# US 2018/0021253 A1 · Peritumoral and intratumoral materials for cancer therapy

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- Number: US 2018/0021253 A1
- Document ID: US20180021253A1
- Status: Published application
- Kind: A1
- Application number: 15/546,852
- Filed: 2016-01-29
- Published: 2018-01-25
- Earliest claimed: 2015-01-30
- Assignees: President and Fellows of Harvard College
- Applicants: President and Fellows of Harvard College
- Inventors: Koshy T. Sandeep; David J. Mooney
- Web page: https://patentgrep.com/patent/US20180021253A1

## CPC

- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/4725: containing further heterocyclic rings
- 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 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/19: Cytokines; Lymphokines; Interferons
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- 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)

## Abstract

The invention provides methods and compositions for reducing tumor-mediated immune evasion and inducing patient-specific immunization.

## Claims

### Claim 1

A method of reducing tumor-mediated immune evasion comprising administering to a tumor site a biodegradable porous polymeric device comprising (a) an inhibitor of T cell or dendritic cell suppression or (b) an immunostimulatory compound, wherein said device lacks a tumor antigen prior to administration to a subject.

### Claim 2 (depends on 1)

The method of claim 1,
(a) wherein the device comprises an inhibitor of T cell or dendritic cell suppression;
(b) wherein the device comprises an immunostimulatory compound;
(c) wherein said inhibitor comprises a transforming growth factor-beta (TGF-β) pathway inhibitor, or a signal transducer and activator of transcription 3 (STAT3) pathway inhibitor;
(d) wherein said inhibitor comprises a small molecule, an aptamer, a protein, an RNAi molecule, an antibody, or an antibody fragment; or
(e) wherein said inhibitor comprises an inhibitor of an immune checkpoint.

### Claim 3

(canceled)

### Claim 4

(canceled)

### Claim 5

(canceled)

### Claim 6 (depends on 2)

The method of claim 2, wherein the small molecule is an organic compound having a molecular weight less than 1000 Daltons.

### Claim 7 (depends on 2)

The method of claim 2, wherein said TGF-β pathway inhibitor comprises LY2157299 GW788388, LY364947, R268712, RepSox, SB525334, or SD208 and said STAT3 pathway inhibitor comprises BP-1-102, S3I-M2001, STA-21, S3I-201, Stattic, Galiellalactone, a polypeptide having the sequence PY*LKTK (where Y* represents phosphotyrosine), and a polypeptide having the sequence Y*LPQTV (where Y* represents phosphotyrosine).

### Claim 8

(canceled)

### Claim 9 (depends on 2)

The method of claim 2, wherein the inhibitor of an immune checkpoint is a PD-1 pathway inhibitor, a LAG-3 pathway inhibitor, an IDO pathway inhibitor, a B7-H3 pathway inhibitor, or a TIM3 pathway inhibitor.

### Claim 10 (depends on 2)

The method of claim 2, wherein said inhibitor is a small molecule, an aptamer, a protein, an RNAi molecule, an antibody, or an antibody fragment.

### Claim 11 (depends on 10)

The method of claim 10, wherein the small molecule is an antibody or an organic compound having a molecular weight less than 1000 Daltons.

### Claim 12

(canceled)

### Claim 13 (depends on 11)

The method of claim 11, wherein said antibody comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

### Claim 14 (depends on 13)

The method of claim 13, wherein (a) the anti-PD-1 antibody is nivolumab, pembrolizumab, or pidilizumab; (b) the anti-PD-L1 antibody is BMS-936559 or MPDL3280A; or (c) the anti-CTLA-4 antibody is ipilimumab.

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17 (depends on 10)

The method of claim 10, wherein the antibody is (a) a Fv, Fab, Fab′, Fab′-SH, F (ab′)2, diabody, a linear antibodies or a scFv or (b) a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody.

### Claim 18

(canceled)

### Claim 19 (depends on 10)

The method of claim 10, wherein said inhibitor is an IDO inhibitor.

### Claim 20 (depends on 19)

The method of claim 19, wherein said IDO inhibitor is an IDO1 inhibitor.

### Claim 21

(canceled)

### Claim 22 (depends on 19)

The method of claim 19, wherein the small molecule is an organic compound having a molecular weight less than 1000 Daltons.

