Methods for inducing a natural killer (NK) cell-mediated immune response and for increasing NK cell activity
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Publication Number
US-8153120-B2
Publication Date
2012-04-10
Expiration Date
Abstract
The present invention relates to the discovery of novel methods of inducing a natural killer (NK) cell-mediated immune response and increasing NK activity in a mammal for the treatment of tumors and virus infections. The method comprises the steps of isolating peripheral blood mononuclear cells (PBMCs) from the subject, exposing the PBMCs in vitro to protein conjugate comprising granulocyte macrophage colony stimulating factor (GM-CSF) covalently linked to a soluble peptide antigen, under conditions effective to activate the PBMCs, and administering the activated PBMCs to the subject. The invention also relates to a method of detecting in a subject a cytotoxic NK cell-meditated immune response or NK cell activity in vitro by CD336 expression and/or lysis of the K562 tumor line. The invention further relates to a method for determining whether a subject has had a therapeutically effective response to a protein conjugate by assessing the NK activity of activated PBMCs from the subject.
Core Innovation
The invention relates to a method for treating cancer in a mammalian subject by isolating peripheral blood mononuclear cells (PBMCs), exposing the PBMCs in vitro to a protein conjugate comprising granulocyte macrophage colony stimulating factor (GM-CSF) covalently linked to a soluble peptide antigen selected from tumor associated antigen (TAA) and an oncogene product, and administering the activated PBMCs to the subject. The method further includes repeating the isolating and exposing steps at least 10 days after previous administering has occurred.
The repeated isolations and exposures are used to improve determining whether the subject has shown a positive therapeutic response to the treatment and therefore whether the subject is a candidate for additional treatment with activated PBMCs. In the improved determination, an NK activity of the activated PBMCs from the second isolation is assessed and compared with an NK level assessed prior to first administering the activated PBMCs.
If the NK activity assessed after repeating has increased significantly, the subject is classified as having shown a positive therapeutic response and as a good candidate for additional activated PBMC administration.
Claims Coverage
The document includes one independent claim. It contains a method for treating cancer by GM-CSF covalently linked to soluble peptide antigens, administering activated PBMCs, and using repeat PBMC activation plus NK-activity comparison to classify positive therapeutic response, based on three inventive features spanning treatment, repeat timing, and NK-response determination.
Treating cancer by GM-CSF covalent peptide protein conjugate-activated PBMCs
A method for treating cancer in a mammalian subject by isolating PBMCs from a subject; exposing the PBMCs in vitro to a protein conjugate comprising granulocyte macrophage colony stimulating factor (GM-CSF) covalently linked to a soluble peptide antigen selected from the group consisting of a tumor associated antigen (TAA) and an oncogene product, under conditions effective to activate the PBMCs; and administering the activated PBMCs to the subject.
Repeating PBMC isolation and GM-CSF-peptide antigen exposure to improve response determination
Repeating step (a) and (b) at least 10 days after previous step (c) has occurred, wherein repeating the isolating and exposing steps improves determining whether the subject has shown a positive therapeutic response to the treatment and therefore whether the subject is a candidate for additional treatment with activated PBMCs.
Classifying positive therapeutic response by significant increase in NK activity after second isolation
Assessing an NK activity of the activated PBMCs from the second isolation; comparing the assessed NK level from step (i) with an NK level assessed prior to first administering the activated PBMCs to the subject; and, if the level of NK activity assessed in step (i) has increased significantly over the level of NK activity assessed prior to the first administration, classifying the subject as having shown a positive therapeutic response to the treatment and therefore being a good candidate for additional treatment by activated PBMC administration.
Overall, the claim set centers on PBMC activation using a covalent GM-CSF-soluble peptide antigen conjugate, administration of activated PBMCs, and a repeat isolation/exposure regimen used to classify positive therapeutic response by significant increase in assessed NK activity compared to pre-treatment levels.
Stated Advantages
Improvement for determining whether the subject has shown a positive therapeutic response to the treatment.
Classification of the subject as having shown a positive therapeutic response and therefore being a good candidate for additional treatment with activated PBMCs.
Documented Applications
Treating tumors/virus infections in a mammalian subject using activated PBMCs generated by in vitro exposure to covalent GM-CSF-soluble peptide antigen protein conjugates linked to tumor-associated antigens (e.g., PAP) or oncogene products (e.g., Her2).
Assessing therapeutic response by measuring NK activity after repeat PBMC/APC isolation and in vitro exposure, including using CD336 surface expression and/or K562 target-cell lysis assays, with examples showing enhanced CD336 expression and K562 cytotoxicity versus placebo.
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