CCL21-encoding recombinant rhabdovirus

Abstract

The present invention relates to the field of oncolytic viruses and, in particular, to a recombinant rhabdovirus, such as a vesicular stomatitis virus that encodes a CCL21 protein in its genome. The invention also relates to the use of the recombinant virus in the treatment of cancer, and also to methods for producing such a virus.

Description

DETAILED DESCRIPTION OF THE INVENTION The following detailed description sets forth several specific details to provide a complete understanding of the present invention. However, it will be evident to a person of average skill that the technology of the present invention can be used without some of these specific details. In other cases, known structures and techniques are not shown in detail so as not to render the present invention ambiguous. The headings are included only for convenience to aid reading and should not be interpreted as limiting the invention to specific aspects or embodiments. Rhabdovirus The rhabdovirus family includes 18 genera and 134 species with negative-sense single-stranded RNA genomes of approximately 10-16 kb (Walke et al., ICTV Virus Taxonomy Profile: Rhabdoviridae, Journal of General Virology, 99:447-448 (2018)). Characteristics of members of the rhabdovirus family include one or more of the following: A bullet- or rod-shaped particle 100–430 nm in length and 45–100 nm in diameter comprising a helical nucleocapsid surrounded by a matrix layer and a lipid envelope, whereas some rhabdoviruses have non-enveloped filamentous viruses. A negative-sense single-stranded RNA of 10.8–16.1 kb, which is mostly non-segmented. A genome encoding at least 5 genes that encode the nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), and glycoprotein (G) of the structural proteins. As used herein, a rhabdovirus may belong to the genus: almendravirus, curiovirus, cytorhabdovirus, dichorhavirus, ephemerovirus, Hapavirus, ledantevirus, lyssavirus, novirhabdovirus, nucleorhabdovirus, perhabdovirus, sigmavirus, sprivivirus, sripuvirus, tibrovirus, tupavirus, varicosevirus or vesiculovirus.Within the genus mentioned herein, rhabdovirus may belong to any of the listed species. The genus almendravirus includes: arboretum almendravirus, balsa almendravirus, Coot Bay almendravirus, Puerto Almendras almendravirus, Rio Chico almendravirus; the genus curiovirus includes: curiónopolis curiovirus, Inri curiovirus, Itacaiunas curiovirus, Rochambeau curiovirus;The genus Cythorhabdovirus includes: Alfalfa dwarf cytorhabdovirus, Barley yellow striate mosaic cytorhabdovirus, Broccoli necrotic yellows cytorhabdovirus, Colocasia bobone disease-associated cytorhabdovirus, Festuca leaf streak cytorhabdovirus, Lettuce necrotic yellows cytorhabdovirus, Lettuce yellow motile cytorhabdovirus, Northern cereal mosaic cytorhabdovirus, Sonchus cytorhabdovirus 1, Strawberry crinkle cytorhabdovirus, Wheat American striate mosaic cytorhabdovirus; The dichorhavirus genus includes: Coffee ringspot dichorhavirus, Orchid fleck dichorhavirus;the genus of ephemerovirus includes: Adelaide River ephemerovirus, Berrimah ephemerovirus, Bovine fever ephemerovirus (bovine ephemerovirus), Kimberley ephemerovirus, Koolpinyah ephemerovirus, Kotonkan ephemerovirus, Obodhiang ephemerovirus, Yaphemerovirus; the genus hapavirus includes: Flanders hapavirus, Gray Lodge hapavirus, Hart Park hapavirus, Joinjakaka hapavirus, Kamese hapavirus, La Joya hapavirus, Landjia hapavirus, Manitoba hapavirus, Marco hapavirus, Mosqueiro hapavirus, Mossuril hapavirus, Ord hapavirus, Ngaan Rivering hapavirus, Parry Creek hapavirus, Wongabel hapavirus; The genus of ledantevirus includes: Barur ledantevirus, Fikirini ledantevirus, Fukuoka ledantevirus, Kanyawara ledantevirus, Kern Canyon ledantevirus, Keuraliba ledantevirus, Kolente ledantevirus, Kumasi ledantevirus, Le Dantec ledantevirus, ledantevirus del Mountélago, Mountélagon Nishimuro ledantevirus, Nkolbisson ledantevirus, Oita ledantevirus, Wuhan ledantevirus, Yongjia ledantevirus;the genus lyssavirus includes: Aravan lyssavirus, Australian bat lyssavirus, Bokeloh bat lyssavirus, Duvenhage lyssavirus, European bat lyssavirus type 1, European bat lyssavirus type 2, European bat lyssavirus Gannoruwa bat, Ikoma lyssavirus, Irkut lyssavirus, Khujand lyssavirus, Lagos bat lyssavirus, Lleida bat lyssavirus, Mokola lyssavirus, Rabies lyssavirus, Shimoniélago bat lyssavirus, de Shimoniélago bat lyssavirus western Caucasian; the genus novirhabdovirus includes: Hirame novirhabdovirus, Piscine novirhabdovirus, Salmonid novirhabdovirus, Snakehead novirhabdovirus;The genus nucleorhabdovirus includes: Datura yellow vein nucleorhabdovirus, Eggplant mottled dwarf nucleorhabdovirus, Maize fine streak nucleorhabdovirus, Maize Iranian mosaic nucleorhabdovirus, Maize mosaic nucleorhabdovirus, Potato yellow dwarf nucleorhabdovirus, Rice yellow stunt nucleorhabdovirus, Sonchus yellow net nucleorhabdovirus, Sowthistle yellow vein nucleorhabdovirus, Taro vein chlorosis nucleorhabdovirus; the genus perhabdovirus includes: Anguillid perhabdovirus, Perch perhabdovirus, Sea trout perhabdovirus;The genus Sigmavirus includes: Drosophila affinis sigmavirus, Drosophila ananassae sigmavirus, Drosophila immigrans sigmavirus, Drosophila meianogaster sigmavirus, Drosophila obscura sigmavirus, Drosophila tristis sigmavirus, Muscina stabulans sigmavirus; the genus Sprivivirus includes: Carp sprivivirus, Pike fry sprivivirus; the genus Sripuvirus includes: Almpiwar sripuvirus, Chaco sripuvirus, Niakha sripuvirus, Sena Madureira sripuvirus, Sripur sripuvirus; the genus Tibrovirus includes: Bas-Congo tibrovirus, Beatrice HUI tibrovirus, Coastal Plains tibrovirus, Ekpoma 1 tibrovirus, Ekpoma 2 tibrovirus, Sweetwater Branch tibrovirus, Tibrogargan tibrovirus; The genus Tupavirus includes: Durham Tupavirus, Klamath Tupavirus, Tupaia Tupavirus; the genus Varicosavirus includes: lettuce large vein associated varicosavirus;The genus Vesiculovirus includes: Alagoas vesiculovirus, American bat vesiculovirus, Carajas vesiculovirus, Chandipura vesiculovirus, Cocal vesiculovirus, Indiana vesiculovirus, Isfahan vesiculovirus, Jurona vesiculovirus, Malpais Spring vesiculovirus, Maraba vesiculovirus, Morreton vesiculovirus, New Jersey vesiculovirus, Perinet vesiculovirus, Piry vesiculovirus, Radi vesiculovirus, Yug Bogdanovac vesiculovirus, or Moussa virus. Preferably, the recombinant rhabdovirus of the invention is an oncolytic rhabdovirus. In this context, oncolytic has its common meaning known in the prior art and refers to the ability of the rhabdovirus to infect and lyse (break down) cancer cells, but not normal cells (to any significant extent). Preferably, the oncolytic rhabdovirus can replicate in cancer cells. The oncolytic activity can be assessed in different assay systems known to the mid-level practitioner (an example in vitro assay is described in Muik et al., Cancer Res., 74(13), 3567-78, 2014). It is noteworthy that an oncolytic rhabdovirus can infect and lyse only specific types of cancer cells. Furthermore, the oncolytic effect can vary depending on the type of cancer cells. In a preferred configuration, rhabdovirus belongs to the genus Vesiculovirus. Vesiculovirus species have been defined primarily by serological means in conjunction with phylogenetic analyses of their genomes. Biological characteristics such as host variation and transmission mechanisms are also used to distinguish viral species within the genus. Thus, the genus Vesiculovirus forms a distinct monophyletic group supported by maximum likelihood trees inferred from complete L-sequences. Viruses assigned to different species within the genus Vesiculovirus may have one or more of the following characteristics: A) a minimum amino acid sequence divergence of 20% in L; B) a minimum amino acid sequence divergence of 10% in N; C) a minimum amino acid sequence divergence of 15% in G; D) can be distinguished in serological tests; and E) occupies different ecological niches as evidenced by differences in arthropod hosts and / or vectors. Vesicular stomatitis virus (VSV), and in particular VSV-GP (recombinant with GP from LCMV), is preferred. Advantageous properties of VSV-GP include one or more of the following: highly potent and rapid (<8h) inactivator; oncolytic virus; possible systemic application; reduced neurotropism / neurotoxicity; lytic reproduction and induces immunogenic cell death; non-replication in healthy human cells due to interferon (IFN) response; strong activation of innate immunity; approximately 3kb of space for antigens and immunomodulatory payloads; recombinant with an arenavirus glycoprotein from lymphocytic choriomeningitis virus (LCMV); and favorable safety characteristics in terms of reduced neurotoxicity and lower sensitivity to neutralizing antibody responses and complement destruction compared to wild-type VSV (VSV-G).Specifically, it replicates in tumor cells, which have lost the ability to generate and respond to innate antiviral immune responses (e.g., type I IFN signaling); abortive replication in “healthy cells” so that it is rapidly excluded from normal tissues; viral replication in tumor cells that produces the induction of immunogenic cell death, release of tumor-associated antigens, local inflammation, and induction of antitumor immunity. The invention is carried out in a recombinant vesicular stomatitis virus, which encodes in its genome at least one vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G), and at least one CCL21 protein or a functional variant thereof, preferably human CCL21. In a preferred embodiment, the recombinant vesicular stomatitis virus encodes in its genome at least one vesicular stomatitis virus nucleoprotein (N) comprising an amino acid sequence as indicated in SEQ ID NO:7 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:7, a phosphoprotein (P) comprising an amino acid sequence as indicated in SEQ ID NO:8 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:8, and a large protein (L) comprising an amino acid sequence as indicated in SEQ ID NO:9 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:9. NO:9, and a matrix protein (M) comprising an amino acid sequence as indicated in SEQ ID NQ:10 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NQ:10. A person of intermediate skill will understand that modifications can be made to the sequence of the nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), or glycoprotein (G) of vesicular stomatitis virus without losing the basic functions of those proteins. Such functional variants, as used herein, retain all or part of their basic function or activity. The L protein, for example, is the polymerase and has an essential role during viral transcription and replication. A functional variant of this protein must retain at least some of its capacity. A good indication of retention of basic functionality or activity is the successful production of viruses, including these functional variants, that are still capable of replicating and infecting tumor cells.Virus production and tests for infection and replication in tumor cells can be assessed in different assay systems known to the mid-level trade person (an example in vitro assay is described in Muik et al., Cancer Res., 74(13), 3567-78, 2014). In a preferred embodiment, the recombinant vesicular stomatitis virus encodes in its genome at least one vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G) and at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the large protein (L) comprises an amino acid sequence that has > 80% sequence identity with respect to SEQ ID NO:9. In a preferred embodiment, the recombinant vesicular stomatitis virus encodes in its genome the jzRQnn / ι ζηζ / E / γ less a vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G) and at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the nucleoprotein (N) comprises an amino acid sequence having >90% sequence identity with respect to SEQ ID NO:7. In another preferred embodiment, the recombinant vesicular stomatitis virus encodes in its genome at least one vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G) and at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the large protein (L) comprises an amino acid sequence having a sequence identity equal to or greater than 80% of SEQ ID NO:9 and the nucleoprotein (N) comprises an amino acid sequence having > 90% sequence identity with respect to SEQ ID NO:7. In a preferred embodiment of the invention, the RNA genome of the recombinant rhabdovirus of the invention comprises or consists of a sequence as shown in SEQ ID NO: 24. In addition, the RNA genome of the recombinant rhabdovirus of the invention may also comprise or consist of such sequences, wherein the nucleic acids of the RNA genome are exchanged according to the degeneracy of the genetic code, without any alteration of the respective amino acid sequence. In another preferred embodiment of the invention, the RNA genome of the recombinant rhabdovirus of the invention comprises or consists of a coding sequence that is at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 24. It is worth noting that a recombinant rhabdovirus of the invention may encode in its genome other cargoes, such as tumor antigens, other chemokines, cytokines, or other immunomodulatory elements. In another embodiment, the recombinant rhabdovirus of the invention additionally encodes a sodium iodide symporter protein (NIS) in its genome. Expression of NIS and co-incubation with, for example, 125l allows the use