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Varian Medical : "Immune Modulators in Combination with Radiation Treatment" in Patent Application Approval Process (USPTO 20170360932)

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01/04/2018 | 09:06 pm

By a News Reporter-Staff News Editor at Cancer Vaccine Week -- A patent application by the inventor Parry, Renate (Oakland, CA), filed on June 16, 2017, was made available online on December 28, 2017, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Varian Medical Systems Inc.).

This patent application is assigned to Varian Medical Systems Inc.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Radiation therapy is a key therapeutic modality for patients with cancer. Radiation can be delivered to the tumor with submillimeter precision while mostly sparing normal tissue, ultimately leading to tumor cell killing. However, the tumor cell's ability to escape the cell killing effects of radiation and/or to develop resistance mechanisms can counteract the tumor cell killing action of radiotherapy, potentially limiting the therapeutic effect of radiotherapy to treat cancer. Furthermore, the potential for normal tissue toxicity can impact the therapeutic window of radiation therapy as a treatment paradigm.

"Radiation-induced tumor cell death leads to release of tumor antigens from lysed cells, increased MHC-1 expression on antigen presenting cells, and enhanced diversity of the intratumoral T-cell population. These factors and others are key to initiate activation of the body's own immune systems to eradicate cancer cells. Immune modulators are being explored to activate the body's own immune system, but are known to have limitations as monotherapy (e.g., response rate in patients). The response rate of immune modulators when used as monotherapy is in the range of 20-30% of the targeted patient population. Combination approaches such as using two immune modulators or an immune modulator with a targeted anti-cancer drug have limitations due to systemic normal tissue toxicity."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventor's summary information for this patent application: "The methods described herein provide the dual benefits of anti-tumor efficacy and normal tissue protection when combining an immune modulator with ionizing radiation to treat cancer patients. Methods described herein can be used to treat local and metastatic cancers by administering ionizing radiation therapy to deliver a highly conformal dose to the tumor, and an immune modulator. This combination therapy has the potential to improve both the efficacy of radiation therapy both locally and systemically, and the efficacy of the immune modulators. The methods described herein also allow for the classification of patients into groups for receiving optimized radiation treatment based on patient specific biomarker signatures. The biomarker signature includes markers that have been shown to correlate with tumor agressiveness, radioresistance and poor prognosis.

"In some aspects, provided herein is a method for treating a tumor in a subject with cancer comprising administering ionizing radiation and an immune modulator to the tumor. In some embodiments, the amount of ionizing radiation and immune modulator administered to the subject is effective at treating the tumor, for example, effective at killing one or more tumor cells, reducing the growth rate or size of the tumor, or eliminating the tumor from the body of the subject. In some embodiments, the immune modulator is selected from the group consisting of an inhibitor to an inhibitory checkpoint molecule, an activator of a stimulatory checkpoint molecule, a chemokine inhibitor, an inhibitor of macrophage migration inhibitory factor (MIF), a growth factor, a cytokine, an interleukin, an interferon, an antibody that binds to an immune system cell, a cellular immune modulator, a vaccine, an oncolytic virus, and any combination thereof. Administration of the immune modulator was unexpectedly found to increase the anti-tumor response when combined with radiation therapy.

"In some embodiments, the inhibitor to the inhibitory checkpoint molecule is a small molecule drug, or an antibody or a fragment thereof that specifically binds to the inhibitory checkpoint molecule and inhibits its activity, wherein the inhibitory checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, BTLA, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, CD47, CD48, CD160, CD244 (2B4), CHK1, CHK2, CGEN-15049, ILT-2, ILT-4, LAG-3, VISTA, gp49B, PIR-B, TIGIT, TIM1, TIM2, TIM3, TIM4, and KIR, and ligands thereof. In some embodiments, the activator of the stimulatory checkpoint molecule is a small molecule drug, polypeptide-based activator, or polynucleotide-based activator that specifically binds to the stimulatory checkpoint molecule and increases its activity, wherein the stimulatory checkpoint molecule is selected from the group consisting of B7-1 (CD80), B7-2 (CD86), 4-1BB (CD137), OX40 (CD134), HVEM, inducible costimulator (ICOS), glucocorticoid-induced tumor necrosis factor receptor (GITR), CD27, CD28, CD40, and ligands thereof. In some instances, the chemokine inhibitor is a small molecule drug, or antibody or fragment thereof that specifically binds to the chemokine (or its receptor) and inhibits chemokine activity. In some embodiments, the chemokine is selected from the group consisting of CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL5, CCL26, CCL27, CCL28, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL5, and CXCL16. In some embodiments, the chemokine inhibitor binds to a chemokine receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR, 4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, and CXCR7. In some cases, the inhibitor of MIF is a small molecule drug, or antibody or fragment thereof that specifically binds to MIF and inhibits MIF activity.

