# US 2022/0105143 A1 · T cell repertoire dynamics and oncolytic viral therapy

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- Number: US 2022/0105143 A1
- Document ID: US20220105143A1
- Status: Published application
- Kind: A1
- Application number: 17/427,446
- Filed: 2020-02-21
- Published: 2022-04-07
- Earliest claimed: 2019-02-22
- Applicants: Oncolytics Biotech Inc.
- Inventors: Grey Wilkinson
- Web page: https://patentgrep.com/patent/US20220105143A1

## CPC

- A61K 35/765: Reovirus; Rotavirus
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C12N 2720/12021: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2720/12032: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Provided herein are methods of treating cancer in a subject. The methods include administering to the subject one or more doses of an oncolytic virus (e.g., in an initial round of treatment); selecting a subject with a T-cell population exhibiting high peripheral clonality; and administering to the subject with a T-cell population exhibiting high peripheral clonality a one or more subsequent doses of the oncolytic virus (e.g., in a second round of treatment).

## Claims

### Claim 1

A method of treating cancer in a subject, the method comprising:
(i) administering to the subject a one or more doses of an oncolytic virus;
(ii) selecting a subject with a T-cell population exhibiting high peripheral clonality after treatment with the one or more doses of the oncolytic virus; and
(iii) administering to the subject with a T-cell population exhibiting high peripheral clonality one or more subsequent doses of the oncolytic virus.

### Claim 2 (depends on 1)

The method of claim 1, wherein the peripheral clonality is greater than 0.06.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject also has a T cell population with low diversity.

### Claim 4 (depends on 3)

The method of claim 3, wherein the T cell population diversity is less than 1800 rearrangements.

### Claim 5 (depends on 1)

The method of claim 1, wherein the cancer is an adenocarcinoma.

### Claim 6 (depends on 1)

The method of claim 1, wherein the cancer is breast cancer or pancreatic adenocarcinoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein approximately 103 to 1012 plaque forming units (PFU) of the oncolytic virus is administered to the subject.

### Claim 8 (depends on 1)

The method of claim 1, wherein approximately 108 to 1012 PFU of the oncolytic virus is administered to the subject.

### Claim 9 (depends on 1)

The method of claim 1, wherein approximately 108 to 1012 TCID50 of the oncolytic virus is administered to the subject.

### Claim 10 (depends on 1)

The method of claim 1, wherein the oncolytic virus is administered as an intravenous infusion.

### Claim 11 (depends on 1)

The method of claim 1, further comprising administering one or more additional therapeutic agents to the subject.

### Claim 12 (depends on 11)

The method of claim 11, wherein the additional therapeutic agent is a chemotherapeutic agent.

### Claim 13 (depends on 11)

The method of claim 11, wherein the additional agent is an immune checkpoint inhibitor or an aromatase inhibitor.

### Claim 14 (depends on 13)

The method of claim 13, wherein the immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor.

### Claim 15 (depends on 13)

The method of claim 13, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, lambrolizumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab.

### Claim 16 (depends on 1)

The method of claim 1, wherein selection of the subject with a T cell population with high peripheral clonality and low diversity results in longer progression free survival or overall survival of the subject treated with the oncolytic virus as compared subjects without selection or as compared to subjects lacking a T cell population with high peripheral clonality and low diversity after one or more doses of the oncolytic virus.

### Claim 17 (depends on 1)

The method of claim 1, wherein the oncolytic virus is selected from the group consisting of a reovirus, a Newcastle disease virus (NDV), a vesicular stomatitis virus (VSV), an adenovirus, a vaccinia virus, a parapox orf virus, a Sindbis virus, and a herpes simplex virus.

### Claim 18 (depends on 17)

The method of claim 17, wherein the reovirus is a mammalian reovirus.

### Claim 19 (depends on 18)

The method of claim 18, wherein the reovirus is a human reovirus.

### Claim 20 (depends on 18)

The method of claim 18, wherein the reovirus is selected from the group consisting of serotype 1 reoviruses, serotype 2 reoviruses, serotype 3 reoviruses.

### Claim 21 (depends on 20)

The method of claim 20, wherein the reovirus is a serotype 3 reovirus.

### Claim 22 (depends on 21)

The method of claim 21, wherein the serotype 3 reovirus is a Dearing strain reovirus.

### Claim 23 (depends on 18)

The method of claim 18, wherein the reovirus is deposited as IDAC Accession No. 190907-01.

### Claim 24 (depends on 18)

The method of claim 18, wherein the reovirus comprises a lambda-3 polypeptide having one or more amino acid modifications, a sigma-3 polypeptide having one or more amino acid modifications, a mu-1 polypeptide having one or more amino acid modifications, a mu-2 polypeptide having one or more amino acid modifications, or any combination thereof.

### Claim 25 (depends on 18)

The method of claim 18, wherein the reovirus comprises one or more of the following polypeptides:
a sigma-3 polypeptide having one or more amino acid modifications, wherein the one or more amino acid modifications are selected from the group consisting of a Leu at residue 14, a Lys at residue 198, or any combination thereof, numbered relative to GenBank Accession No. K02739, wherein when the amino acid sequence comprises a Leu at residue 14, the amino acid sequence further comprises at least one additional modification in the amino acid sequence; a mu-1 polypeptide having at least one amino acid modification, wherein the at least one amino acid modification comprises an Asp at residue 73 numbered relative to GenBank Accession No. M20161.1;
a lambda-3 polypeptide having one or more amino acid modifications, wherein the one or more amino acid modifications are selected from the group consisting of a Val at residue 214, an Ala at residue 267, a Thr at residue 557, a Lys at residue 755, a Met at residue 756, a Pro at residue 926, a Pro at residue 963, a Leu at residue 979, an Arg at residue 1045, a Val at residue 1071, or any combination thereof, numbered relative to GenBank Accession No. M24734.1, wherein when the amino acid sequence comprises a Val at residue 214 or a Val at residue 1071, the amino acid sequence further comprises at least one additional modification in the amino acid sequence; or
a mu-2 polypeptide having at least one amino acid modification, wherein the at least one amino acid modification comprises a Ser at residue 528 numbered relative to GenBank Accession No. AF461684.1.

### Claim 26 (depends on 18)

The method of claim 18, wherein the reovirus comprises one or more of the following genome segments:
a S4 genome segment having one or more nucleic acid modifications, wherein the one or more nucleic acid modifications in the S4 genome segment are selected from the group consisting of an A at position 74 and an A at position 624, numbered relative to GenBank Accession No. K02739;
a M2 genome segment having at least one nucleic acid modification, wherein the at least one nucleic acid modification comprises a C at position 248, numbered relative to GenBank Accession No. M20161.1;
a L1 genome segment comprising one or more nucleic acid modifications, wherein the one or more nucleic acid modifications are selected from the group consisting of a T at position 660, a G at position 817, an A at position 1687, a G at position 2283, an ATG at positions 2284-2286, a C at position 2794, a C at position 2905, a Cat position 2953, an A at position 3153, a G at position 3231, numbered relative to GenBank Accession No. M24734.1; or
a M1 genome segment having at least one nucleic acid modification, wherein the at least one nucleic acid modification comprises a T at position 1595, numbered relative to GenBank Accession No. AF461684.1.

### Claim 27 (depends on 18)

The method of claim 18, wherein the reovirus is a recombinant reovirus.

### Claim 28 (depends on 18)

The method of claim 18, wherein the reovirus is a modified reovirus.