CA3158900A1 - Methods for treating cancers using gm-csf encoding polynucleotide and additional agents - Google Patents
Methods for treating cancers using gm-csf encoding polynucleotide and additional agents Download PDFInfo
- Publication number
- CA3158900A1 CA3158900A1 CA3158900A CA3158900A CA3158900A1 CA 3158900 A1 CA3158900 A1 CA 3158900A1 CA 3158900 A CA3158900 A CA 3158900A CA 3158900 A CA3158900 A CA 3158900A CA 3158900 A1 CA3158900 A1 CA 3158900A1
- Authority
- CA
- Canada
- Prior art keywords
- cancer
- individual
- dose
- cells
- patients
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0083—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the administration regime
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/13—Tumour cells, irrespective of tissue of origin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0016—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0066—Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
- C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5152—Tumor cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
- C12N2310/141—MicroRNAs, miRNAs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/344—Position-specific modifications, e.g. on every purine, at the 3'-end
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
- C12N2310/531—Stem-loop; Hairpin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
- C12N2310/533—Physical structure partially self-complementary or closed having a mismatch or nick in at least one of the strands
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Virology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Plant Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Mycology (AREA)
- Developmental Biology & Embryology (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202062960583P | 2020-01-13 | 2020-01-13 | |
| US62/960,583 | 2020-01-13 | ||
| US202063034868P | 2020-06-04 | 2020-06-04 | |
| US63/034,868 | 2020-06-04 | ||
| US202063061634P | 2020-08-05 | 2020-08-05 | |
| US63/061,634 | 2020-08-05 | ||
| PCT/US2021/013130 WO2021146213A1 (en) | 2020-01-13 | 2021-01-12 | Methods for treating cancers using gm-csf encoding polynucleotide and additional agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3158900A1 true CA3158900A1 (en) | 2021-07-22 |
Family
ID=76857765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3158900A Pending CA3158900A1 (en) | 2020-01-13 | 2021-01-12 | Methods for treating cancers using gm-csf encoding polynucleotide and additional agents |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US11400170B2 (https=) |
| EP (1) | EP4090380A1 (https=) |
| JP (1) | JP7815124B2 (https=) |
| CN (1) | CN115335085A (https=) |
| CA (1) | CA3158900A1 (https=) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4440704A2 (en) * | 2021-11-30 | 2024-10-09 | Gradalis, Inc. | Methods for treatment response to cancers |
| WO2025117756A1 (en) * | 2023-11-28 | 2025-06-05 | Gradalis, Inc. | Neoantigen immunotherapy |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8916530B2 (en) | 2005-11-18 | 2014-12-23 | Gradalis, Inc. | Individualized cancer therapy |
| US8906874B2 (en) | 2006-11-09 | 2014-12-09 | Gradalis, Inc. | Bi-functional shRNA targeting Stathmin 1 and uses thereof |
| US8758998B2 (en) | 2006-11-09 | 2014-06-24 | Gradalis, Inc. | Construction of bifunctional short hairpin RNA |
| US8252526B2 (en) | 2006-11-09 | 2012-08-28 | Gradalis, Inc. | ShRNA molecules and methods of use thereof |
| EP2217244A4 (en) * | 2007-11-12 | 2011-08-31 | Bipar Sciences Inc | TREATMENT OF NUTRITIONAL CANCER AND EGG CANCER WITH A PARP INHIBITOR ALONE OR IN COMBINATION WITH ANTITUMOROUS MEDICINES |
| US8969068B2 (en) | 2008-04-30 | 2015-03-03 | Gradalis, Inc. | Processes for the preparation of highly pure plasmid compositions by enzymatic digestion of colanic acid |
| CA2772057C (en) | 2009-09-03 | 2016-02-02 | Strike Bio, Inc. | Targeted delivery using tissue-specific peptidomimetic ligands |
| KR101543350B1 (ko) | 2009-10-30 | 2015-08-11 | 베이롤 칼리지 오브 메드신 | Pdx-1을 발현하는 신경내분비 종양에서 pdx-1 종양유전자를 표적화한 신규한 치료용 rna 간섭 기법 |
| US9157084B2 (en) * | 2009-12-23 | 2015-10-13 | Gradalis, Inc. | Furin-knockdown bi-functional RNA |
| SG181880A1 (en) * | 2009-12-23 | 2012-07-30 | Gradalis Inc | Furin-knockdown and gm-csf-augmented (fang) cancer vaccine |
| WO2015086473A1 (en) | 2013-12-09 | 2015-06-18 | Institut Curie | Methods for detecting inactivation of the homologous recombination pathway (brca1/2) in human tumors |
| SG11201811564QA (en) * | 2016-06-29 | 2019-01-30 | Tesaro Inc | Methods of treating ovarian cancer |
-
2021
- 2021-01-12 CA CA3158900A patent/CA3158900A1/en active Pending
- 2021-01-12 EP EP21704094.8A patent/EP4090380A1/en active Pending
- 2021-01-12 JP JP2022542739A patent/JP7815124B2/ja active Active
- 2021-01-12 CN CN202180009173.8A patent/CN115335085A/zh active Pending
- 2021-01-25 US US17/157,790 patent/US11400170B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| EP4090380A1 (en) | 2022-11-23 |