of NIS as an imaging indicator (Carlson et al., Current Gene Therapy, 12, 3347, 2012). recombinant rhabdovirus Certain wild-type rhabdovirus strains, such as wild-type VSV strains, are known to be neurotoxic. It has also been indicated that infected individuals are capable of rapidly mounting a strong humoral response with high antibody titers that primarily target the glycoprotein. Neutralizing antibodies that target the G glycoprotein of rhabdoviruses in general, and VSV specifically, can limit viral spread and thus protect individuals against viral reinfection. However, viral neutralization limits the repeated application of rhabdovirus to cancer patients. To eliminate these disadvantages, the wild-type rhabdovirus G glycoprotein can be replaced with the glycoprotein from another virus. In this context, glycoprotein replacement refers to (i) replacing the gene encoding the wild-type G glycoprotein with the gene encoding the GP glycoprotein from another virus, and / or (ii) replacing the wild-type G glycoprotein with the GP glycoprotein from another virus. In a preferred embodiment, the rhabdovirus G glycoprotein is replaced by the GP glycoprotein of lymphocytic choriomeningitis virus (LCMV), preferably with the WE-HPL strain. In a more preferred embodiment, the rhabdovirus is a vesicular stomatitis virus with the GP glycoprotein of lymphocytic choriomeningitis virus (LCMV), preferably with the WE-HPI strain. Such a VSV is described, for example, in WO2010 / 040526, and is designated VSV-GP. The advantages offered are (i) loss of VSV-G-mediated neurotoxicity and (ii) lack of vector neutralization by antibodies (as shown in mice). The GP glycoprotein of lymphocytic choriomeningitis virus (LCMV) can be GP1 or GP2. The invention includes glycoproteins from different LCMV strains. In particular, LCMV-GP can be derived from wild-type LCMV or the LCMV strains LCMV-WE, LCMV-WE-HPI, and LCMV-WE-Hplopt. In a preferred embodiment, the gene encoding the LCMV GP glycoprotein encodes a protein with an amino acid sequence as shown in SEQ ID NO:11 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence in SEQ ID NO:11, while maintaining the functional properties of the recombinant rhabdovirus comprising a GP glycoprotein encoding an amino acid sequence as shown in SEQ ID NO:11. In another modality, the G glycoprotein of the recombinant rhabdovirus is replaced by the GP glycoprotein of Dandenong virus (DANDV) or Mopeia virus (MOPV). In a more preferred modality, the recombinant rhabdovirus is a vesicular stomatitis virus in which the G glycoprotein is replaced by the GP glycoprotein of Dandenong virus (DANDV) or Mopeia virus (MOPV). The advantages offered are (i) loss of VSV-G-mediated neurotoxicity and (ii) lack of vector neutralization by antibodies (as shown in mice). The Dandenong virus (DANDV) is an Old World arenavirus. To date, only one strain is known to the average person of the trade, comprising a GP glycoprotein that can be used in the present invention as a donor of the GP glycoprotein comprising the recombinant rhabdovirus of the invention. The DANDV GP glycoprotein comprising the recombinant rhabdovirus of the invention has more than six glycosylation sites, in particular, seven glycosylation sites. A preferred example GP glycoprotein is that comprising DANDV, accessible under GenBank number EU136038.In one embodiment, the gene encoding the DNADV GP glycoprotein encodes an amino acid sequence as shown in SEQ ID NO:12 or an amino acid sequence having at least 80, 85, 90 or 95% sequence identity with the amino acid sequence of SEQ ID NO:12, while maintaining the functional properties of the recombinant rhabdovirus comprising a GP glycoprotein encoding an amino acid sequence as shown in SEQ ID NO:12. Mopeia virus (MOPV) is an Old World arenavirus. Several strains are known to the average person of the trade, comprising a GP glycoprotein, which can be used in the present invention as donors of the GP glycoprotein comprising the recombinant rhabdovirus of the invention. The GP glycoprotein of MOPV comprising the recombinant rhabdovirus of the invention has more than 6 glycosylation sites, in particular, 7 glycosylation sites. A preferred example GP glycoprotein is that comprising Mopeia virus accessible under GenBank number AY772170. In one embodiment, the gene encoding the GP glycoprotein of MOPV encodes a protein with an amino acid sequence as shown in SEQ ID NO:13 or an amino acid sequence having at least 60, 65, 70, 75, 80, jzRQnn / i ζηζ / E / γ 85, 90 or 95% sequence identity with the amino acid sequence of SEQ ID NO:13, while maintaining the functional properties of the recombinant rhabdovirus comprising a GP glycoprotein encoding an amino acid sequence as shown in SEQ ID NO:13. CCL21 and functional variants of CCL21 Surprisingly, a recombinant rhabdovirus encoding the CCL21 protein in its genome was found to induce tumor cell lysis in combination with immunogenic cell death and stimulation of innate immune cells in the tumor microenvironment. Furthermore, prolonged survival rates were observed in an established mouse tumor model treated with this CCL21-armed recombinant rhabdovirus. CCL21 belongs to the CC chemokine family and is also known as secondary lymphoid tissue (SLC) chemokine, exodus-2, ckb9, scya21, TCA4, or 6Ckine. CCL21 contains a C-terminal region that binds to the extracellular matrix. CCL21 also binds to the cell surface receptor CCR7 and thus exerts its function, such as attracting and activating T lymphocytes and dendritic cells. CCR7 is expressed on a wide variety of peripheral T lymphocytes and dendritic cells in both healthy individuals and cancer patients. Thus, in one aspect, the recombinant rhabdovirus that encodes in its genome at least one CCL21 protein or a functional variant thereof can increase the recruitment of T lymphocytes and dendritic cells to the tumor microenvironment. In another aspect, the local expression of the highly potent chemokine CCL21 also increases the recruitment of immune cells, preferentially T lymphocytes and dendritic cells, in the tumor microenvironment and the improved efficacy of recombinant rhabdovirus. Yet another aspect, the recombinant rhabdovirus that encodes in its genome at least one CCL21 protein or a functional variant thereof acts as an innate immune stimulator. In one respect, recombinant rhabdoviruses that encode at least one CCL21 protein or a functional variant thereof in their genome transform cold tumors into hot tumors. Specifically, the resulting pro-inflammatory tumor microenvironment transforms non-T-cell-infiltrated (“cold”) tumors into T-cell-infiltrated (“hot”) tumors and is accompanied by the generation of an adaptive antitumor immune response in lymph nodes draining tumors. The human CCL21 protein was described, for example, in M. Nagira et al, The Journal of Biological Chemistry, 272, 19518-19524 (August 1, 1997) and is a highly basic polypeptide of 134 amino acids in total with a putative signal peptide of 23 amino acids: MAQSLALSLLILVLAFGIPRTQGSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKR SQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP (SEQ IDNO:1) A particular CCL21 protein includes CCL21 comprising or consisting of the following sequence: SDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQH LDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP (SEQ ID NO:2) Preferably, a CCL21 protein comprises or consists of a protein having the following sequence: SDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQH LDKTPSPQKPAQGCR (SEQ ID NO:4) or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with respect to SEQ ID NO:4. Most preferably, a CCL21 protein comprises or consists of a protein having the following sequence: SDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQH LDKTPSPQKPAQG (SEQ ID NO:3) or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with respect to SEQ ID NO:3. The term “signal peptide” or “signal peptide sequence” describes a peptide sequence, typically 10 to 30 amino acids long, located at the N-terminus of a newly synthesized secretory pathway or membrane polypeptide. This sequence directs the polypeptide across or into a cell membrane (the plasma membrane in prokaryotes and the endoplasmic reticulum membrane in eukaryotes). It is generally subsequently removed. Specifically, the signal peptide can direct the polypeptide to the cell's secretory pathway. It is noteworthy that for the present invention, other signal peptide sequences (i.e., different from the wild-type) can be used in conjunction with the CCL21 protein. Such different signal peptide sequences can replace the original wild-type signal peptide sequence. A signal peptide includes peptides that direct a newly synthesized protein from the ribosome to the ER and then to the Golgi apparatus for transport to the plasma membrane or out of the cell. Generally, these include a chain of hydrophobic amino acids and include immunoglobulin leader sequences as well as others familiar to those with a mid-level understanding of the craft. Signal peptides include, in particular, peptides that can be acted upon by signal peptidase, a specific protease located on the cisternal face of the endoplasmic reticulum.Signal peptides are familiar to those with a mid-level skill set and can include any known signal peptide. The signal peptide is incorporated into the N-terminus of the protein, and processing of the CCL21 protein by signal peptidase produces the biologically active form. In a preferred embodiment, the signal peptide has a sequence shown in SEQ ID NO:6. In a related preferred embodiment, the CCL21 protein comprises or consists of a protein having the following sequence: MGWSCIILFLVATATGVHSSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQA ELCADPKELWVQQLMQHLDKTPSPQKPAQG (SEQ ID NO:5) or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 90%, 95%, 98%, 99% or 100% identity with respect to SEQ ID NO:5. In a related embodiment, a CCL21 protein includes a protein comprising or consisting of the amino acids of SEQ ID No: 2, 3, or 4, or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID No: 2, 3, or 4, and further comprising a signal peptide sequence. In a preferred embodiment, the signal peptide sequence comprises or consists of amino acids 1-19 of SEQ ID No: 5. A CCL21 protein also includes a protein comprising or consisting of the amino acids of SEQ ID No: 2, 3 or 4 or, respectively, having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with respect to SEQ ID No: 2, 3 or 4 and, furthermore, comprising a signal peptide sequence comprising or consisting of amino acids 1-23 of SEQ ID No: 1. A CCL21 protein also includes a protein that corresponds to plasmin-processed forms of CCL21. CCL21 contains a unique extended C-terminus (e.g., human CCL21 approximately 30 amino acids) with a net positive charge that contributes to the binding of extracellular matrix components, such as heparin-like glycosaminoglycans. Truncation / deletion of the C-terminus drastically reduces binding to heparin-like glycosaminoglycans. CCL21 is processed within the human body by plasmin, which is defective in some types of human cancer. It has been shown that the need to cleave plasmin can be overcome by encoding the bioactive (i.e., biologically active) N-terminus fragment of CCL21, which resembles plasmin-processed forms of CCL21, in a recombinant rhabdovirus.Plasmin-processed forms of CCL21 are characterized by a truncation / deletion of the C terminal, resulting in a reduced ability to bind to heparin and / or heparan sulfate that can be measured by methods known to people of mid-level skill. In this context, a reduced ability to bind to heparin and / or heparan sulfate refers to a comparison with a CCL21 protein having SEQ ID NO:1 or 2 and a binding capacity that is reduced to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or less of the binding capacity of the CCL21 protein with the sequence as shown in SEQ ID NO:1 or 2 (respectively, with or without signal peptide sequence) when evaluated in the same assay and under the same conditions. Plasmin is a serine protease that dissolves fibrin blood clots. In addition to fibrinolysis, plasmin proteolyzes proteins in various other systems: it activates collagenases, some mediators of the complement system, and weakens the Graafian follicle wall, resulting in ovulation. It cleaves fibrin, fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin belongs to the serine protease family. Plasmin is released as a proenzyme, called plasminogen, from the liver into the systemic circulation. The conversion of plasminogen to active plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562 by, for example, tissue plasminogen activator (tPA), urokinase-like plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The cleavage of the CCL21 protein by plasmin can occur in cell-surface-bound CCL21 or in vitro, in either case by incubating the CCL21 protein with plasmin. Therefore, a plasmin-processed CCL21 protein includes CCL21 comprising or consisting of a sequence corresponding to amino acids 1-88 of SEQ ID NO:2 or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with amino acids 1-88 of SEQ ID NO:2. Furthermore, a CCL21 protein includes CCL21 comprising or consisting of a 7RQnn / l 7P7 / B / Y sequence that corresponds to amino acids 1-91 of SEQ ID NO:2 or that has at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with amino acids 1-91 of SEQ ID NO:2. A CCL21 protein also includes CCL21 comprising or consisting of a sequence