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Definitions

• Interferon has many clinical benefits. For example, interferon is known to up-regulate the immune system. It thus is potentially useful for recruiting the patient's innate immune system to identify and attack cancer cells. Interferon's efficacy as an anti -cancer agent, however, has to date proven wanting. This has been puzzling.
• the most effective bladder cancer treatment currently approved in The United States is intra-urethral Bacillus Calmette-Guerin vaccine.
• the antigenic vaccine is thought to stimulate bladder cells to express interferon, which in turn recruits the patient's innate immune system to better recognize cancer cell surface antigens and attack cancer cells. In over a third of cases, however, the vaccine is ineffective.
• interferon advantageously stimulates certain aspects of the patient's immune system, yet also up-regulates expression of Programmed Cell Death Protein 1.
• the resulting increase in Programmed Cell Death Protein 1 in turn down-regulates protective T cell function. This impairs the effectiveness of T cells in identifying and attacking cells bearing cancer cell-surface antigen.
• interferon produces two conflicting actions: it both increases immune system activity, yet inhibits the ability of the immune system to identify cancer cell-surface antigens.
• Figure 1 is a chart measuring PD-L1 expression in response to interferon exposure, for the RT112 and SW780 human cell lines. Horizontal axis: interferon amount. Vertical axis: polypeptide expressed.
• Figure 2 is a chart measuring TRAIL expression in response to interferon exposure, for the RT112 and SW780 human cell lines. Horizontal axis: interferon amount. Vertical axis: polypeptide expressed.
• Figure 3 is a chart measuring IRFl expression in response to interferon exposure, for the RTl 12 and SW780 human cell lines. Horizontal axis: interferon amount. Vertical axis: polypeptide expressed.
• Figure 4 is a photograph of a PAGE gel showing in vitro dose response to increasing interferon alpha, in an SW780 human cancer cell line.
• Horizontal axis interferon amount.
• Vertical axis polypeptide expressed.
• Figure 5 measures expression in RTl 12 cells of IRFl, FOXAl and PD-Ll in response to interferon exposure, see Example 2.
• IRFl served as an interferon-stimulated gene control.
• FOXAl is an example of a type I interferon regulated gene that did not change expression after interferon exposure.
• Figure 6 measures expression in UC3 cells of IRFl, FOXAl and PD-Ll in response to interferon exposure, see Example 2.
• IRFl served as an interferon-stimulated gene control.
• FOXAl is an example of a type I interferon regulated gene that did not change expression after interferon exposure.
• Figure 7 measures expression in T24 cells of IRFl, FOXAl and PD-Ll in response to interferon exposure, see Example 2.
• IRFl served as an interferon-stimulated gene control.
• FOXAl is an example of a type I interferon regulated gene that did not change expression after interferon exposure.
• Figure 8 measures expression in UC14 cells of IRFl, FOXAl and PD-Ll in response to interferon exposure, see Example 2.
• IRFl served as an interferon-stimulated gene control.
• FOXAl is an example of a type I interferon regulated gene that did not change expression after interferon exposure.
• Figure 9 is a photograph of a 6-lane PAGE gel. It measures the presence of PD-Ll polypeptide after exposing BBN972 cells to murine interferon. Lanes are (left to right) 0 73 (zero), 1 x 10°, 1 x 10 1 , 1 x 10 2 , 1 x 10 3 and 1 x 10 4 international units interferon / mL of
• Figure 10 is a photograph of a 6-lane PAGE gel. It measures the presence of PD-L1
• Figure 11 is a photograph of a 6-lane PAGE gel. It measures the presence of actin
• Figure 12 is a photograph of a 6-lane PAGE gel. It measures the presence of actin
• Figure 19 compares normalized (mean +/- SD) radiance over time in male mice.
• Figure 20 shows "survival portions,” i.e., data showing the survival of propensity to
• Interferons are a group of signaling proteins. They are expressed and secreted by
• a virus-infected cell releases interferons
• Interferons may be sorted or classified according to the type of receptor through
• interferons are often thus sorted into three kinds: Type I 121 (interferons which bind to human IFN- ⁇ / ⁇ receptors), Type II (interferons which binds to the
• Type III interferons which bind to human IFN- ⁇ receptors
• Type I IFN 124 modulate functions of the immune system.
• Administration of Type I IFN has been shown to
• a virus-infected cell releases viral particles that can infect
• the infected cell can prepare neighboring cells against a potential
• PTK protein kinase R
• eIF-2 130 protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms
• RNAse L Another cellular enzyme, RNAse L—also induced by interferon action— destroys RNA
• ISGs genes that have roles in combating viruses and other actions produced by interferon.
• MHC II expression increases presentation of viral peptides to helper T cells; these cells 146 release cytokines (such as more interferons and interleukins, among others) that signal to and
• glycoprotein 150 glycoprotein, viral RNA, bacterial endotoxin (lipopolysaccharide), bacterial flagella, CpG
• pattern recognition receptors such as membrane bound Toll like receptors or the
• 152 cytoplasmic receptors RIG-I or MDA5 can trigger release of IFNs.
• TLR3 TLR3
• RNA viruses the ligand for this receptor is double-stranded RNA (dsRNA). After binding
• this receptor activates the transcription factors IRF3 and NF-kB, which are important
• RNA interference technology tools for initiating synthesis of many inflammatory proteins.
• siRNA or vector-based reagents can either silence or stimulate interferon pathways.
• cytokines such as interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and
• 160 colony-stimulating factor can also enhance interferon production.