| US20210220488A1 (en) | 2021-07-22 |
| CN115335085A (zh) | 2022-11-11 |
| US11400170B2 (en) | 2022-08-02 |
| JP2023510853A (ja) | 2023-03-15 |
| JP7815124B2 (ja) | 2026-02-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Frederico et al. | Making a cold tumor hot: the role of vaccines in the treatment of glioblastoma | |
| Stultz et al. | How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer | |
| Wilky | Immune checkpoint inhibitors: The linchpins of modern immunotherapy | |
| Morabito et al. | Treatment of small cell lung cancer | |
| Agarwal et al. | Novel molecular targets for the therapy of castration-resistant prostate cancer | |
| US10864180B2 (en) | Combination of immunotherapy with local chemotherapy for the treatment of malignancies | |
| US11266726B2 (en) | Compositions and methods for the treatment of HER2-expressing solid tumors | |
| US12533395B2 (en) | Manipulation of meningeal lymphatic vasculature for brain and CNS tumor therapy | |
| US20180128833A1 (en) | Methods of treating with tumor membrane vesicle-based immunotherapy and predicting therapeutic response thereto | |
| US20250235467A1 (en) | Dendritic cell vaccination in parallel to chemotherapy | |
| US11400170B2 (en) | Methods for treating cancers | |
| JP2026002868A (ja) | 固形腫瘍の治療方法 | |
| US20230390345A1 (en) | Combination therapy comprising her-2-dc1 vaccine, a probiotic, and semaphorin | |
| WO2021146213A1 (en) | Methods for treating cancers using gm-csf encoding polynucleotide and additional agents | |
| AU2024236982A1 (en) | Mutants of a ligand-dependent corepressor (lcor) and uses thereof | |
| JP7551053B2 (ja) | 化学療法後の樹状細胞ワクチン接種 | |
| Hays | Trends in precision oncology and precision medicine 2.0 | |
| De Mello et al. | What will we expect from novel therapies to esophageal and gastric malignancies? | |
| EP4153783A1 (en) | Tumor mutational burden associated with sensitivity to immunotherapy in locally advanced or metastatic urothelial carcinoma | |
| Roche et al. | Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors | |
| EP4440704A2 (en) | Methods for treatment response to cancers | |
| Fogh et al. | 8 Neoplastic Disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MFA | Maintenance fee for application paid |
Free format text: FEE DESCRIPTION TEXT: MF (APPLICATION, 4TH ANNIV.) - STANDARD Year of fee payment: 4 |
|
| U00 | Fee paid |
Free format text: ST27 STATUS EVENT CODE: A-1-1-U10-U00-U101 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: MAINTENANCE REQUEST RECEIVED Effective date: 20241218 |
|
| U11 | Full renewal or maintenance fee paid |
Free format text: ST27 STATUS EVENT CODE: A-1-1-U10-U11-U102 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: MAINTENANCE FEE PAYMENT DETERMINED COMPLIANT Effective date: 20241218 Free format text: ST27 STATUS EVENT CODE: A-1-1-U10-U11-U102 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: MAINTENANCE FEE PAYMENT PAID IN FULL Effective date: 20241218 |
|
| D11 | Substantive examination requested |
Free format text: ST27 STATUS EVENT CODE: A-1-1-D10-D11-D117 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: REQUEST FOR EXAMINATION RECEIVED Effective date: 20250102 |
|
| P11 | Amendment of application requested |
Free format text: ST27 STATUS EVENT CODE: A-1-1-P10-P11-P101 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: AMENDMENT RECEIVED - VOLUNTARY AMENDMENT Effective date: 20250102 |
|
| W00 | Other event occurred |
Free format text: ST27 STATUS EVENT CODE: A-1-1-W10-W00-W111 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: CORRESPONDENT DETERMINED COMPLIANT Effective date: 20250102 |
|
| D00 | Search and/or examination requested or commenced |
Free format text: ST27 STATUS EVENT CODE: A-1-1-D10-D00-D118 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: REQUEST FOR EXAMINATION REQUIREMENTS DETERMINED COMPLIANT Effective date: 20250114 |
|
| W00 | Other event occurred |
Free format text: ST27 STATUS EVENT CODE: A-1-1-W10-W00-W111 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: CORRESPONDENT DETERMINED COMPLIANT Effective date: 20250114 |
|
| P11 | Amendment of application requested |
Free format text: ST27 STATUS EVENT CODE: A-1-1-P10-P11-P102 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: AMENDMENT DETERMINED COMPLIANT Effective date: 20250205 |
|
| P13 | Application amended |
Free format text: ST27 STATUS EVENT CODE: A-1-1-P10-P13-X000 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: APPLICATION AMENDED Effective date: 20250205 |
|
| D11 | Substantive examination requested |
Free format text: ST27 STATUS EVENT CODE: A-1-2-D10-D11-D155 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: ALL REQUIREMENTS FOR EXAMINATION DETERMINED COMPLIANT Effective date: 20250430 |
|
| W00 | Other event occurred |
Free format text: ST27 STATUS EVENT CODE: A-2-2-W10-W00-W100 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: LETTER SENT Effective date: 20250505 |