Antibody-interferon fusion proteins for enhancing adoptive T cell therapies for the treatment of cancer
In various embodiments methods are provided that involve the use of antibody-interferon (Ab-IFN) fusion proteins to boost the cancer-fighting capacity of adoptive T cell therapies (ACT), including any T cells that are manipulated and grown outside the body, then returned to the patient with the goal of having the infused T cells home to sites of tumor and destroy the cancer in an immunologic attack. Illustrative, but non-limiting, adoptive T cell therapies include chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes (TILs), virus-specific T cells, and T cell receptor transgenic T cells.
1. A method of treating a cancer in a mammal, said method comprising:
first administering to said mammal a targeted interferon where said targeted interferon comprises an interferon attached to an antibody that binds to CD20 and
later administering to said mammal an adoptive T cell therapy targeted to said cancer, where said adoptive T cell therapy comprises administration of chimeric antigen receptor (CAR) T cells targeted to CD19;
wherein said targeted interferon improves recognition of tumor cells, and/or cytotoxicity, and/or activation and survival of said adoptive T cell therapy as compared to the use of said adoptive T cell therapy in the absence of said targeted interferon, wherein said cancer is selected from the group consisting of diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, primary mediastinal lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, marginal zone lymphoma, and primary CNS lymphoma.
2. The method of claim 1 , wherein said targeted interferon increases cytokine production by effector T cells targeting said cancer compared to the use of said CAR T cells in the absence of said targeted interferon.
3. The method of claim 1 , wherein said antibody is an antibody comprising said targeted interferon comprises an antibody selected from the group consisting of a single chain Fv (scFv), a FAB, a (Fab′) 2 , an (scFv) 2 , and a full immunoglobulin.
4. The method of claim 1 , wherein said interferon comprises an interferon selected from the group consisting of interferon alpha (IFNα), mutant interferon alpha, interferon beta (IFNβ), and interferon gamma (IFNγ).
5. The method of claim 4 , wherein said interferon is an interferon alpha subtype selected from the group consisting of IFNα14, IFNα2, IFNα1, IFNα4, IFNα5, IFNα6, IFNα7, IFNα8, IFNα10, IFNα13, IFNα16, IFNα17, and IFNα21.
6. The method of claim 1 , wherein said antibody is chemically coupled to said interferon, or said antibody is directly joined to said interferon.
7. The method of claim 1 , wherein said antibody is joined to said interferon with a single amino acid or peptide linker.
8. The method of claim 7 , wherein:
said peptide linker joins said interferon to the carboxyl terminus of the CH3 domain of said antibody; or
said peptide linker joins the amino terminus of said interferon to the carboxyl terminus of the CH3 domain of said antibody; or
said peptide linker joins the carboxyl terminus of said interferon to the carboxyl terminus of the CH3 domain of said antibody.
9. The method of claim 7 , wherein the amino acid sequence of said peptide linker is selected from the group consisting of
(SEQ ID NO: 31)
GGG, GGS, GGGGS,
(SEQ ID NO: 32)
SGGGGS,
(SEQ ID NO: 33)
GGGGSGGGGS,
(SEQ ID NO: 34)
A EAAAK A,
(SEQ ID NO: 35)
A EAAAK EAAAK A,
(SEQ ID NO: 36)
A EAAAK EAAAK EAAAK A,
(SEQ ID NO: 37)
A EAAAK EAAAK EAAAK EAAAK A,
(SEQ ID NO: 38)
A EAAAK EAAAK EAAAK EAAAK EAAAK A,
(SEQ ID NO: 39)
AEAAAKEAAAKAG,
(SEQ ID NO: 40)
AEAAAKEAAAKAGS,
(SEQ ID NO: 41)
GGGGG,
(SEQ ID NO: 42)
GGAGG,
(SEQ ID NO: 43)
GGGGGGGG,
(SEQ ID NO: 44)
GAGAGAGAGA,
(SEQ ID NO: 45)
RPLSYRPPFPFGFPSVRP,
(SEQ ID NO: 46)
YPRSIYIRRRHPSPSLTT,
(SEQ ID NO: 47)
TPSHLSHILPSFGLPTFN,
(SEQ ID NO: 48)
RPVSPFTFPRLSNSWLPA,
(SEQ ID NO: 49)
SPAAHFPRSIPRPGPIRT,
(SEQ ID NO: 50)
APGPSAPSHRSLPSRAFG,
(SEQ ID NO: 51)
PRNSIHFLHPLLVAPLGA,
(SEQ ID NO: 52)
MPSLSGVLQVRYLSPPDL,
(SEQ ID NO: 53)
SPQYPSPLTLTLPPHPSL,
(SEQ ID NO: 54)
NPSLNPPSYLHRAPSRIS,
(SEQ ID NO: 55)
LPWRTSLLPSLPLRRRP,
(SEQ ID NO: 56)
PPLFAKGPVGLLSRSFPP,
(SEQ ID NO: 57)
VPPAPVVSLRSAHARPPY,
(SEQ ID NO: 58)
LRPTPPRVRSYTCCPTP,
(SEQ ID NO: 59)
PNVAHVLPLL TVPWDNLR,
(SEQ ID NO: 60)
CNPLLPLCARSPAVRTFP,
(SEQ ID NO: 61)
LGTPTPTPTPTGEF,
(SEQ ID NO: 62)
EDFTRGKL,
(SEQ ID NO: 63)
L EAAAR EAAAR EAAAR EAAAR,
(SEQ ID NO: 64)
L EAAAR EAAAR EAAAR,
(SEQ ID NO: 65)
L EAAAR EAAAR,
(SEQ ID NO: 66)
L EAAAR,
(SEQ ID NO: 67)
EAAAR EAAAR EAAAR EAAAR,
(SEQ ID NO: 68)
EAAAR EAAAR EAAAR,
(SEQ ID NO: 69)
EAAAR EAAAR,
(SEQ ID NO: 70)
EAAAR,
(SEQ ID NO: 71)
LTEEQQEGGG,
(SEQ ID NO: 72)
TEEQQEGGG,
(SEQ ID NO: 73)
LAKLKQKTEQLQDRIAGGG,
(SEQ ID NO: 74)
LELKTPLGDT THTCPRCPEP KSCDTPPPCP RCPEPKSCDT
PPPCPRCPEP KSCDTPPPCP RCPGG, and
(SEQ ID NO: 75)
LEPKSSDKTHTSPPSPGG.
10. The method of claim 1 , wherein said targeted interferon comprises an interferon alpha 14 attached to an antibody comprising the variable region of rituximab.
11. The method of claim 10 , wherein said antibody is an IgG.
12. The method of claim 10 , wherein said antibody is attached to said interferon by an SGGGGS (SEQ ID NO:27) linker.
13. The method of claim 1 , wherein said adoptive T cell therapy is administered 30 days or less after administration of said targeted interferon.