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Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients.

Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG - Prostate Cancer (2015)

Bottom Line: Methods.There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores.Conclusions.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA ; Department of Medicine, Wayne State University, Detroit, MI 48201, USA.

ABSTRACT
Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.

No MeSH data available.


Related in: MedlinePlus

Profile of serum cytokines. Analysis of sequential serum samples at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]) shows increased levels of IL-2, IFN-γ, GM-CSF, and IL-10 and meanratio of Th1/Th2 = [IL-2+IFNγ]/[IL-4+IL-10] shows a dominant Th1 type response during aATC infusions in partial responder CRPC patient (FG60163). (b) and (c) Similar cytokine profiles and Th1 cytokine responses were seen in two minor responder CRPC patients (FG60202 and FG91760) during and after aATC infusions.
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fig4: Profile of serum cytokines. Analysis of sequential serum samples at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]) shows increased levels of IL-2, IFN-γ, GM-CSF, and IL-10 and meanratio of Th1/Th2 = [IL-2+IFNγ]/[IL-4+IL-10] shows a dominant Th1 type response during aATC infusions in partial responder CRPC patient (FG60163). (b) and (c) Similar cytokine profiles and Th1 cytokine responses were seen in two minor responder CRPC patients (FG60202 and FG91760) during and after aATC infusions.

Mentions: The in vivo response calculated as the mean Th1[IL-2+IFNγ]/Th2 [IL-4+IL-5] ratio of cytokines remained predominantly Th1 polarized throughout treatment. Figures 4(a)–4(c) show Th1 and Th2 cytokines patterns for patients FG60163, FG60202, and FG91760, respectively. All three patients (2-MR and 1-PR) showed increases in IL-2, GM-CSF, and IFN-γ (Th1 cytokines) compared to baseline levels (preIT) in sequential testing of the serum. Th2 cytokine IL-10 also showed comparable pattern as Th1 cytokines. Other Th2 cytokines IL-4 and IL-5 could not be detected. These findings are consistent with increased specific cytotoxic T lymphocyte responses observed in EliSpots of patient postinfusion PBMC exposed to tumor cells. These observations show that the endogenous immune systems of cancer patients can be shifted to favor an antitumor immune environment by infusion of armed ATC.


Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients.

Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG - Prostate Cancer (2015)

Profile of serum cytokines. Analysis of sequential serum samples at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]) shows increased levels of IL-2, IFN-γ, GM-CSF, and IL-10 and meanratio of Th1/Th2 = [IL-2+IFNγ]/[IL-4+IL-10] shows a dominant Th1 type response during aATC infusions in partial responder CRPC patient (FG60163). (b) and (c) Similar cytokine profiles and Th1 cytokine responses were seen in two minor responder CRPC patients (FG60202 and FG91760) during and after aATC infusions.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4352947&req=5

fig4: Profile of serum cytokines. Analysis of sequential serum samples at baseline (preimmunotherapy [preIT]), during infusions (post inf#), and postimmunotherapy (1 week postimmunotherapy [1W postIT], 1 month postimmunotherapy [1 M postIT], and one year postimmunotherapy [1Y postIT]) shows increased levels of IL-2, IFN-γ, GM-CSF, and IL-10 and meanratio of Th1/Th2 = [IL-2+IFNγ]/[IL-4+IL-10] shows a dominant Th1 type response during aATC infusions in partial responder CRPC patient (FG60163). (b) and (c) Similar cytokine profiles and Th1 cytokine responses were seen in two minor responder CRPC patients (FG60202 and FG91760) during and after aATC infusions.
Mentions: The in vivo response calculated as the mean Th1[IL-2+IFNγ]/Th2 [IL-4+IL-5] ratio of cytokines remained predominantly Th1 polarized throughout treatment. Figures 4(a)–4(c) show Th1 and Th2 cytokines patterns for patients FG60163, FG60202, and FG91760, respectively. All three patients (2-MR and 1-PR) showed increases in IL-2, GM-CSF, and IFN-γ (Th1 cytokines) compared to baseline levels (preIT) in sequential testing of the serum. Th2 cytokine IL-10 also showed comparable pattern as Th1 cytokines. Other Th2 cytokines IL-4 and IL-5 could not be detected. These findings are consistent with increased specific cytotoxic T lymphocyte responses observed in EliSpots of patient postinfusion PBMC exposed to tumor cells. These observations show that the endogenous immune systems of cancer patients can be shifted to favor an antitumor immune environment by infusion of armed ATC.

Bottom Line: Methods.There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores.Conclusions.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA ; Department of Medicine, Wayne State University, Detroit, MI 48201, USA.

ABSTRACT
Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.

No MeSH data available.


Related in: MedlinePlus