IP Library › Granted Patent US 12,258,581
Granted Patent B2
US 12,258,581 · App. 17/494,633 · Granted Mar 25, 2025

T cell manufacturing compositions and methods

Inventors: Marit M. Van Buuren (Belmont, MA); Divya Reddy Lenkala (Watertown, MA); Joost Huibert Van Den Burg (Amsterdam, NL); Jessica Kohler (Boston, MA); Matthew Goldstein (Jamaica Plain, MA); Ed Fritsch (Concord, MA); Renate De Boer (Diemen, NL); Ton Schumacher (Aloemehomal, NL); Noor Bakker (Stuyvesantstraat, NL)
Assignees: BioNTech US Inc.; Stichting Het Nederlands Kanker Instituut—Antoni Van Leeuwenhoek Ziekenhis
C12N5/0636A61K39/4611A61K39/464401A61K39/46449A61P35/00A61K2039/572C12N2501/26C12N2501/998
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Quick Facts
Patent No.
US 12,258,581
App. No.
17/494,633
Granted
Mar 25, 2025
Kind
B2
Abstract

The generation of antigen specific T cells by controlled ex vivo induction or expansion can provide highly specific and beneficial T cell therapies. The present disclosure provides T cell manufacturing methods and therapeutic T cell compositions which can be used for treating subjects with cancer and other conditions, diseases and disorders personal antigen specific T cell therapy.

Claims (30)

1. A method of preparing cancer antigen-specific T cells ex vivo suitable for T cell therapy in a human subject, the method comprising:

(a) depleting CD25+ cells from a population of immune cells comprising antigen presenting cells (APCs) and T cells, thereby forming a depleted population of immune cells comprising a first population of APCs and T cells, wherein the population of immune cells is from a biological sample from a human subject; and

(b) incubating the depleted population of immune cells for a first time period in the presence of:

(i) FMS-like tyrosine kinase 3 receptor ligand (FLT3L), and

(ii) (A) a polypeptide comprising one or more cancer antigen epitope sequences expressed by cancer cells of a human subject with cancer; or (B) a polynucleotide encoding the polypeptide comprising the one or more cancer antigen epitope sequences expressed by the cancer cells of the human subject with cancer; thereby forming a population of stimulated T cells; and

(c) expanding the population of stimulated T cells, thereby forming an expanded population of T cells, wherein expanding comprises expanding T cells derived from naïve CD8+ T cells or naïve CD4+ T cells; wherein the expanded population of T cells comprises T cells that are specific to a complex comprising (i) a first cancer antigen epitope sequence of the one or more cancer antigen epitope sequences and (ii) an MHC protein expressed by the cancer cells or APCs of the human subject with cancer; wherein:

(i) at least 0.1% of CD8+ T cells that are specific to the complex in the expanded population of T cells are derived from the naïve CD8+ T cells from the biological sample from the human subject, or

(ii) at least 0.1% of CD4+ T cells that are specific to the complex in the expanded population of T cells are derived from the naïve CD4+ T cells from the biological sample from the human subject.

2. The method of claim 1 , wherein steps (b) and (c) are performed in less than 28 days.

3. The method of claim 1 , wherein a fraction of CD8+ T cells of total number of CD8+ T cells in the expanded population of T cells that are specific to the complex is at least two-fold higher than a fraction of CD8+ T cells of total number of CD8+ T cells in the biological sample that are specific to the complex.

4. The method of claim 1 , wherein a fraction of CD4+ T cells of total number of CD4+ T cells in the expanded population of T cells that are specific to the complex is at least two-fold higher than a fraction of CD4+ T cells of total number of CD4+ T cells in the biological sample that are specific to the complex.

5. The method of claim 1 , wherein the biological sample is from the human subject with cancer.

6. The method of claim 1 , wherein expanding further comprises contacting the population of stimulated T cells with a second population of mature APCs that has been incubated with FLT3L.

7. The method of claim 6 , wherein the second population of mature APCs has been incubated with FLT3L for at least 1 day prior to contacting the population of stimulated T cells with the second population of mature APCs.