corresponding to amino acids 1-104 of SEQ ID NO:2 or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with amino acids 1-104 of SEQ ID NO:2. The C-terminus CCL21 protein is characterized by the deletion and / or mutation of amino acids in the extended C-terminus of a CCL21 protein. By deleting and / or mutating amino acids in the extended C-terminus, binding to heparin-like glycosaminoglycans is reduced. In a preferred embodiment, the CCL21 protein truncated at the C terminus comprises or consists of SEQ ID NO:2 or has at least 70%, 72%, 74%, 76%, 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with amino acids 1-79 of SEQ ID NO:2, provided that the protein lacks at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 amino acid residues indicated in positions 80-111, or where one or more of these residues are mutated.In another preferred embodiment, the C-terminating CCL21 is a CCL21 comprising or consisting of SEQ ID NO:2 or having at least 70%, 72%, 74%, 76%, 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with amino acids 1-79 of SEQ ID NO:2, wherein all amino acids 80-111 of SEQ ID NO:2 are deleted (i.e., 32 deletions). In each case, the plasmin-processed CCL21 or the C-terminus truncated CCL21 may further comprise a signal peptide sequence. In particular, signal peptide sequences comprising or consisting of amino acids 1-23 of SEQ ID NO:1 or amino acids 1-19 of SEQ ID NO:5 are preferred. Other signal peptide sequences may also be used to replace the original signal peptide sequence. Therefore, in a preferred embodiment, the plasmin-processed or C-terminus truncated CCL21 protein comprises or consists of a protein having the following sequence: MGWSCIILFLVATATGVHSSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQA ELCADPKELWVQQLMQHLDKTPSPQKPAQG (SEQ ID NO:5) or having at least 70%, 72%, 74%, 76%, 78%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with respect to SEQ ID NO:5. A CCL21 protein may also include CCL21 with a truncated signal peptide sequence. In this context, “truncated” refers to a signal peptide sequence that is shorter than the original signal peptide sequence but still retains at least a portion of its functionality to act as a signal peptide. For example, the human signal peptide sequence comprises or consists of amino acids 1–23 of SEQ ID NO:1. A CCL21 with a truncated signal peptide sequence may have 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 of the amino acids 1–23 of SEQ ID NO:1. In another example, the signal peptide may comprise or consist of the sequence as shown in SEQ ID NO:6. A CCL21 with a truncated signal peptide sequence may have 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 of the amino acids 1-18 of SEQ ID jzRQnn / ι ζηζ / E / γ NO:6. A CCL21 protein with a truncated signal peptide sequence can also be a protein comprising any of the sequences in SEQ ID No: 2-4 and, in addition, a signal peptide sequence that is shorter than the original signal peptide sequence. Again, by way of example, a signal peptide sequence can have 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 of the amino acids 1-23 of SEQ ID No: 1; or, in another example, the signal peptide can comprise or consist of the sequence as shown in SEQ ID No: 6. A CCL21 with a truncated signal peptide sequence can have 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 of the amino acids 1-18 of SEQ ID NO:6. The CCL21 protein can be of any origin, including mouse and rat. Preferably, the CCL21 protein is of human origin. Functional variants of a CCL21 protein include biologically active variants and biologically active fragments of the CCL21 proteins described above. Variants may have one or more different amino acids at a position within a specifically described CCL21 protein. Variants may share approximately 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more amino acid identity with such a CCL21 protein. Fragments have the same amino acids as a given specifically described CCL21 protein but may lack a specific portion or region of the CCL21 protein. As used herein, the terms “identical” or “percent identity,” in the context of two or more polypeptide or nucleic acid sequences, refer to two or more sequences or subsequences that are identical or have a specified percentage of identical amino acid or nucleotide residues when compared and aligned for maximum match. To determine the percentage identity, the sequences are aligned for optimal comparison (for example, spaces may be introduced into the sequence of a first amino acid or nucleic acid sequence to achieve optimal alignment with a second amino acid or nucleic acid sequence). The nucleotides or amino acid residues are then compared at the corresponding amino acid or nucleotide positions.When a position in the first sequence is occupied by the same nucleotide or amino acid residue as the corresponding position in the second sequence, the molecules are identical at that position. The percentage of identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions (e.g., overlapping positions) x 100). In some embodiments, the two sequences being compared have the same length after spaces are introduced within the sequences, as appropriate (e.g., excluding any additional sequence that extends beyond the sequences being compared). The percentage of identity or the percentage of similarity between two sequences can be determined using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm used to compare two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Nati. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Nati. Acad. Sci. USA 90:5873-5877. This algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403-410. Nucleotide searches with BLAST can be performed using the NBLAST program, score = 100, word length = 12, to obtain nucleotide sequences homologous to a nucleic acid encoding a protein of interest. Protein searches with BLAST can be performed using the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to a protein of interest. To obtain spaced alignments for comparative purposes, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used for a repeated search that detects distant relationships between molecules (Id.). When using the BLAST, Gapped BLAST, and PSI-Blast programs, you can use the default parameters of the respective programs (e.g., XBLAST and NBLAST).Another preferred, non-limiting example of a mathematical algorithm used to compare sequences is the Myers-Miller algorithm, CABIOS (1989). This algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When using the ALIGN program to compare amino acid sequences, a weighted residue table of PAM120, a gap length penalty of 12, and a gap penalty of 4 can be used. Additional algorithms for sequence analysis are known in the prior art and include ADVANCE and ADAM, as described in Torellis and Robotti, 1994, Comput. Appl. Biosci. 10:3-5; and FASTA, as described in Pearson and Lipman, 1988, Proc. Nati. Acad. Sci. USA 85:2444-8. In FASTA, ktup is a control option that sets the sensitivity and speed of the search.If ktup=2, similar regions in the two sequences being compared are found by examining pairs of aligned residues; if ktup=1, single aligned amino acids are examined. Ktup can be set to 2 or 1 for protein sequences, or from 1 to 6 for DNA sequences. If ktup is not specified, the default value is 2 for proteins and 6 for DNA. Alternatively, protein sequence alignment can be performed using the CLUSTAL W algorithm, as described in Higgins et al., 1996, Methods Enzymol. 266:383-402. In both cases, the functional variants include only biologically active variants and fragments of CCL21. For the purposes of this invention, the biological activity of the CCL21 variant or fragment—encoded in the genome of a recombinant rhabdovirus—is determined after its expression in a respective cell or tumor cell. This means that the biological activity is determined in the context of a recombinant rhabdovirus encoding the CCL21 variant or fragment (e.g., in a Transwell assay or in vitro tumor model). Preferably, the biological activity is determined using a vesiculovirus encoding the CCL21 variant or fragment. More preferably, the biological activity is determined using a VSV-GP encoding the CCL21 variant or fragment. Biological activity may include one or more of the following capabilities: chemoattractant activity, antitumor activity, modulation of cytokine expression, such as increased expression of interferon-gamma (IFN-gamma) polypeptides or decreased expression of transforming growth factor-beta (TGF-beta) polypeptides in a syngeneic mammalian cell population, including CD8-expressing T lymphocytes, CD4-expressing T lymphocytes, antigen-presenting cells, and tumor cells. Evaluation of biological activity may be carried out without limitation, for example, according to the protocol shown in the Examples. For the purposes of the invention, the functional variant or fragment of the CCL21 protein is biologically active if it exhibits at least 30% 7RQnn / l 7Π7 / Β / Y 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the activity of a CCL21 protein with the sequence shown in SEQ ID NO:1 or 2 (respectively, with or without signal peptide sequence) if evaluated in the same assay and under the same conditions. Without intending to limit themselves to any single theory, the inventors discovered that, after treatment of tumor cells with VSV-GP, various chemokines and cytokines are upregulated in response. CCL21 is one of the chemokines that is not upregulated in tumor cells after VSV-GP treatment. The data presented here show that a VSV-GP encoding the CCL21 protein in its genome is particularly effective in cancer treatment and is targeted to further enhance the infiltration of immune cells into tumors infected by the oncolytic virus, thereby further boosting antitumor immunity. More surprisingly, recombinant rhabdoviruses encoding a CCL21 protein comprising or containing the SEQ ID NO:3 or 4 sequences, and in particular SEQ ID NO:5, are even more potent and effective in tumor treatment compared to the full-length CCL21 protein and are more active without the need for proteolytic processing. These CCL21 proteins are preferred over the full-length CCL21 protein due to their smaller size. Multiple or longer transgenes can negatively affect the viability, stability, oncolytic capacity, producibility, or expression of the rhabdovirus, as well as the transgene itself. The use of smaller transgenes also allows for the addition of extra transgenes to a rhabdovirus that may have limitations in its capacity to accommodate other transgenes. Rhabdoviruses have negative-sense single-stranded RNA (ssRNA) as their genetic material (genome). Negative-sense ssRNA viruses require RNA polymerase to synthesize positive-sense RNA. The positive-sense RNA acts as viral mRNA, which is translated into proteins for the production of new viral material. With the newly formed virus, more negative-sense RNA molecules are produced. A typical rhabdovirus genome encodes at least five structural proteins in the order 3'-NP-MGL-5'. The genome may contain other short intergenic regions or additional genes between the structural proteins and, therefore, may vary in length and organization. According to the invention, the CCL21 gene can be inserted at any location in the rhabdovirus genome. The transcriptional efficiency of the CCL21 gene can be influenced by the insertion site. In general, the transcriptional efficiency of the CCL21 gene decreases from the 3' insertion to the 5' insertion. The CCL21 gene can be inserted at the following genome locations: 3'-CCL21-NPMGL-5', 3'-N-CCL21-P-MG-L-5', 3'-NP-CCL21-MGL-5', 3'-NPM-CCL21-GL-5', 3'-NPMG-CCL21-L-5', or 3'-NPMGL-CCL21-5'. In a preferred embodiment, the CCL21 gene is inserted between the G protein and the L protein. After infection of tumor cells, the CCL21 gene encoded in the recombinant rhabdovirus genome is transcribed into positive-sense RNA and then translated into the CCL21 protein by the tumor cell. The expression “encoding” refers to the inherent property of specific nucleotide sequences in a nucleic acid to serve as templates for the synthesis of other polymers and macromolecules in biological processes that have a defined sequence of nucleotides (e.g., RNA molecules) or amino acids and the resulting biological properties. Therefore, a gene encodes a protein if the desired protein is produced in a cell or other biological system through transcription and subsequent translation of the mRNA.Both the coding strand, the nucleotide sequence that is identical to the mRNA sequence, and the non-coding strand can serve as templates for the transcription of a gene, and this can be referred to as the encoding of the protein or other product of that gene. Nucleic acid and nucleotide sequences that encode proteins may include introns. Preferably, the transcription of the CCL21 gene is not under the control of its own promoter and is strictly linked only to viral replication, thus ensuring the targeted expression of CCL21 to the site of viral replication and spread (tumor). Therefore, the transcription of the CCL21 gene is not controlled by additional elements, such as promoters or inducible gene expression elements. It will be noted that a nucleic acid sequence can be varied with or without changes to the primary sequence of the encoded polypeptide. A nucleic acid that encodes a protein includes any nucleic acid that has different nucleotide sequences but encodes the same amino acid sequence of