investigated levels of Foxp3+ Treg cells in peripheral blood of patients before and after treatment. Patient 101–13 showed expansion of CD4+Foxp3+ Tregs during all cycles of treatment and they bounced to baseline level by the end of study (data not shown). Overall analysis for all patients showed the expansion of CD4+Foxp3+Nap− Tregs; Treg levels were significantly higher at most time points after treatment, compared to pre-treatment level. Of note, the Treg expansion was detected mainly after 3 days of treatment within any of the cycles (Figure 4B). Immunotherapeutic modalities such as therapeutic cancer vaccines may expand tumour antigen-specific Tregs as well as antigen-specific T effector cells, which can induce immune suppression and dampen the expansion of tumour antigen-specific T effector cells [13]. Nap staining was combined with Foxp3 intracellular staining to determine the levels of Nap-specific Foxp3+ Tregs. Prior to treatment, Foxp3 was expressed mainly within CD4+Nap− T cells, compared to CD4+Nap+ T cells (p = 0.006). Interestingly, Foxp3 expansion was seen within the CD4+Nap− T cells, but not within the CD4+Nap+ subpopulation at any time point after treatment (Figures 4A and 4B).


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)

Foxp3 expression within CD4+Nap+/− T cellsExample of flow cytometric plots in PBMCs of patient 101–13 pre and two time points during cycle 1 of treatment is shown in (A). Cells were gated on lymphocytes and CD4+ T cells. The figure shows the mean percentage +/− SEM of cells having Foxp3 expression within CD4+Nap+ and CD4+Nap− T cells (B) for all patients before and at all investigated time points during/following treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Foxp3 expression within CD4+Nap+/− T cellsExample of flow cytometric plots in PBMCs of patient 101–13 pre and two time points during cycle 1 of treatment is shown in (A). Cells were gated on lymphocytes and CD4+ T cells. The figure shows the mean percentage +/− SEM of cells having Foxp3 expression within CD4+Nap+ and CD4+Nap− T cells (B) for all patients before and at all investigated time points during/following treatment.
Mentions: We investigated levels of Foxp3+ Treg cells in peripheral blood of patients before and after treatment. Patient 101–13 showed expansion of CD4+Foxp3+ Tregs during all cycles of treatment and they bounced to baseline level by the end of study (data not shown). Overall analysis for all patients showed the expansion of CD4+Foxp3+Nap− Tregs; Treg levels were significantly higher at most time points after treatment, compared to pre-treatment level. Of note, the Treg expansion was detected mainly after 3 days of treatment within any of the cycles (Figure 4B). Immunotherapeutic modalities such as therapeutic cancer vaccines may expand tumour antigen-specific Tregs as well as antigen-specific T effector cells, which can induce immune suppression and dampen the expansion of tumour antigen-specific T effector cells [13]. Nap staining was combined with Foxp3 intracellular staining to determine the levels of Nap-specific Foxp3+ Tregs. Prior to treatment, Foxp3 was expressed mainly within CD4+Nap− T cells, compared to CD4+Nap+ T cells (p = 0.006). Interestingly, Foxp3 expansion was seen within the CD4+Nap− T cells, but not within the CD4+Nap+ subpopulation at any time point after treatment (Figures 4A and 4B).

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