### Claim 23 (depends on 22)

The method of claim 22, wherein the small molecule is INCB24360 or NLG919.

### Claim 24 (depends on 1)

The method of claim 1, wherein
(a) said device further comprises an immunogenic cell death-inducing chemotherapeutic agent;
(b) said device further comprises an immunogenic cell death-inducing chemotherapeutic agent, and wherein said chemotherapeutic agent comprises a member of the anthracycline class of compounds;
(c) said device further comprises an immunogenic cell death-inducing chemotherapeutic agent, and wherein said chemotherapeutic agent comprises doxorubicin;
(d) said tumor comprises a solid tumor or localized tumor mass;
(e) said device does not comprise a purified tumor antigen or tumor cell lysate prior to administration to said tumor site;
(f) said device comprises a hydrogel;
(g) said device comprises a cryogel;
(h) said device comprises a cryogel, wherein said cryogel comprises pores;
(i) said device comprises a methacrylated gelatin cryogel or a click alginate cryogel;
(j) said device comprises an alginate hydrogel;
(k) said device comprises an alginate hydrogel, wherein the alginate hydrogel is an alginate cryogel;
(l) said device comprises an alginate hydrogel, wherein said alginate hydrogel comprises a click alginate;
(m) the device is administered via injection;
(n) the device is administered via injection, wherein the device is injected into the tumor;
(o) the device is administered via injection, wherein the device is injected to a site in the subject within about 0.1-10 mm from the tumor;
(p) the device further comprises a cytokine or a mRNA or expression vector that encodes a cytokine;
(q) the device further comprises a cytokine or a mRNA or expression vector that encodes a cytokine, wherein the cytokine is granulocyte macrophage colony-stimulating factor (GM-CSF), FMS-like tyrosine kinase 3 ligand (Flt3L), Chemokine (C-C Motif) Ligand 20 (CCL20), Interleukin 15 (IL-15), Chemokine (C Motif) Ligand 1 (XCL1), Chemokine (C-X-C Motif) Ligand 10 (CXCL10), Interferon Alpha 1 (IFN-alpha), Interferon Beta (IFN-beta), or Interleukin 12 (IL-12);
(r) the device has a volume of about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl or less than about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl; or
(s) said device further comprises laponite.

### Claim at position 25

25-39. (canceled)

### Claim 40

(canceled)

### Claim 41 (depends on 2)

The method of claim 2, wherein the device further comprises an immunostimulatory compound.

### Claim 42 (depends on 41)

The method of claim 41, wherein the immunostimulatory compound is CpG, polyinosine-polycytidylic acid (poly (I:C)) PEI-poly (I:C), polyadenylic-polyuridylic acid (poly (A:U)), PEI-poly (A:U), double stranded ribonucleic acid (RNA), monophosphoryl lipid A (MPLA), or Imiquimod.

### Claim 43

(canceled)

### Claim 44

(canceled)

### Claim 45

A method of treating a subject afflicted with a tumor, comprising administering to a tumor site a biodegradable porous polymeric device comprising (a) an inhibitor of T cell or dendritic cell suppression or (b) and immunostimulatory compound, wherein said device lacks a tumor antigen prior to administration to a subject.

### Claim 46 (depends on 45)

The method of claim 45, wherein
(a) the device comprises an inhibitor of T cell or dendritic cell suppression;
(b) the device comprises an immunostimulatory compound;
(c) (i) one such biodegradable porous polymeric device is administered to the subject; or (ii) two such biodegradable porous polymeric devices are administered to the subject;
(d) said device comprises an alginate hydrogel;
(e) said device comprises an alginate hydrogel, wherein said alginate hydrogel comprises a click alginate;
(f) the device is administered via injection;
(g) the device is administered via injection, wherein the device is injected into the tumor;
(h) the device is administered via injection, wherein the device is injected to a site in the subject within about 0.1-10 mm from the tumor;
(i) the device further comprises a cytokine;
(j) the device further comprises a cytokine, wherein the cytokine is granulocyte macrophage colony-stimulating factor (GM-CSF), FMS-like tyrosine kinase 3 ligand (Flt3L), Chemokine (C-C Motif) Ligand 20 (CCL20), Interleukin 15 (IL-15), Chemokine (C Motif) Ligand 1 (XCL1), Chemokine (C—X-C Motif) Ligand 10 (CXCL10), Interferon Alpha 1 (IFN-alpha), Interferon Beta (IFN-beta), or Interleukin 12 (IL-12);
(k) the device has a volume of about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl or less than about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl;
(l) said subject has been identified as comprising a solid tumor;
(m) said subject has been identified as comprising a solid tumor, wherein the method further comprises contacting the tumor with radiation; or
(n) said subject has been identified as comprising a solid tumor, wherein the method further comprises systemically administering a chemotherapeutic agent to the subject.