the protein due to the degeneracy of the genetic code. A person of intermediate skill has the knowledge to select a nucleic acid sequence that will result in the expression of a CCL21 protein and, in particular, for any specific CCL21 protein as disclosed herein. Nucleic acid molecules encoding amino acid sequences of the CCL21 protein are prepared by a variety of methods known in the prior art.These methods include, but are not limited to, isolation from a natural source or preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of a previously prepared CCL21 protein. Pharmaceutical compositions The pharmaceutically acceptable effective amount, or actual therapeutic dose, will, of course, depend on factors known to those at the mid-level of practice, such as the patient's age and weight, the route of administration, and the severity of the illness. In any case, the recombinant rhabdovirus will be administered in doses and in a manner that allows for the delivery of a pharmaceutically acceptable effective amount according to the patient's particular condition. In general, for the treatment and / or relief of the diseases, disorders, and conditions mentioned herein, and depending on the specific disease, disorder, or condition to be treated, the potential of the specific recombinant rhabdovirus of the invention to be used, the specific route of administration, and the specific pharmaceutical formulation or composition used, the recombinant rhabdovirus of the invention will generally be administered, for example, twice a week, in weekly or monthly doses, but this may vary significantly, especially depending on the parameters mentioned above. Therefore, in some cases, it may be sufficient to use less than the minimum dose indicated above, while in other cases, it may be necessary to exceed the upper limit. When administering large quantities, it may be convenient to divide them into several smaller doses and spread them out throughout the day. For use in treatment, the recombinant rhabdovirus of the invention is formulated into pharmaceutical compositions suitable for facilitating administration to animals or humans. Typical formulations can be prepared by mixing the recombinant virus with physiologically acceptable carriers, excipients, or stabilizers in the form of aqueous solutions or aqueous or non-aqueous suspensions. The carriers, excipients, modifiers, or stabilizers are non-toxic at the doses and concentrations used. They include buffer systems, such as phosphate, citrate, acetate, and other organic or inorganic acids and their salts; antioxidants, including ascorbic acid and methionine; preservatives, such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol;and m-cresol; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone or polyethylene glycol (PEG); amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, oligosaccharides, or polysaccharides and other carbohydrates, including glucose, mannose, sucrose, trehalose, dextrins, or dextrans; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn protein complexes); and / or ionic or non-ionic surfactants, such as TWEEN™ (polysorbates), PLURONICS™, or fatty acid esters or sugar esters. Excipients can also have a release-modifying or absorption-modifying function. In one embodiment, the recombinant rhabdovirus of the invention is formulated in a pharmaceutical composition comprising Tris, arginine, and optionally citrate. Tris is preferably used at a concentration of approximately 1 mM to approximately 100 mM. Arginine is preferably used at a concentration of approximately 1 mM to approximately 100 mM. Citrate may be present at a concentration of up to 100 mM. A preferred formulation comprises approximately 50 mM of Tris and 50 mM of arginine. The pharmaceutical composition may be supplied as a liquid, a frozen liquid, or in lyophilized form. The frozen liquid may be stored at temperatures between approximately 0°C and approximately -85°C, including temperatures between -70°C and -85°C and approximately -15°C, 16°C, -17°C, -18°C, -19°C, -20°C, -21°C, -22°C, -23°C, -24°C, or approximately -25°C. The recombinant rhabdovirus or pharmaceutical composition of the invention need not be formulated with one or more agents currently used to prevent or treat the disorder in question, but may optionally be formulated in this manner. The effective amount of such other agents depends on the amount of recombinant antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used at the same doses and by the routes of administration described herein, or approximately 1 to 99% of the doses described herein, or at any dose and by any route considered empirically / clinically appropriate. For the prevention or treatment of disease, the appropriate dose of the recombinant rhabdovirus or pharmaceutical composition of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of recombinant rhabdovirus, the severity and progression of the disease, whether the recombinant rhabdovirus is administered for preventive or therapeutic purposes, prior treatment, the patient's medical history and response to the recombinant rhabdovirus, and the treating physician's judgment. The recombinant rhabdovirus or pharmaceutical composition of the invention is appropriately administered to the patient either as a single dose or in a series of treatments. jzRQnn / ι ζηζ / E / γ Depending on the type and severity of the illness, a candidate starting dose of recombinant rhabdovirus may be approximately 10⁸ to 10¹³ infectious particles as measured by TCIDs for administration to the patient, either, for example, by one or more separate doses or by continuous infusion. For repeated administrations over several days or more, depending on the condition, treatment is generally continued until the desired suppression of disease symptoms is achieved. An example dose of recombinant rhabdovirus is in the range of approximately 10⁸ to 10¹³ infectious particles as measured by TCIDs. Therefore, the patient may be administered one or more doses of approximately 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ infectious particles as measured by TCIDs (or any combination thereof).These doses can be administered intermittently, for example, once a week or every three weeks (e.g., so that the patient receives approximately two to approximately twenty, or, for example, approximately six doses of the recombinant rhabdovirus). A higher initial loading dose can be administered, followed by one or more lower doses, or vice versa. However, other dosing regimens may be useful. The course of this treatment is easily monitored using conventional techniques and assays. The efficacy of the recombinant rhabdovirus of the invention, and of the compositions comprising it, can be evaluated by any suitable in vitro assay, cell assay, in vivo assay, and / or animal model known per se, or any combination thereof, depending on the specific disease involved. Suitable assays and animal models will be obvious to a person of average skill and, for example, include the assays and animal models used in the examples below. The pharmaceutically acceptable effective quantity or actual therapeutic dose will, of course, depend on factors known to practitioners, such as the patient's age and weight, the route of administration, and the severity of the illness. In any case, the recombinant rhabdovirus of the invention will be administered in doses and in a manner that permits the delivery of a pharmaceutically acceptable effective quantity according to the patient's particular condition. Alternatively, the recombinant rhabdovirus or pharmaceutical composition of the invention can be administered in a volume of approximately 50 ml to approximately 100 ml, inclusive of all numbers within that variation, depending on the size of the area to be treated, the viral titer used, the route of administration, and the desired effect of the method. For intratumoral administration, the volume is preferably between about 50 μΙ to about 5 ml, including volumes of about 100 μΙ, 200 μΙ, 300 μΙ, 400 μΙ, 500 μΙ, 600 μΙ, 700 μΙ, 800 μΙ, 900 μΙ, 10ΟΟμΙ, 1100 μΙ, 1200 μΙ, 1300 μΙ, 1400 μΙ, 1500 μΙ, 1600 μΙ, 1700 μΙ, 1800 μΙ, 1900 μΙ, 2000 μΙ, 2500 μΙ, 3000 μΙ, 3500 μΙ, 4000 μΙ, or approximately 4500 μΙ. In a preferred embodiment, the volume is approximately 1000 μΙ. For systemic administration, for example, by infusion of recombinant rhabdovirus, the volumes can naturally be higher. Alternatively, a concentrated solution of recombinant rhabdovirus can be diluted in a larger volume of infusion solution directly before infusion. In particular, for intravenous administration, the volume is preferably between 1 ml and 100 ml, including volumes of approximately 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, 55 ml, 60 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, or approximately 100 ml. In a preferred mode, the volume is between approximately 5 mi and 15 mi; with greater preference, the volume is approximately 6 mi, 7 mi, 8 mi, 9 mi, 10 mi, 11 mi, 12 mi, 13 mi, or approximately 14 mi. Preferably, the same formulation is used for intratumoral and intravenous administration. The dose and / or volume ratio between intratumoral and intravenous administration may be approximately 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or approximately 1:20. For example, a dose and / or volume ratio of 1:1 means that the same dose and / or volume is administered intratumorally and intravenously, whereas, for example, a dose and / or volume ratio of approximately 1:20 means that the dose and / or volume administered intravenously is twenty times greater than the dose and / or volume administered intratumorally. Preferably, the dose and / or volume ratio between intratumoral and intravenous administration is approximately 1:9. An effective concentration of recombinant rhabdovirus desirably ranges from approximately 10⁸ to 10¹⁴ vector genomes per milliliter (vg / ml). Infectious units can be measured as described in McLaughlin et al., J Virol.;62(6):1963-73 (1988). Preferably, the concentration is approximately 1.5 x 10⁹ to approximately 1.5 x 10¹³, and, more preferably, approximately 1.5 x 10⁹ to approximately 1.5 x 10¹¹. In one embodiment, the effective concentration is approximately 1.5 x 10⁹. In another embodiment, the effective concentration is approximately 1.5 x 10¹⁰. In another embodiment, the effective concentration is approximately 1.5 x 10¹¹. In yet another embodiment, the effective concentration is approximately 1.5 x 10¹². In another embodiment, the effective concentration is approximately 1.5 x 10¹³. In yet another embodiment, the effective concentration is approximately 1.5 x 10¹⁴.It may be advisable to use the lowest effective concentration to reduce the risk of unwanted effects. However, the treating physician may select other doses within these variations, taking into account the physical condition of the subject (preferably a human being) being treated, the subject's age, the specific type of cancer, and the stage to which the cancer has progressed, if it is progressive. An effective target concentration of recombinant rhabdovirus can be expressed using the TCID50. The TCID50 can be determined, for example, using the Spearman-Kárber method. Desirable variations include an effective target concentration between 1 x 10⁸ / ml and 1 x 10¹⁴ / ml of TCID50. Preferably, the effective target concentration is approximately 1 x 10⁹ to approximately 1 x 10¹² / ml, and, more preferably, approximately 1 x 10⁹ to approximately 1 x 10¹¹ / ml. In one modality, the effective target concentration is approximately 1 x 10¹⁰ / ml. In a preferred modality, the target concentration is 5 x 10¹⁰ / ml. In another modality, the effective target concentration is approximately 1.5 x 10¹¹ / ml. In one modality, the effective target concentration is approximately 1 x 10¹² / ml. In another modality, the effective target concentration is approximately 1.5 x 1013 / ml. An effective target dose of recombinant rhabdovirus can also be expressed using TCID50. Desirable variations include a target dose between 1 x 10⁸ and 1 x 10¹⁴ of TCID50. Preferably, the target dose is approximately 1 x 10⁹ to approximately 1 x 10¹³, and, more preferably, approximately 1 x 10⁹ to approximately 1 x 10¹². In one modality, the effective concentration is approximately 1 x 10¹⁰. In a preferred modality, the effective concentration is approximately 1 x 10¹¹. In one modality, the effective concentration is approximately 1 x 10¹². In another modality, the effective concentration is approximately 1 x 10¹³. In another aspect, a kit or parts kit is provided containing materials useful for the treatment, prevention, and / or diagnosis of the disorders described herein. The kit or parts kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, intravenous solution bags, etc. The containers may be made of a variety of materials, such as glass or plastic. The container holds a composition that is, by itself or in combination with another composition, effective for the treatment, prevention, and / or diagnosis of the disorder, and it may have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a stopper that can be pierced with a hypodermic injection needle). At least one active agent in the composition is the recombinant rhabdovirus or pharmaceutical composition of the invention.The label or leaflet indicates that the composition is used to treat the specified condition. Furthermore, the kit or parts kit may comprise (a) a first container holding a composition, wherein