"In some aspects, provided herein is a method for treating a tumor in a subject with cancer comprising administering ionizing radiation and an immune modulator to the tumor. The method comprises (a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker(s), tumor cell marker(s), circulating marker(s), and any combination thereof; (b) comparing the expression level of the one or more biomarkers to an expression level of the one or more biomarkers in a normal tissue sample; and © administering to the tumor in the subject a treatment comprising ionizing radiation and an immune modulator if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level in the normal tissue sample. The biomarker can be CD44, milk fat globule-EGF factor 8 (MFG-E8), CD68, TGF.beta., a TGF.beta.-pathway related biomarker, or any combination thereof.

"In certain aspects, provided herein is a method of identifying a subject with cancer as a candidate for treatment comprising ionizing radiation and an immune modulator. The method includes: (a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker(s), tumor cell marker(s), circulating marker(s), imaging marker(s), and any combination thereof; (b) comparing the expression level of the one or more biomarkers to an expression level of the one or more biomarkers in a normal tissue sample; and © classifying the subject as a candidate for treatment comprising ionizing radiation and the immune modulator if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level in the normal tissue sample. The biomarker can be CD44, MFG-E8, CD68, TGF.beta., a TGF.beta.-pathway related biomarker, or any combination thereof.

"In other aspects, provided herein is a method of selecting a treatment for a subject with cancer. The method comprises: (a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker(s), tumor cell marker(s), circulating marker(s), and any combination thereof; (b) comparing the expression level of the one or more biomarkers to an expression level of the one or more biomarkers in a normal tissue sample; and © selecting a treatment comprising ionizing radiation and an immune modulator if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level in the normal tissue sample. The biomarker can be CD44, MFG-E8, CD68, TGF.beta., a TGF.beta.-pathway related biomarker, or any combination thereof.

"In some embodiments, the subject is administered ionizing radiation and/or combination therapy comprising ionizing radiation and an immune modulator if the expression level of CD44 is increased and/or the expression level of MFG-E8 is decreased relative to the expression level in a normal or control sample. In some embodiments, the amount of ionizing radiation and/or the amount of an immune modulator administered to the subject is increased if the expression level of CD44 is increased and/or the expression level of MFG-E8 is decreased relative to the expression level in a normal or control sample. On the other hand, the amount of ionizing radiation and/or the amount of an immune modulator administered to the subject can be decreased if the expression level of CD44 is decreased and/or the expression level of MFG-E8 is increased relative to the expression level in a normal or control tissue sample.

"In some embodiments, the subject is administered ionizing radiation and/or combination therapy comprising ionizing radiation and an immune modulator if the expression level of CD68 is increased relative to the expression level in a normal or control tissue sample. In some embodiments, the amount of ionizing radiation and/or the amount of an immune modulator administered to the subject is increased if the expression level of CD68 is increased relative to the expression level in a normal or control tissue sample. On the other hand, the amount of ionizing radiation and/or the amount of an immune modulator administered to the subject can be decreased if the expression level of CD68 is decreased relative to the expression level in a normal or control tissue sample.

"Provided herein are improved methods for treating a tumor that include administering an immune modulator and ionizing radiation to the subject with cancer. This combination therapy can elicit an increased anti-cancer response compared to immune modulator monotherapy or radiation monotherapy.

"In some aspects, provided herein is use of ionizing radiation and an immune modulator for treating a tumor in a subject. In some embodiments, the use comprises a combination of ionizing radiation and an immune modulator described herein.

"In another aspect, the disclosure provides an immune modulator for use in a method of treating a tumor in a subject with cancer, characterized in that the method comprises administering ionizing radiation and the immune modulator to the tumor.

"In another aspect, provided herein is an immune modulator for use in a method of treating a tumor in a subject with cancer, characterized in that the method comprises:

"(a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker(s), tumor cell marker(s), circulating marker(s), and any combination thereof;

"(b) comparing the expression level of the one or more biomarkers to an expression level of the one or more biomarkers in a normal tissue sample; and

"© administering to the tumor in the subject a treatment comprising ionizing radiation and an immune modulator if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level in the normal tissue sample.

"Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures."

URL and more information on this patent application, see: Parry, Renate. Immune Modulators in Combination with Radiation Treatment. Filed June 16, 2017 and posted December 28, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170360932%22.PGNR.&OS=DN/20170360932&RS=DN/20170360932

Keywords for this news article include: Antibodies, Pharmaceuticals, Cancer, Oncology, Biomarkers, Immunology, Radiotherapy, Therapeutics, CD44 Antigens, Blood Proteins, Immunoglobulins, Membrane Proteins, Radiation Therapy, Biological Factors, Biological Markers, Cytokine Receptors, Chemokine Receptors, Chemotactic Factors, Combination Therapy.

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