### Claim 47

(canceled)

### Claim 48 (depends on 45)

The method of claim 45, wherein treating the subject comprises
(a) reducing the volume of the tumor;
(b) reducing the growth of the tumor;
(c) reducing metastasis of the tumor;
(d) increasing the survival of the subject;
(e) increasing the progression free survival of the subject;
(f) increasing a T cell response to an antigen within the tumor; and/or
(g) vaccinating the subject to an antigen within the tumor.

### Claim 49 (depends on 48)

The method of claim 48, wherein treating the subject comprises reducing the volume of the tumor at least about (a) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100%; or (b) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100% within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 28, 35, 41, 48, 180, 365 or 1-365 days or within about 1-12 months.

### Claim at position 36

50-58. (canceled)

### Claim 59 (depends on 46)

The method of claim 46, wherein the device further comprises an immunostimulatory compound.

### Claim 60 (depends on 59)

The method of claim 59, wherein the immunostimulatory compound is CpG, polyinosine-polycytidylic acid (poly (I:C)) PEI-poly (I:C), polyadenylic-polyuridylic acid (poly (A:U)), PEI-poly (A:U), double stranded ribonucleic acid (RNA), monophosphoryl lipid A (MPLA), or Imiquimod.

### Claim 61

(canceled)

### Claim 62

(canceled)

### Claim 63

A biodegradable porous polymeric device comprising at least two of
(a) a compound that induces immunogenic cell death of a tumor cell;
(b) a compound that attracts an immune cell to or into the device;
(c) an immunostimulatory compound; and
(d) a compound that inhibits tumor-mediated T cell or dendritic cell suppression.

### Claim 64 (depends on 63)

The device of claim 63,
(a) comprising an immunostimulatory compound;
(b) comprising an immunostimulatory compound, wherein the immunostimulatory compound comprises a CpG oligonucleotide, poly (I:C), monophosphoryl lipid A (MPLA), imiquimod, or a cyclic dinucleotide;
(c) comprising a compound that induces immunogenic cell death of a tumor cell;
(d) comprising a compound that induces immunogenic cell death of a tumor cell, wherein the compound that induces immunogenic cell death of a tumor cell comprises doxorubicin, mitoxantrone, oxaliplatin, or paclitaxel;
(e) comprising a compound that attracts an immune cell to or into the device;
(f) comprising a compound that attracts an immune cell to or into the device, wherein compound that attracts an immune cell to or into the device is GM-CSF, Flt3L, XCL1, IL-2, or IL-12;
(g) comprising a compound that attracts an immune cell to or into the device, wherein the compound that attracts an immune cell to or into the device attracts a dendritic cell into the device;
(h) comprising a compound that inhibits tumor-mediated T cell or dendritic cell suppression;
(i) comprising a compound that inhibits tumor-mediated T cell or dendritic cell suppression, wherein the compound that inhibits tumor-mediated T cell or dendritic cell suppression comprises a TGF-β inhibitor, a STAT3 inhibitor, an IDO inhibitor, an anti-PD-1 antibody, or an anti-CTLA-4 antibody;
(j) wherein said device lacks a patient-derived tumor cell antigen prior to administration to a patient; or
(k) having a volume of at least about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl or less than about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 50-500 μl.

### Claim at position 43

65-74. (canceled)

### Claim 75 (depends on 63)

A non-human mammal or a syringe comprising the device of claim 63.

### Claim 76

(canceled)

### Claim 77 (depends on 63, 75)

The syringe of claim 75, which is pre-loaded and packaged with the device of claim 63.

### Claim at position 47

78-79. (canceled)