the composition comprises the recombinant rhabdovirus or pharmaceutical composition of the invention; and (b) a second container holding a composition, wherein the composition comprises another cytotoxic or therapeutic agent, such as a PD-1 pathway inhibitor or SMAC mimetic. The kit or parts kit, in this embodiment of the invention, may also include a package insert indicating that the compositions can be used to treat a particular condition, especially cancer. Alternatively, or additionally, the kit or parts kit may also comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution.It may also include other materials that are convenient from a commercial and user point of view, including other shock absorbers, solvents, filters, needles, and syringes. In a further aspect, a recombinant rhabdovirus of the invention is used in combination with a device for administering the recombinant rhabdovirus, such as a syringe, pen injector, micropump, or other device. Preferably, a recombinant rhabdovirus of the invention is contained in a kit of parts, which also includes a package insert with instructions for using the recombinant rhabdovirus. Medical uses Another aspect of the invention provides a recombinant rhabdovirus that encodes in its genome at least one CCL21 protein or a functional variant thereof for use in medicine. The recombinant rhabdovirus of the invention effectively induces lysis of tumor cells in combination with immunogenic cell death and stimulation of innate immune cells in the tumor microenvironment. Consequently, the recombinant rhabdoviruses of the invention are useful for the treatment and / or prevention of cancer. In another aspect, the recombinant rhabdovirus of the invention can be used in a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of a recombinant rhabdovirus to an individual who has cancer, thereby relieving one or more symptoms of cancer. In another aspect, the invention also provides for the use of a recombinant rhabdovirus according to the invention for the manufacture of a medicament for the treatment and / or prevention of cancer. In another aspect, the recombinant rhabdovirus of the invention can be used in a method for treating and / or preventing gastrointestinal cancer, lung cancer, or head and neck cancer, comprising administering a therapeutically effective amount of a recombinant rhabdovirus to an individual who has gastrointestinal cancer, lung cancer, or head and neck cancer, thereby relieving one or more symptoms of gastrointestinal cancer, lung cancer, or head and neck cancer. For the prevention or treatment of a disease, the appropriate dose of recombinant rhabdovirus will depend on several factors, such as the type of disease being treated, as defined above, the severity and progression of the disease, whether the recombinant rhabdovirus is being administered for preventive or therapeutic purposes, prior treatment, the patient's medical history, the response to the recombinant rhabdovirus, and the treating physician's judgment. The recombinant rhabdovirus is administered to the patient either as a single dose or in a series of treatments. In one respect, cancer is a solid tumor. Solid tumors can include brain cancer, colorectal cancer, oropharyngeal squamous cell carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, esophageal carcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, cholangiocarcinoma, urothelial carcinoma of the bladder, metastatic melanoma, prostate carcinoma, breast carcinoma, head and neck squamous cell carcinoma (HNSCC), glioblastoma, non-small cell lung cancer, brain tumor, or small cell lung cancer. Treatment is preferred for gastrointestinal cancer, lung cancer, and head and neck cancer. Recombinant rhabdovirus is administered by any suitable means, including oral, parenteral, subcutaneous, intratumoral, intravenous, intradermal, intraperitoneal, intrapulmonary, and intranasal routes. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Additionally, recombinant rhabdovirus is adequately administered by pulse infusion. Doses are administered by injection, preferably intravenously or subcutaneously, depending, in part, on whether the administration is short-term or chronic. Depending on the specific recombinant rhabdovirus of the invention and its specific pharmacokinetics and other properties, it can be administered daily, every second, third, fourth, fifth, or sixth day, weekly, monthly, and so forth. An administration regimen may include long-term weekly treatment. “Long-term” means at least two weeks and, preferably, months or years in duration. The treatment schedule may include various regimens and, in general, will require the administration of multiple doses to the patient over one, two, three, or four weeks, followed optionally by one or more additional rounds of treatment. In one aspect, the recombinant rhabdovirus of the invention is administered to the patient in up to 1, 2, 3, 4, 5, or 6 doses over a specified period. Preferably, the first round of treatment concludes after three weeks. During the three-week treatment period, the recombinant rhabdovirus may be administered to the patient as described in the following schedules: (i) once on day 0; (ii) on day 0 and day 3; (iii) on day 0, day 3, and day 6; (iv) on day 0, day 3, day 6, and day 9; (v) on day 0 and day 5; (vi) on day 0, day 5 and day 10; (vii) on day 0, day 5, day 10 and day 15.These regimens can be repeated, and a second or third round of treatment may be necessary, depending on the outcome of the first round. Based on calculations for the first round of treatment, the second round of treatment preferably includes additional treatments on day 21, day 42, and day 63. In a preferred embodiment, the recombinant rhabdovirus of the invention is administered to the patient according to the following schedule: on day 0, day 3, day 21, day 42, and day 63. Herein, the term “suppression” is used in the same context as “improvement” and “relief,” and means an attenuation or reduction of one or more features of the disease. The recombinant rhabdovirus or the pharmaceutical composition of the invention shall be formulated, dosed, and administered in a manner that respects good medical practice. Some factors considered in this context are the particular disorder being treated, the particular mammal being treated, the patient’s clinical condition, the cause of the disorder, the site of administration of the agent, the method of administration, the timing of administration, and other factors known to physicians. The “therapeutically effective amount” of recombinant rhabdovirus to be administered will depend on such considerations and is the minimum amount necessary to prevent, improve, or treat the clinical symptoms of cancer, in particular, the minimum amount that is effective against these disorders. In another aspect, the recombinant rhabdovirus of the invention can be administered multiple times and in multiple doses. In one aspect, the first dose of the recombinant rhabdovirus is administered intratumorally, and subsequent doses are administered intravenously. In another aspect, the first dose and at least one or more subsequent doses of the recombinant rhabdovirus are administered intratumorally, and subsequent doses are administered intravenously. Subsequent doses may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the initial intratumoral administration. In another aspect, the first dose of recombinant rhabdovirus is administered intravenously, and subsequent doses are administered intratumorally. These subsequent doses can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the initial intravenous administration. In another aspect, the recombinant rhabdovirus is administered intravenously, and subsequent doses of the recombinant rhabdovirus are administered intratumorally. In another aspect, the recombinant rhabdovirus is administered at each time point intravenously and intratumorally. As previously stated, the recombinant rhabdoviruses of the invention are highly useful for stimulating an immune response against cancer cells. It was observed that the potential for strong immune activation was restricted to the tumor microenvironment. Therefore, in a preferred embodiment, the recombinant rhabdovirus jzRQnn / ι ζηζ / E / γ of the invention can be administered systemically to a patient. Systemic applicability is a fundamental attribute, given that many types of cancer are highly metastatic, and it will allow the treatment of tumor lesions that are difficult to access or inaccessible. Due to these unique immune-stimulating properties, the recombinant rhabdoviruses according to the invention are particularly useful for the treatment of metastatic tumors. Some patients develop resistance to checkpoint inhibitor treatment, and it has been observed that such patients appear to accumulate mutations in the IFN pathway. Therefore, in one respect, the recombinant rhabdovirus of the invention, and in particular the recombinant vesicular stomatitis virus of the invention, is useful for treating patients who have developed resistance to checkpoint inhibitor treatment. Due to the unique immune-promoting properties of the recombinant rhabdovirus, and in particular the recombinant vesicular stomatitis virus of the invention, such treated patients may become suitable for continued checkpoint inhibitor therapy. In a preferred embodiment, the recombinant rhabdovirus of the invention, and in particular the recombinant vesicular stomatitis virus of the invention, is useful for the treatment of patients with non-small cell lung cancer who have completed checkpoint inhibitor therapy with a PD-1 or PD-L1 inhibitor, for example, PD-1 or PD-L1 antagonist antibodies. It is worth noting that any of the above pharmaceutical formulations or therapeutic methods can be carried out using any of the recombinant rhabdoviruses or pharmaceutical compositions of the invention. Combinations The present invention also provides combination therapies / methods that offer certain advantages compared to currently used and / or prior art therapies / methods. These advantages may include in vivo efficacy (e.g., improved clinical response, extent of response, increased response rate, duration of response, disease stabilization rate, duration of stabilization, time to disease progression, progression-free survival (PFS) and / or overall survival (OS), last appearance of resistance, and the like), safe and well-tolerated administration, and a reduction in the frequency and severity of adverse events. The recombinant rhabdoviruses of the invention can be used in combination with other pharmacologically active ingredients, such as prior art or reference compounds, such as cytostatic or cytotoxic substances, cell proliferation inhibitors, antiangiogenic substances, steroids, immune modulators / checkpoint inhibitors, and the like. The cytostatic and / or cytotoxic active substances that can be administered in combination with the recombinant rhabdoviruses of the invention include, among others, hormones, hormone analogues and antihormones, aromatase inhibitors, LHRH agonists and antagonists, growth factor inhibitors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factors (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor (HGF)), the inhibitors being, e.g., growth factor (anti)antibodies, growth factor (anti)antibodies and 7RQnn / l 7P7 / B / Y tyrosine kinase inhibitors, for example, cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, and trastuzumab; antimetabolites (for example, antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), gemcitabine, irinotecan, doxorubicin, TAS-102, capecitabine, and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (for example, anthracyclines); platinum derivatives (for example, cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes,such as paclitaxel, docetaxel); angiogenesis inhibitors, including bevacizumab, ramucirumab and aflibercept, tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors (such as volasertib), CDK inhibitors, including CDK9 inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), inhibitors of protein / protein interaction, MEK inhibitors, ERK inhibitors, FLT3 inhibitors,BRD4 inhibitors, IGF-1R inhibitors, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogues (e.g., everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceutical products, immunotherapeutic agents such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, LAG3, and TIM3 / immunoglobulin binding molecules such as ipilimumab, nivolumab, pembrolizumab), and various other agents Chemotherapeutic agents, such as amifostine, anagrelide, clodronat, filgrastim, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane,Pamidronate and porfimer; proteasome inhibitors (such as bortezomib); Smac and BH3 mimetics; agents that restore p53 function, including the mdm2-p53 antagonist; inhibitors of the Wnt / beta-catenin signal transduction pathway; and / or cyclin-dependent kinase 9 inhibitors. The recombinant rhabdovirus of the invention can be used in combination therapy with a PD-1 pathway inhibitor or a SMACm / IAP antagonist. Such combination therapy can be administered as a non-fixed (e.g., free) combination of the substances or in the form of a fixed combination, including a kit of parts. In this context, “assembly” or “combination” within the meaning of this invention includes, among others, a product derived from the mixture or combination of more than one active agent and includes both fixed and