8. The method of claim 6 , wherein expanding further comprises contacting the population of stimulated T cells with a third population of mature APCs, wherein the third population of mature APCs has been incubated with FLT3L prior to contacting the population of stimulated T cells with the third population of mature APCs.

9. The method of claim 1 , wherein the biological sample is a peripheral blood sample, a leukapheresis sample or an apheresis sample.

10. The method of claim 1 , wherein incubating comprises incubating the depleted population of immune cells in the presence of FLT3L and an RNA encoding the polypeptide.

11. The method of claim 1 , wherein the polypeptide is from 8 to 50 amino acids in length.

12. The method of claim 1 , wherein each of the one or more cancer antigen epitope sequences contains a mutation and binds to an MHC protein expressed by cancer cells of the human subject with cancer with a stronger affinity than a corresponding wild-type epitope sequence.

13. The method of claim 1 , wherein the one or more cancer antigen epitope sequences comprises two or more cancer antigen epitope sequences that are expressed by cancer cells of the human subject with cancer.

14. The method of claim 13 , wherein the expanded population of T cells comprises T cells that are specific to:

(A) a first complex comprising (i) a first cancer antigen epitope sequence of the two or more cancer antigen epitope sequences and (ii) an MHC protein expressed by the cancer cells or APCs of the human subject with cancer, and

(B) a second complex comprising (i) a second cancer antigen epitope sequence of the two or more cancer antigen epitope sequences and (ii) an MHC protein expressed by the cancer cells or APCs of the human subject with cancer.

15. The method of claim 1 , wherein depleting comprises contacting the population of immune cells with a CD25 binding agent.

16. The method of claim 1 , wherein depleting further comprises depleting CD14+ cells from the population of immune cells.

17. The method of claim 1 , wherein depleting further comprises depleting CD19+ cells from the population of immune cells.

18. The method of claim 1 , wherein the expanded population of T cells comprises at least 1×10{circumflex over ( )}6 total CD8+ T cells or at least 1×10{circumflex over ( )}6 total CD4+ T cells.

19. The method of claim 1 , wherein the method further comprises harvesting the expanded population of T cells, cryopreserving the expanded population of T cells, preparing a pharmaceutical composition containing the expanded population of T cells or administering a pharmaceutical composition comprising the expanded population of T cells to the human subject with cancer.

20. The method of claim 1 , wherein the method further comprises stimulating one or more populations of APCs with one or more cytokines or growth factors, thereby obtaining one or more APC preparations comprising matured APCs, and wherein expanding comprises contacting the population of stimulated T cells with the one or more APC preparations comprising matured APCs.

21. The method of claim 20 , wherein the one or more cytokines or growth factors comprise GM-CSF, IL-4, FLT3L, TNF-α, IL-1β, PGE1, IL-6, IL-7, IFN-α, R848, LPS, ss-rna40, poly I:C, or a combination thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 8, 2021
From: VAN BUUREN, MARIT M.; LENKALA, DIVYA REDDY; KOHLER, JESSICA; GOLDSTEIN, MATTHEW; FRITSCH, ED
To: NEON THERAPEUTICS, INC.
Reel/Frame 057742/0507 →
MERGER Recorded Oct 8, 2021
From: NEON THERAPEUTICS, INC.
To: BIONTECH US INC.
Reel/Frame 057742/0578 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 8, 2021
From: VAN DEN BERG, JOOST HUIBERT; DE BOER, RENATE; SCHUMACHER, TON; BAKKER, NOOR
To: STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Reel/Frame 057742/0685 →
Continuity (7)
Continuation 16735555 · Jan 6, 2020
Continuation PCTUS2018059896 · Nov 8, 2018
Provisional Application 62737625 · Sep 27, 2018
Provisional Application 62618445 · Jan 17, 2018
Provisional Application 62588590 · Nov 20, 2017
Provisional Application 62583229 · Nov 8, 2017
Related Publication 20220177840A1 · Jun 9, 2022
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Cited By (1)
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