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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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Cytokine response (pg/mL) in plasma at pre-dose and 3 hours after the first and second day of 3 cycles of Nap treatment. Green frame shows Good MSKCC risk score and red frame shows Intermediate MSKCC risk score(A): IL-2 response in 17 of 18 patients from the UK. The patients were categorized according to their OS. Patients having over median of baseline anti-SEA/E-120 (High anti-S; > 53.5 pmol/mL) or IL-6 (High IL-6; > 7 pg/mL) are depicted. (B): IL-2, IFN-γ, TNF-α, IL-6 and IL-10 and response in the four patients with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 (patients 101–01, 101–11, 101–13 and 106–01).
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Figure 5: Cytokine response (pg/mL) in plasma at pre-dose and 3 hours after the first and second day of 3 cycles of Nap treatment. Green frame shows Good MSKCC risk score and red frame shows Intermediate MSKCC risk score(A): IL-2 response in 17 of 18 patients from the UK. The patients were categorized according to their OS. Patients having over median of baseline anti-SEA/E-120 (High anti-S; > 53.5 pmol/mL) or IL-6 (High IL-6; > 7 pg/mL) are depicted. (B): IL-2, IFN-γ, TNF-α, IL-6 and IL-10 and response in the four patients with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 (patients 101–01, 101–11, 101–13 and 106–01).

Mentions: Seventeen of 18 Nap treated patients were analyzed for cytokine production as response to Nap. Cytokine production was measured pre-dose and 3 hours after Nap injection and the resulting increased plasma concentration served as a biomarker for Nap induced T lymphocyte activation and expansion. IL-2 may serve as a surrogate marker for T lymphocyte expansion. The T cell cytokines IL-2 and IFN-γ were elevated 3 hours after Nap (Figure 5 and Table 2). In addition to IL-2 and IFN-γ, Nap caused an increase of other cytokines including IL-6, IL-10 and TNF-α (Figure 5B). For most patients the induced systemic IL-2 levels were greatest during the first treatment cycle and were negligible during cycles 2 and 3. Patient 101–13 having a pronounced T cell response, including expansion of T cells also in cycle 2, showed increased plasma levels of IL-2 and other cytokines also in cycle 2 (Figure 5B). The different cytokines had distinct timely profiles. 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 showed high IL-2 production as measured in plasma during the first Nap treatment cycle (Figure 5B). Furthermore, IL-2 production was most pronounced in the patients with low anti-SEA/E-120 (as below). The inverse relationship between anti-SEA/E-120 antibody concentration in plasma and IL-2 production was also shown for the whole study (ASCO annual meeting 2013 abstract ID 3073, European Cancer Congress (ECCO) 2013 abstract ID 2710 and manuscript submitted for publication).


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)

Cytokine response (pg/mL) in plasma at pre-dose and 3 hours after the first and second day of 3 cycles of Nap treatment. Green frame shows Good MSKCC risk score and red frame shows Intermediate MSKCC risk score(A): IL-2 response in 17 of 18 patients from the UK. The patients were categorized according to their OS. Patients having over median of baseline anti-SEA/E-120 (High anti-S; > 53.5 pmol/mL) or IL-6 (High IL-6; > 7 pg/mL) are depicted. (B): IL-2, IFN-γ, TNF-α, IL-6 and IL-10 and response in the four patients with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 (patients 101–01, 101–11, 101–13 and 106–01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Cytokine response (pg/mL) in plasma at pre-dose and 3 hours after the first and second day of 3 cycles of Nap treatment. Green frame shows Good MSKCC risk score and red frame shows Intermediate MSKCC risk score(A): IL-2 response in 17 of 18 patients from the UK. The patients were categorized according to their OS. Patients having over median of baseline anti-SEA/E-120 (High anti-S; > 53.5 pmol/mL) or IL-6 (High IL-6; > 7 pg/mL) are depicted. (B): IL-2, IFN-γ, TNF-α, IL-6 and IL-10 and response in the four patients with the most pronounced Nap-specific T lymphocyte reduction on day 4 and expansion on day 8 (patients 101–01, 101–11, 101–13 and 106–01).
Mentions: Seventeen of 18 Nap treated patients were analyzed for cytokine production as response to Nap. Cytokine production was measured pre-dose and 3 hours after Nap injection and the resulting increased plasma concentration served as a biomarker for Nap induced T lymphocyte activation and expansion. IL-2 may serve as a surrogate marker for T lymphocyte expansion. The T cell cytokines IL-2 and IFN-γ were elevated 3 hours after Nap (Figure 5 and Table 2). In addition to IL-2 and IFN-γ, Nap caused an increase of other cytokines including IL-6, IL-10 and TNF-α (Figure 5B). For most patients the induced systemic IL-2 levels were greatest during the first treatment cycle and were negligible during cycles 2 and 3. Patient 101–13 having a pronounced T cell response, including expansion of T cells also in cycle 2, showed increased plasma levels of IL-2 and other cytokines also in cycle 2 (Figure 5B). The different cytokines had distinct timely profiles. 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 showed high IL-2 production as measured in plasma during the first Nap treatment cycle (Figure 5B). Furthermore, IL-2 production was most pronounced in the patients with low anti-SEA/E-120 (as below). The inverse relationship between anti-SEA/E-120 antibody concentration in plasma and IL-2 production was also shown for the whole study (ASCO annual meeting 2013 abstract ID 3073, European Cancer Congress (ECCO) 2013 abstract ID 2710 and manuscript submitted for publication).

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