non-fixed (e.g., free) combinations, including kits, and uses, such as, for example, the simultaneous, concurrent, sequential, successive, alternating, or separate use of the components or agents. The term “fixed combination” refers to the administration of both active agents to a patient simultaneously as a single entity or dose. The term “non-fixed combination” refers to the administration of both active agents to a patient as separate entities, either simultaneously, concurrently, or sequentially without specific time limits, where such administration provides therapeutically acceptable levels of the two compounds in the patient's body.The latter also applies to cocktail therapy, for example, the administration of three or more active agents. The invention provides a recombinant rhabdovirus in combination with a PD1 pathway inhibitor or a SMACm / IAP antagonist for use in the treatment of cancer types described herein, preferably for the treatment of solid cancer types. The invention also provides for the use of a recombinant rhabdovirus in combination with a PD-1 pathway inhibitor or a SMACm / IAP antagonist for the manufacture of a medicament for the treatment and / or prevention of cancer types described herein, preferably for the treatment of solid cancer types. The invention also provides a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of a recombinant rhabdovirus of the invention and a PD-1 pathway inhibitor or a SMACm / IAP antagonist to an individual with cancer, thereby alleviating one or more symptoms of the cancer. The recombinant rhabdovirus of the invention and the PD-1 pathway inhibitor or the SMACm / IAP antagonist can be administered concomitantly, sequentially, or alternately. The recombinant rhabdovirus of the invention and the PD-1 pathway inhibitor or a SMACm / IAP antagonist can be administered by the same or different routes. Preferably, the PD-1 pathway inhibitor or SMACm / IAP antagonist is administered intravenously, and the recombinant rhabdovirus of the invention is administered intratumorally. In another embodiment, the PD-1 pathway inhibitor or the SMACm / IAP antagonist is administered intravenously, and the recombinant rhabdovirus of the invention is administered at least once intratumorally, with subsequent doses of the recombinant rhabdovirus administered intravenously.Subsequent doses may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the initial intratumoral administration. In a preferred modality, the PD-1 pathway inhibitor or the SMACm / PAI antagonist is administered 21 days after the initial intratumoral administration. In particular, treatments with the recombinant rhabdovirus of the invention in combination with the following are preferred: (i) SMAC mimetics (SMACmj / IAP antagonists), (ii) immunotherapeutic agents, including anti-PD-1 and anti-PD-L1 agents and anti-LAG3 agents, such as pembrolizumab and nivolumab, and antibodies such as those disclosed in WO2017 / 198741. A combination provided herein comprises (i) a recombinant rhabdovirus of the invention and (iia) a PD-1 pathway inhibitor, preferably an antagonist antibody targeting PD-1 or PD-L1 or (ib) a SMACm / IAP antagonist. The use of such a combination comprising (i) and (iia) or (i) and (ib) is also provided for the treatment of cancer types as described herein. jzRQnn / ι ζηζ / E / γ In another aspect, a combination therapy is provided comprising the use of (i) a recombinant rhabdovirus of the invention and (ii) a PD-1 pathway inhibitor or (ii) a SMACm / IAP antagonist. In said combination therapy, the recombinant rhabdovirus of the invention may be administered concomitantly, sequentially, or alternately with the PD-1 pathway inhibitor or SMACm / IAP antagonist. For example, “concomitant” administration includes administering the active agents within the same general period, for example, on the same day but not necessarily at the same time. Alternating administration includes administering one agent for a period, for example, over the course of a few days or a week, and then administering the other agent for a subsequent period, for example, over the course of a few days or a week, and then repeating the pattern for one or more cycles. Sequential or successive administration includes administering one agent for a first period (for example, over the course of a few days or a week) using one or more doses, followed by administering the other agent for a second period (for example, over the course of a few days or a week) using one or more doses.An overlapping schedule can also be used, which involves administering the active agents on different days during the treatment period, not necessarily in a regular sequence. Variations from these general guidelines can also be employed, for example, depending on the agents used and the patient's condition. The sequential treatment schedules include administration of the recombinant rhabdovirus of the invention followed by administration of the PD-1 pathway inhibitor or the SMACm / IAP antagonists. The sequential treatment schedules also include administration of the PD-1 pathway inhibitor or the SMACm / IAP antagonists followed by administration of the recombinant rhabdovirus of the invention. Sequential treatment schedules may include administrations 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or 31 days after each one. A PD-1 pathway inhibitor in the context of the present invention and all its embodiments is a compound that inhibits the interaction of PD-1 with its receptors. A PD-1 pathway inhibitor may affect PD-1 pathway signaling, preferably through the PD-1 receptor. The PD-1 inhibitor may be any inhibitor directed against any member of the PD-1 pathway capable of antagonizing PD-1 pathway signaling. The inhibitor may be an antagonistic antibody acting on any member of the PD-1 pathway, preferably directed against the PD-1 receptor, PD-L1, or PD-L2. Furthermore, the PD-1 pathway inhibitor may be a fragment of the PD-1 receptor or the PD-1 receptor itself that blocks the activity of PD-1 ligands. PD-1 antagonists are known in the prior art, for example, as discussed in Li et al., Int. J. Mol. Sci. 2016, 17, 1151 (which is incorporated herein by reference). Any PD-1 antagonist, especially antibodies such as those disclosed by Li et al., as well as other antibodies disclosed herein below, may be used according to the invention. Preferably, the PD-1 antagonist of the present invention and all its embodiments is selected from the group consisting of the following antibodies: jzRQnn / ι ζηζ / Ε / γ • pembrolizumab (anti-PD-1 antibody); • nivolumab (anti-PD-1 antibody); • pidilizumab (anti-PD-1 antibody); • PDR-001 (anti-PD-1 antibody); • PD1-1, PD1-2, PD1-3, PD1-4, and PD1-5 as disclosed herein below (anti-PD-1 antibodies) • atezolizumab (anti-PD-L1 antibody); • avelumab (anti-PD-L1 antibody); • durvalumab (anti-PD-L1 antibody). Pembrolizumab (formerly known as lambrolizumab; trade name Keytruda; also known as MK-3475), disclosed, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134-44, is a humanized IgG4 monoclonal antibody that binds to PD-1; it contains a mutation in C228P designed to prevent Fe-mediated cytotoxicity. Pembrolizumab is disclosed, for example, in US 8,354,509 and WO2009 / 114335. It was approved by the FDA for the treatment of patients with unresectable or metastatic melanoma and patients with metastatic NSCLC. Nivolumab (CAS Registry No. 946414-94-4; BMS-936558 or MDX1106b) is a fully human IgG4 monoclonal antibody that specifically blocks PD-1 and lacks detectable antibody-dependent cell-mediated toxicity (ADCC). Nivolumab is disclosed, for example, in US 8008449 and WO2006 / 121168. It was approved by the FDA for the treatment of patients with unresectable or metastatic melanoma, metastatic NSCLC, and advanced renal cell carcinoma. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1 κ monoclonal antibody that binds to PD-1. Pidilizumab is disclosed, for example, in WO2009 / 101611. PDR-001 or PDR001 is a humanized, high-affinity, ligand-blocking, anti-PD-1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1. PDR-001 is disclosed in WO2015 / 112900 and WO2017 / 019896. The PD1-1 to PD1-5 antibodies are antibody molecules defined by the sequences shown in Table 1, where HC denotes the heavy chain (full length) and LC denotes the light chain (full length): jzRQnn / ι ζηζ / E / γ Table 1 SEQ ID NO: Volume number Secuencia amino acids 14 HCde PD1-1 EVMLVESGGGLVQPGGSLRLSCTASGFTFSASAMSWVRQAPGKGLEW VAYISGGGGDTYYSSSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSNVNYYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG 15 LCde PD1-1 EIVLTQSPATLSLSPGERAMSCRASENIDTSGISFMNWYQQKPGQAPK LLIYVASNQGSGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQSKEVP WTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC 16 HCde PD1-2 EVMLVESGGGLVQPGGSLRLSCTASGFTFSASAMSWVRQAPGKGLEW VAYISGGGGDTYYSSSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSNPNYYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG 17 LCde PD1-2 EIVLTQSPATLSLSPGERATMSCRASENIDTSGISFMNWYQQKPGQAPK LLIYVASNQGSGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQSKEVP WTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC SEQ ID NO: Number of amino acids 18 HC of PD1-3 EVMLVESGGGLVQPGGSLRLSCTASGFTFSKSAMSWVRQAPGKGLEW VAYISGGGGDTYYSSSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSNVNYYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG 19 LCde PD1-3 EIVLTQSPATLSLSPGERAMSCRASENIDVSGISFMNWYQQKPGQAPK LLIYVASNQGSGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQSKEVP WTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC 20 HC of PD1-4 EVMLVESGGGLVQPGGSLRLSCTASGFTFSKSAMSWVRQAPGKGLEW VAYISGGGGDTYYSSSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSNVNYYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG 21 LCde PD1-4 EIVLTQSPATLSLSPGERATMSCRASENIDVSGISFMNWYQQKPGQAPK LLIYVASNQGSGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQSKEVP WTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC SEQ ID NO: Sequence name Sequence of amino acids 22 HC of PD1-5 EVMLVESGGGLVQPGGSLRLSCTASGFTFSKSAMSWVRQAPGKGLEW VAYISGGGGDTYYSSSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARHSNVNYYAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG 23 LCde PD1-5 EIVLTQSPATLSLSPGERATMSCRASENIDVSGISFMNWYQQKPGQAPK LLIYVASNQGSGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQSKEVP WTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC 7RQnn / l 7Π7 / Β / Υ Specifically, the anti-PD-1 antibody molecule described above has: (PD1-1:) a heavy chain comprising the amino acid sequence of SEQ ID NO:14, and a light chain comprising the amino acid sequence of SEQ ID NO:15; or (PD1-2:) a heavy chain comprising the amino acid sequence of SEQ ID NO:16, and a light chain comprising the amino acid sequence of SEQ ID NO:17; or (PD1-3:) a heavy chain comprising the amino acid sequence of SEQ ID NO:18, and a light chain comprising the amino acid sequence of SEQ ID NO:19; or (PD1-4:) a heavy chain comprising the amino acid sequence of SEQ ID NO:20, and a light chain comprising the amino acid sequence of SEQ ID NO:21; or (PD1-5:) a heavy chain comprising the amino acid sequence of SEQ ID NO:22, and a light chain comprising the amino acid sequence of SEQ ID NO:23. Atezolizumab (Tecentriq, also referred to as MPDL3280A) is a phage-derived human IgG1k monoclonal antibody that targets PD-L1 and is described, for example, in Deng et al. mAbs 2016;8:593-603. It was approved by the FDA for the treatment of patients with urothelial carcinoma. Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody and is described in, for example, Boyerinas et al. Cancer Immunol. Res. 2015;3:1148-1157. Durvalumab (MEDI4736) is a human IgG1 k monoclonal antibody with high specificity to PD-L1 and is described in, for example, Stewart et al. Cancer Immunol. Res. 2015;3:1052-1062 or in Ibrahim et al. Semin. Oncol. 2015;42:474-483. Other PD-1 antagonists, disclosed in Li et al. (supra), or known to be in clinical trials, such as AMP-224, MEDI0680 (AMP-514), REGN2810, BMS-936559, JS001-PD-1, SHR-1210, BMS-936559, TSR-042, JNJ-63723283, MEDI4736, MPDL3280A and MSB0010718C, can be used as an alternative or in addition to the antagonists mentioned above. It is intended that INNs, as used herein, encompass all biosimilar antibodies that have the same, or substantially the same, amino acid sequences as the originating antibody, including, among others, those biosimilar antibodies authorized by 42 USC §262 subsection (k) in the United States of America and equivalent regulations in other jurisdictions. The PD-1 antagonists listed above are known in the state of the art with their respective preparation, therapeutic use and properties. jzRQnn / ι ζηζ / E / γ In one embodiment, the PD-1 antagonist is pembrolizumab. In another embodiment, the PD-1 antagonist is nivolumab. In another embodiment, the PD-1 antagonist is pidilizumab. In another embodiment, the PD-1 antagonist is atezolizumab. In another embodiment, the PD-1 antagonist is avelumab. In another embodiment, the PD-1 antagonist is durvalumab. In another embodiment, the PD-1 antagonist is PDR-001. In another embodiment, the PD-1 antagonist is PD1-1. In another embodiment, the PD-1 antagonist is PD1-2. In another embodiment, the PD-1 antagonist is PD1-3. In another embodiment, the PD-1 antagonist is PD1-4. In another embodiment, the PD-1 antagonist is PD1-5. The SMAC mimetic within the meaning of this invention and all its embodiments It is a compound that binds to IAP proteins and induces their degradation. Preferably, the mimetic within the present invention and all its embodiments is selected from the group consisting of the following (A0): SMAC in the • a SMAC mimetic (i.e. a compound) as disclosed (in a generic or specific manner) in WO 2013 / 127729, or a pharmaceutically acceptable salt thereof; • a SMAC mimetic (i.e., a compound) as disclosed (in a generic or specific manner) in WO 2015 / 025018, or a pharmaceutically acceptable salt thereof; • a SMAC mimetic (i.e., a compound) as disclosed (in a generic or specific manner) in WO 2015 / 025019, or a pharmaceutically acceptable salt thereof; • a SMAC mimetic (i.e., a compound) as disclosed (in a generic or specific manner) in WO 2016 / 023858, or a pharmaceutically acceptable salt thereof; • a SMAC mimetic (i.e., a compound) as disclosed (in a generic or specific manner) in WO 2008 / 0016893, or a pharmaceutically acceptable salt thereof; • LCL161, i.e., Compound A in Example 1 of WO 2008 / 016893 (page 28 / 29;

