Vaccine and uses thereof in cell therapy
The present disclosure relates to compositions and methods for enhancing T cell response in vivo. For example, a method of enhancing T cell response in a subject or treating a subject having cancer, the method comprising: administering an effective amount of a composition comprising modified cells to the subject having a form of cancer associated with or expressing an antigen, for example, a solid tumor antigen; and administering (1) a nucleic acid encoding the antigen, (2) additional modified cells comprising the nucleic acid or the antigen, or (3) microorganisms, for example cold viruses, comprising the nucleic acid or the antigen. In embodiments, the modified cells comprise mixed cells targeting a solid tumor antigen and a white blood cell (WBC) antigen. In embodiments, the modified cells comprise a dominant negative form of an immune checkpoint molecule (e.g., PD-1). In embodiments, the modified cells comprise an exogenous polynucleotide encoding a therapeutic agent, such as IL-12 and IFNγ.
1 . A method of enhancing expansion of T cells, the method comprising:
obtaining lipid particles comprising a polynucleotide encoding a solid tumor antigen;
contacting a population of dendritic cells (DCs) and a population of lymphocytes with the lipid particles, the population of lymphocytes comprising a first population of T cells comprising a CAR binding CD19 and a second population of T cells comprising a CAR binding the solid tumor antigen; and
allowing expansion of the first and second population of T cells, wherein a level of the expansion of the first and second population of T cells is greater than a level of expansion of a first and a second population of T cells contacted with the population of DCs but without lipid particles.
2 . The method of claim 1 , wherein the tumor antigen comprises tMUC1, PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, CLDN 18.2, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Rα2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-α, ErbB2, EpCAM, EGFRvIII, MAGE A4, EGFR, or a combination thereof.
3 . The method of claim 2 , wherein the polynucleotide encoding the antigen comprises transcribed RNA encapsulated in liposomes.
4 . The method of claim 1 , wherein the lipid particles comprise N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA), dioleoylphosphatidylethanolamine (DOPE), or a combination of DOTMA and cholesterol.
5 . The method of claim 1 , wherein the polynucleotide encodes SEQ ID NO: 1, and the CAR binding the solid tumor antigen comprises SEQ ID NO: 5 or 6.
6 . The method of claim 1 , wherein the lipid particles comprise lipid nanoparticles (LNPs).
7 . The method of claim 1 , wherein the lipid particles comprise a polynucleotide encoding a costimulatory signal-related molecule selected from the group consisting of anti-CD28, CD40L, anti-4-1BB, and agonists of CD28, CD40, or 4-1BB.
8 . The method of claim 1 , wherein the population of T cells comprises one or more dominant negative forms of an immune checkpoint molecule.
9 . The method of claim 8 , wherein the immune checkpoint molecule comprises PD-1, cytotoxic T lymphocyte antigen-4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte-activation protein 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), natural killer cell receptor 2B4 (2B4), or CD160.
10 . The method of claim 1 , wherein a ratio of the population of DCs to the population of T cells is from about 100:1 to about 1:100.
11 . The method of claim 10 , wherein the ratio of the population of DCs to the population of T cells is from about 1:1 to about 1:10.
12 . The method of claim 1 , wherein the contacting is performed in the presence of a cytokine comprising IL-2, IL-7, IL-15, IL-21, or a combination thereof.
13 . The method of claim 1 , wherein the first population of T cells or the second population of T cells comprises an intracellular signaling domain of a CD3-zeta (CD3ζ) chain, a CD28 signaling domain, a 4-1BB signaling domain, or a combination thereof.
14 . The method of claim 1 , wherein the first population of T cells or the second population of T cells has reduced expression of an endogenous TRAC gene.
15 . The method of claim 1 , wherein the contacting is performed for a time period ranging from about 1 day to about 10 days.
16 . The method of claim 1 , wherein the tumor antigen is GUCY2C.
17 . The method of claim 1 , wherein the tumor antigen is ACPP.
18 . The method of claim 1 , wherein the tumor antigen is TSHR.
19 . The method of claim 1 , wherein the contacting step comprises administering the population of DCs and the population of T cells to a subject simultaneously or sequentially via intravenous injection, intratumoral injection, or intraperitoneal injection.