• Interferon therapy is used (in combination with chemotherapy and radiation) as a
• This treatment can be used in hematological malignancy
• leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular
• inhibitors such as Telaprevir (IncivekTM) May 2011, Boceprevir (VICTRELISTM) May 2011 171 or the nucleotide analog polymerase inhibitor Sofosbuvir (SOVALDITM) December 2013.
• interferon may be administered as an exogenous polypeptide.
• transgene by transfecting a host cell with a vector delivering the interferon transgene.
• IFN interferon
• interferon 188 biologically active fragments, and allelic forms.
• interferon 188 biologically active fragments, and allelic forms.
• IFN Interferon-Coupled Device
• Human interferon-a has at least 14
• interferon-alphas include human interferon alpha subtypes including, but not limited to, a-1
• Type 2 interferons are
• interferon ⁇ (EP 77,670 A and EP 146,354 A) and subtypes.
• 209 gamma has at least 5 identified subtypes, including interferon omega 1 (GenBank Accession
• 211 may be accomplished by conventional recombinant DNA techniques based on the well-
• 219 proteins are generally identified as associating with the Type 1 IFN receptor complex
• IFN- ⁇ is generally identified as associating with the type II IFN receptor.
• IFN-inducible transcription factors that bind to IFN response elements presented in IFN-
• Type 1 and/or Type 2 IFN receptors are considered interferons for purposes of our
• PD-1 Programmed Cell Death Protein 1
• CD279 is a protein that in
• PD-1 belongs to the immunoglobulin superfamily
• PD-L1 and PD-L2 functions as a cell surface receptor, binding to two known ligands, PD-L1 and PD-L2.
• 234 PD-1 plays an important role in down-regulating the human immune system by
• the immune regulatory effect of PD-1 is effected by culling active T cells while
• PD-1 promotes apoptosis of antigen-specific T cells in lymph
• 239 PD-L1 can be highly expressed in certain tumors. This leads to reduced proliferation
• PD-1 is expressed on T cells and pro-B cells. PD-1, functioning as an immune
• T-cells which in turn reduces autoimmunity and promotes self-tolerance.
• the 246 inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis
• Programd death 1 is a type I membrane protein of 268 amino acids.
• PD-1 is a member of 249 amino acids.
• 251 includes an extracellular IgV domain followed by a trans-membrane region and an
• the intracellular tail contains two phosphorylation sites located in an
• PD-1 is expressed on the surface of activated T
• 260 PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family.
• PD-L1 and PD-L2 are members of the B7 family.
• LI protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and
• PD-L1 mRNA can be detected in the heart, lung, thymus, spleen,
• Pembrolizumab (KEYTRUDATM or MK-3475, commercially available from Merck &
• Pembrolizumab has been made accessible to advanced
• checkpoint inhibitors Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers).
• interferon polypeptide 290 interferon polypeptide, or by administering an agent which induces cells to express interferon
• the agent can be an antigenic vaccine (such as a virus, or BCG vaccine or Mycobacterium
• the agent can be a transgene
• this can be an antigenic virus or bacteria which also delivers an interferon transgene.
• EXAMPLE 1 - IFNa induces PD-L1 and TRAIL expression.
• Interferon-alpha has not been notably effective clinically. Iposited that this
• RT112 and SW780 cells were cultured in media and then
• 318 mIRs were profiled in RT112 using TAQMANTM Array Cards (A and B) (Thermo Fisher). 319 Whole genome mRNA expression profiling was performed in RT112 and UC3 with Illumina
• Results are provided in Figure 1 to 4. In response to exposure to interferon,
• interferon should theoretically be an effective anti-cancer agent, interferon
• 329 may also up-regulate expression of PD-Ll, thus frustrating interferon's therapeutic effect.
• RT112, T24, UC3, and UC14 cells were cultured in media and
• IFIT2 negative regulator of metastasis
• IFNa profile may be useful as an intermediate endpoint to measure response to adenoviral
• Poly I:C is an immunostimulant. It is used in the form of its sodium salt to
• Poly I:C is structurally similar to double-stranded RNA.
• dsRNA is
• Diad Poly I:C administered via intra-peritoneal injection to a patient 381 present in some viruses.
• Diad Poly I:C administered via intra-peritoneal injection to a patient 381 present in some viruses.
• RNA amounts are shown quantitatively, light green showing the least and light red the
• Treatment also up-regulated other immune checkpoint markers.
• Figure 17 shows MB49 tumor size vs time, for subcutaneous C57BL6/J
• 423 line is anti-PDl Monoclonal antibody.
• the lowest (black) line, laying on the X axis itself, is
• Figure 18 shows a Kaplan-Meyer survival curve for female mice with inoculated
• Figure 20 shows "survival portions," i.e., data showing the survival of propensity to
• 443 melanoma is treated by wide local excision and sentinel node biopsy to confirm lack of
• 454 KEYTRUDATM brand pembrolizumab is a humanized monoclonal anti-programmed
• PD-1 antibody IgG4/kappa isotype with a stabilising sequence alteration in the
• INSTILADRINTM 457 INSTILADRINTM is provided in single-dose vials.
• One dose of INSTILADRINTM is
• 460 powder contains 50 mg of pembrolizumab.
• KEYTRUDATM is administered as an
• lexpect that administration of KEYTRUDATM and SYLATRONTM and
• Test subjects are screened for treatment based on the tumor expression of PD-Ll, expression
• the recommended dose of KEYTRUDA is: 200 mg for NSCLC that has not been
• "treating" cancer may be achieved by completely eliminating the

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