[122] ), or a pharmaceutically acceptable salt thereof; • the SMAC mimetic known as Debio-1143, or a pharmaceutically acceptable salt thereof; • the SMAC mimetic known as birinapant, or a pharmaceutically acceptable salt thereof; • the SMAC mimetic known as ASTX-660, or a pharmaceutically acceptable salt thereof; • the SMAC mimetic known as CUDC-427, or a pharmaceutically acceptable salt thereof • any of the SMAC mimetics 1 to 26 in Table 2, or a pharmaceutically acceptable salt thereof: jzRQnn / ι ζηζ / E / γ Table 2: 7RQnn / l Zηζ / E / YΙΛΙ 11 ^N o L i NS O ι / γ' 'kVII II 1 ^sz / HN^ H ΤίΎ^Ι ^¡A^n 12 ji lo νΓΛ-~ Jl II J_ vss / N HN^ H 13 — N 1 ° Η II ^== / γ n HNx H ^¡Av-sN 14 T / z»K 7 )=o / =( ( J y? / ~0 15 T / 7 / =° 22 y} (y 7RQnn / l Zhz / E / YILI 7RQnn / l 7Π7 / E / YILI 21 jj 1 0 HNX H |f^l 22 \>Nx A 0 Pi Ó- Jl II i JN HNX H 1 23 N^so if^T JL JL JL yn HNX HA^N-^0 1 24 ^°·^κ ÍX,N ° Jl II ^ss / 'γ ν ν'λ^ HNx H \^N·^O 1 25 I / 7 / =° IZ y) jQ^° / =\ ( j W í / \ o 7RQnn / l Zhz / E / YILI jzRQnn / i žiz / E / γίΛι Los Compuestos de ejemplo 1 a 10 en la Tabla 2 se divulgan en WO 2013 / 127729. Los Compuestos de ejemplo 11 a 26 en la Tabla 2 se divulgan en WO 2016 / 023858. As used herein, the term “SMAC mimetic / IAP antagonist” also includes the SMAC mimetics listed above in the form of a tautomer, a pharmaceutically acceptable salt, a hydrate, or a solvate (which includes a hydrate or solvate of a pharmaceutically acceptable salt). It also includes the SMAC mimetic in all its solid, preferably crystalline, forms and in all crystalline forms of its pharmaceutically acceptable salts, hydrates, and solvates (which include hydrates and solvates of pharmaceutically acceptable salts). All SMAC mimetics listed above are known in the prior art, along with their respective syntheses and properties. All patent applications cited above are incorporated herein by reference in their entirety. In one embodiment, the SMAC mimetic is LCL161, or a pharmaceutically acceptable (A1) salt thereof. In another form, the pharmaceutically acceptable SMAC mimetic (A2). In another form, the pharmaceutically acceptable SMAC mimetic (A3). In another form, the pharmaceutically acceptable SMAC mimetic (A4). In another form, the pharmaceutically acceptable SMAC mimetic (A5). In another form, the pharmaceutically acceptable SMAC mimetic (A6). In another form, the pharmaceutically acceptable SMAC mimetic (A7). In another form, the pharmaceutically acceptable SMAC mimetic (A8). In another form, the pharmaceutically acceptable SMAC mimetic (A9). In another embodiment, the SMAC mimetic is Compound 1 in Table 2, or a salt of this is Compound 2 in Table 2, or a salt of this is Compound 3 in Table 2, or a salt of this is Compound 4 in Table 2, or a salt of this is Compound 5 in Table 2, or a salt of this is Compound 6 in Table 2, or a salt of this is Compound 7 in Table 2, or a salt of this is Compound 8 in Table 2, or a salt of this is Compound 9 in Table 2, or a pharmaceutically acceptable salt of this (A10). In another modality, the pharmaceutically acceptable mimetic (A11). In another modality, the mimetic of SMAC SMAC is the Compound Compound in Table 2, Table 2, a salt of this pharmaceutically acceptable (A12). In another form, the pharmaceutically acceptable mimetic (A13). In another form, the pharmaceutically acceptable mimetic (A14). In another form, the pharmaceutically acceptable mimetic (A15). In another form, the pharmaceutically acceptable mimetic (A16). In another form, the pharmaceutically acceptable mimetic (A17). of of of of of In another form, the pharmaceutically acceptable mimetic (A18). In another modality, the pharmaceutically acceptable mimetic (A19). In another form, the pharmaceutically acceptable mimetic (A20). In another modality, the pharmaceutically acceptable mimetic (A21). In another form, the pharmaceutically acceptable mimetic (A22). In another form, the pharmaceutically acceptable mimetic (A23). In another form, the pharmaceutically acceptable mimetic (A24). of of of In another form, the pharmaceutically acceptable mimetic (A25). In another form, the pharmaceutically acceptable mimetic (A26). In another modality, the mimetic of SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC SMAC is the the the the the the the the the the the the the the the the the Compound Compound Compound Compound Compound Compound Compound Compound in the Board 2, a salt of this in the Board 2, a salt of this in the Board 2, a salt of this Compound 20 Compound Compound Compound Compound Compound 25 Compound 26 in in in in in in in in in in in the the Board Board 2, 2, Table 2, Table 2, Table 2, Table 2, the the the a a a a a a a a salt salt salt salt salt salt salt of of of of of of of of this this this this this this Board Board Board 2, 2, 2, Table 2, Table 2, Table 2, a a a a a a a salt salt salt salt salt salt salt of of of of of of of this this this this this this pharmaceutically acceptable (A27). All modalities (A1) to (A27) are preferred modalities of modality (A0) with respect to the nature of the SMAC mimetic. In a preferred embodiment in relation to combination therapies, the recombinant rhabdovirus is a recombinant vesicular stomatitis virus encoding in its genome at least one CCL21 protein or a functional variant thereof, preferably human CCL21, selected from the group comprising: (i) plasmin-processed CCL21 protein, (ii) CCL21 protein truncated at the C-terminus, (iii) a protein comprising SEQ ID NO:2 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:3, (v) a protein comprising SEQ ID NO:4 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,(vi) a protein according to any of (i) - (v) also comprising a signal peptide sequence, (vii) a protein comprising SEQ ID NO:1 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:1, or (viii) a protein comprising SEQ ID NO:5 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:5, wherein the gene encoding the recombinant vesicular stomatitis virus glycoprotein G is replaced by the gene encoding the lymphocytic choriomeningitis virus (LCMV) glycoprotein GP, ​​and / or the glycoprotein G is replaced by the LCMV glycoprotein GP. In another preferred embodiment in relation to combination therapy, the recombinant rhabdovirus is a recombinant vesicular stomatitis virus encoding in its genome a vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G), and at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the CCL21 protein or the functional variant thereof is selected from the group comprising: (i) plasmin-processed CCL21 protein, (ii) CCL21 protein truncated at the C terminus, (iii) a protein comprising SEQ ID NO:2 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,(v) a protein comprising SEQ ID NO:4 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:4, (vi) a protein according to any of (i) - (v) also comprising a signal peptide sequence, (vii) a protein comprising SEQ ID NO:1 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:1, or (viii) a protein comprising SEQ ID NO:5 or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:5, wherein the gene encoding vesicular stomatitis virus glycoprotein G is replaced by the gene encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein GP,and / or the glycoprotein G is replaced by the LCMV glycoprotein GP, ​​and wherein the nucleoprotein (N) comprises an amino acid as indicated in SEQ ID NO:7 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, the phosphoprotein (P) comprises an amino acid as indicated in SEQ ID NO:8 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:8, the large protein (L) comprises an amino acid as indicated in SEQ ID NO:9 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:9, and the matrix protein (M) comprises an amino acid as indicated in SEQ ID NQ:10 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:10. In a more preferred modality in relation to combination therapies, recombinant rhabdovirus is a recombinant vesicular stomatitis virus that encodes in its genome at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the CCL21 protein or functional variant thereof comprises SEQ ID NO:5 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with respect to SEQ ID NO:5, wherein the gene encoding the glycoprotein G of recombinant vesicular stomatitis virus is replaced by the gene encoding the glycoprotein GP of lymphocytic choriomeningitis virus (LCMV), and / or the G glycoprotein is replaced by the GP glycoprotein of LCMV. While the recombinant rhabdovirus combination of the invention, and in particular the vesicular stomatitis virus of the invention, together with PD-1 inhibitors or SMACm / IAP antagonists, was exceptionally effective in the treatment of certain cancers, the inventors discovered that the combination of a vesicular stomatitis virus that does not encode an additional charge, i.e., does not encode a CCL21 protein, was also effective when combined with a PD-1 pathway inhibitor or an SMACm / IAP antagonist. In particular, the combined treatment of a VSV-GP (vesicular stomatitis virus with the LCMV glycoprotein) with a PD-1 pathway inhibitor or SMACm / IAP antagonist, both as described herein, was effective for the treatment of cancer, preferably solid tumors.Therefore, a combination comprising a VSV-GP that does not encode a CCL21 protein and a PD-1 pathway inhibitor, preferably an antagonist antibody targeting PD-1 or PD-L1 or a SMACm / IAP antagonist, is also provided herein. The use of such a combination for the treatment of cancer types as described herein is also provided. A combination therapy comprising the use of a VSV-GP that does not encode a CCL21 protein and a PD-1 pathway inhibitor or a SMACm / IAP antagonist is also provided herein. Regarding the combined treatment of VSV-GP that does not encode a CCL21 protein, it is preferred that the recombinant rhabdovirus be a recombinant vesicular stomatitis virus, wherein the gene encoding the glycoprotein G of the recombinant vesicular stomatitis virus is replaced by the gene encoding the glycoprotein GP of lymphocytic choriomeningitis virus (LCMV), and / or the glycoprotein G is replaced by the LCMV glycoprotein GP. Also in relation to the co-treatment of a VSV-GP that does not encode a CCL21 protein, it is preferred that the recombinant rhabdovirus be a recombinant vesicular stomatitis virus that encodes in its genome a vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G), wherein the gene encoding the glycoprotein G of the jzRQnn / ι ζηζ / E / γ vesicular stomatitis virus is replaced by the gene encoding the glycoprotein GP of lymphocytic choriomeningitis virus (LCMV), and / or the glycoprotein G is replaced by the LCMV glycoprotein GP, ​​and wherein the nucleoprotein (N) comprises an amino acid as indicated in SEQ ID NO:7 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, the phosphoprotein (P) comprises an amino acid as indicated in SEQ ID NO:8 or a functional variant at least 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:8, the large protein (L) comprises an amino acid as indicated in SEQ ID NO:9 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:9, and the matrix protein (M) comprises an amino acid as is indicated in SEQ ID NO:10 or a functional variant at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:10. Virus generation, production, and virus-producing cell The invention also provides a virus-producing cell, characterized in that the cell produces a recombinant rhabdovirus or recombinant vesicular stomatitis virus according to the invention. The cell may have any origin and may be present as a single cell or as part of a cell population. It is preferred that the cell producing a recombinant rhabdovirus or recombinant vesicular stomatitis virus be a mammalian cell. In a more preferred embodiment, the cell producing the virus of the invention is characterized in that the mammalian cell is a multipotent adult progenitor cell (MAPC), a neural stem cell (NSC), a mesenchymal stem cell (MSC), a HeLa cell, a HEK cell, any HEK293 cell (e.g., HEK293F or HEK293T), a Chinese hamster ovary cell (CHO), a baby hamster kidney cell (BHK), or a Vero cell or a bone marrow-derived tumor-infiltrating cell (BM-TIC). Alternatively, the virus-producing cell may be a human cell, monkey cell, mouse cell, or hamster cell. A person of average skill is familiar with suitable methods for assessing whether a given cell produces a virus and, consequently, whether a particular cell falls within the scope of the present invention. In this respect, the quantity of virus produced by the cell of the invention is not particularly limited. Preferred viral titers are >1 x 10⁷ TCID₅₀ / ml or >1 x 10⁸ genome copies / ml in the crude supernatants of the given cell culture after infection without further downstream processing. In a particular embodiment, the virus-producing cell of the invention is characterized in that the cell comprises one or more expression cassettes for the expression of at least one of the genes selected from the group consisting of η, I, pym genes encoding the N, L, P, and M proteins of VSV and a gp gene encoding LCMV-GP, Dandenong-GP glycoprotein, or Mopeia-GP. Virus-producing cells within the meaning of the invention include classic packaging cells for the production of recombinant rhabdovirus from non-replicating vectors, as well as producer cells for the production of recombinant rhabdovirus from replicating vectors. Typically, the packaging cells comprise one or more plasmids for the expression of essential jzRQnn / ι ζηζ / E / γ genes that are not present in the respective vector for packaging and / or that are necessary for virus production. Such cells are known to a person of intermediate skill, who can select the appropriate cell lines for the desired purpose. The recombinant rhabdovirus of the invention can be produced according to methods known to a person of intermediate skill and include, without limitation, (1) the use of cDNA transfected into a cell or (2) a combination of cDNA transfected into a helper lymphocyte, or (3) cDNA transfected into a cell, which is further infected with a helper / minivirus, thereby providing in trans the remaining components or activities necessary to produce an infectious or non-infectious recombinant rhabdovirus. Using any of these methods (e.g., helper / minivirus, helper lymphocyte line, or cDNA transfection alone), the minimum required components are a DNA molecule containing the cis-acting signals for (1) encapsidation of the genomic (or antigenomic) RNA by the Rhabdovirus N protein, P protein, and L protein and (2) replication of a genomic or antigenomic RNA equivalent (replicative intermediate). A replication element, or replicon, is an RNA strand that minimally contains the leader and backsequences of a rhabdovirus at its 5' and 3' ends. In the genomic sense, the leader is located at the 3' end and the back at the 5' end. Any RNA located between these two replication signals will be replicated. Furthermore, the leader and backsequences must contain the minimal cis-acting elements for encapsidation by the N protein and for polymerase binding, which are necessary to initiate transcription and replication. To prepare a recombinant rhabdovirus, a minivirus containing the G gene would also contain a leader region, a backsequence, and a G gene with the appropriate start and stop signals to produce a G protein mRNA. If the minivirus also contains an M gene, the appropriate start and stop signals to produce the M protein mRNA must also be present. In any gene contained in the recombinant rhabdovirus genome, the gene will be flanked by the appropriate transcription start and stop signals, allowing for gene expression and the production of protein products (Schnell et al., Journal of Virology, pp. 2318–2323, 1996). To produce “non-infectious” recombinant rhabdovirus, the recombinant rhabdovirus must have the minimal replicon elements and the N, P, and L proteins, and must contain the M gene. This produces virus particles that bud off the cell but are non-infectious. To produce “infectious” particles, the virus particles must additionally include proteins that can mediate fusion and attachment of the viral particle, such as through the use of a receptor-binding protein or ligand. The ligand of the native rhabdovirus receptor is the G protein. Any cell that allows the assembly of recombinant rhabdovirus can be used. One method for preparing infectious virus particles comprises a suitable cell line infected with a plasmid encoding T7 RNA polymerase or another suitable bacteriophage polymerase, such as T3 or SP6 polymerases. The cells can then be transfected with single cDNA containing the genes encoding the rhabdovirus G, N, P, L, and M proteins. These cDNAs will provide the proteins for preparing a recombinant rhabdovirus particle. The cells can be transfected using any method known in the prior art. jzRQnn / ι ζηζ / E / γ A “polycistronic cDNA” containing the genomic RNA equivalent of rhabdovirus is also transfected into the cell line. If the infectious recombinant rhabdovirus particle is intended to be lytic in an infected cell, then the genes encoding the N, P, M, and L proteins must be present, as well as any heterologous nucleic acid segments. If the infectious recombinant rhabdovirus particle is not intended to be lytic, then the gene encoding the M protein is not included in the polycistronic DNA. A “polycistronic cDNA” means a cDNA comprising at least transcription units containing the genes encoding the N, P, and L proteins. The recombinant rhabdovirus polycistronic DNA may also contain a gene encoding a protein variant or its polypeptide fragment, or a therapeutic nucleic acid or protein.Alternatively, any protein that will initially associate with the first produced viral particle or fragment thereof can be provided in trans. A polycistronic cDNA comprising a gene encoding CCL21 is also envisaged. The envisaged polycistronic cDNA may contain a gene encoding a protein variant, a gene encoding a marker, a therapeutic nucleic acid, and / or the NPL or NPLM genes. The first step in generating a recombinant rhabdovirus is the expression of an RNA that is a genomic or antigenomic equivalent of a cDNA. The N protein then packages this RNA, and the P / L proteins replicate it. The recombinant virus thus produced can be recovered. If the G protein is absent from the recombinant RNA genome, it is usually provided in trans form. If both the G and M proteins are absent, they are both provided in trans form. To prepare “non-infectious rhabdovirus” particles, the procedure can be the same as above, except that the polycistronic cDNA transfected into the cells may contain only the N, P, and L genes of the rhabdovirus.The polycistronic cDNA of non-infectious rhabdovirus particles may additionally contain a gene that codes for a protein. Typically, transfected cells are incubated for at least 24 hours at the desired temperature, usually around 37°C. For non-infectious virus particles, the supernatant and isolated virus particles are collected. For infectious virus particles, the virus-containing supernatant is collected and transferred to new cells. The new cells are incubated for approximately 48 hours, and the supernatant is collected. Other functions and advantages of the present invention will be evident in the following more detailed Examples which show, by way of example, the principles of this invention. Examples Example 1 Induction of immune infiltration / activation and expression of immune checkpoints in VSV-GP infected tumors Expression / NanoString Analysis (Figure 1) To better understand the impact of therapeutic interventions with the VSV-GP platform, immune cell infiltration (T lymphocytes: CD3 epsilon, CD4, and CD8), activation (CD69, granzyme B (GzmB), and perforin (Prf1)), and immune checkpoint expression (PD-L1 (CD274), PD-1 (Pdcdl), Ctla-4, Tigit, and Lag3) were analyzed in control mice or tumors infected with VSV-GP. For this purpose, C57BL / 6 mice with LLC1-IFNARKO tumors (CLL1 tumor cells knocked out for the interferon-alpha receptor) were used as controls or treated with a single intravenous injection of 1 x 10⁸ TCIDs of VSV-GP. Seven days after treatment, the tumors were excised. Complete RNA was extracted and analyzed using the NanoString “Pan Cancer Immune Profiling Panel” according to the manufacturer's instructions.As illustrated in Figure 1, treatment with VSV-GP resulted in a strong upregulation of the expression of the analyzed genes, which include the PD-L1 and PD-1 genes. Example 2 Efficacy: VSV-GP combo with anti-PD-1 Tumor growth (Figures 2A, 2B, 2C and 2D) Based on the clinical success of PD-1 resp. PD-L1 blocking antibodies in cancer patients and proprietary data (see Figure 1) illustrating that treatment with the VSV-GP platform resulted in the activation of tumor-infiltrating T lymphocytes, consistent with the upregulation of immune checkpoints such as PD-1 and PD-L1, the therapeutic potential of combining VSV-GP-derived therapies with a PD-1 blocking antibody was analyzed using the CT26.CL25-IFNARKO tumor model (CT26.CL25 tumor cells knocked out for the interferon alpha receptor). The engraftment rate of CT26CI25 IFNAR- / - tumor cells injected subcutaneously was 100% (50 / 50 mice). On day 8 (day of virus administration), the median tumor size was 0.05 cm³. Tumor growth continued for 60 days. Sham controls (= untreated) showed 10% spontaneous remission (1 / 10), and one tumor grew at a much slower rate. In mice treated with intravenous VSV-GP alone, 30% (3 / 10 mice) achieved complete remission. PD-1-only treatment initiated on day 11 post-grafting had no effect on tumor growth. Combining VSV-GP with anti-PD-1 resulted in higher tumor remission rates. Complete remissions were observed in 70% (7 / 10 mice) when anti-PD-1 was administered following VSV-GP treatment. The mice remained tumor-free for at least 60 days. Overall, high survival rates were achieved in the combination groups (not shown). Example 3 Memory formation: VSV-GP and VSV-GP / anti-PD-1 combo Tumor growth / re-exposure (Figures 3A, 3B and 3C) Mice cured with VSV-GP / anti-PD-1 combination experiments were protected against re-exposure. Mice in the VSV-GP / anti-PD-1 combination group (n=7) or the VSV-GP-only group (low dose, n=3) underwent re-exposure. Briefly, sc CT26CI25 IFNAR- / - cells were injected into the left flank of the mice, and tumor growth was monitored over time. As a positive control, age- and sex-matched, previously untreated mice (n=10) were grafted with sc CT26CI25 IFNAR- / - cells, and tumor growth was consistent with spontaneous remission as observed previously. No tumor growth was observed in the VSV-GP / anti-PD-1 combination group (n=7) or the VSV-GP-only group (low dose, n=3), indicating that the cured mice developed some immunological memory. 7RQnn / l 7Π7 / Β / Y Example 4 CCL21 cargo selection and VSV-GP-induced gynokine expression in tumors NanoString® expression analysis (Figure 4) The impact of therapeutic interventions using the VSV-GP platform in preclinical tumor models was analyzed by measuring the expression of multiple chemokines (Figure 4). CCL5, CXCL9, CXCL10, and other chemokine expression were strongly upregulated in LLC1-IFNARKO 3 tumors 7 days after a single IV treatment with 1x10® TCIDso of VSV-GP. However, the expression of CCR7 ligands, CCL19, and CCL21 was not upregulated by VSV-GP infection. Example 5 Generation of recombinant VSV-CCL21 Viral rescue (Figures 5A and 5B) Based on the findings described in Example 4, the oncolytic virus VSV-GP genome was genetically engineered to encode the CCL21 gene (see Figures 5A and 5B) in order to locally express the chemokine CCL21 at the tumor site during viral replication and to fill the “immunotherapeutic gap” of VSV-GP (VSV-GP was unable to upregulate the ligands of CCR7, CCL19 and CCL21) and also to enhance immune cell infiltration as well as the therapeutic efficacy of the oncolytic virus VSV-GP. Replication-competent variants of the VSV-GP-CCL21 virus were generated by reverse genetics (gene of interest (GOI) cloning, virus rescue, and repeat plaque purification) from bacterial plasmids containing the cDNA for the complete VSV-GP viral genome and murine or human CCL21 versions. The pVSV-GP-CCL21 plasmids were based on the pVSV-XN1 plasmid [Schnell et al.] containing the complete cDNA genome of the T7 promoter-controlled VSV Indiana serotype. To generate pVSV-GP-CCL21 variants, the complete sequence for VSV envelope protein G was replaced with the codon-optimized sequence of the GP envelope protein from lymphocytic choriomeningitis virus (LCMV, strain WE-HPI). Additionally, a synthetic nucleic acid encoding a CCL21 gene was inserted between the GP glycoprotein and the viral polymerase L using Gibson assembly.Transcription of the CCL21 gene in the context of viral infection is ensured by means of an extra VSV start signal sequence at the 3' end and an additional stop signal sequence at the 5' end of the open reading frame of CCL21 (Figure 5A). Infectious viruses were recovered (or rescued) from plasmid cDNA by transfecting HEK293T or any other VSV-permissive cell line using standard transfection methods (e.g., CaPO4 precipitation, liposomal DNA delivery). Briefly, HEK293T cells were transfected with pSF-CAG-amp-based expression plasmids encoding the VSV N, P, and L proteins, as well as codon-optimized T7 polymerase. Additionally, the plasmid encoding the viral genomic cDNA of VSV-GP, VSV-GP-CCL21, or a variant thereof, was co-transfected (Figure 5B). In the first stage of the rescue process, the T7 polymerase transcribes the viral RNA genome from the plasmid-encoded viral cDNA. In a second stage, the VSV P and L proteins, which are expressed exogenously from the co-transfected plasmids, further amplify the viral RNA genomes.The viral RNA genomes are cotranscriptionally encapsidated by the VSV N protein. Additionally, the P / L polymerase complex allows transcription of the full set of viral gene products N, P, M, GP, and L, as well as the inserted CCL21 variants. The viral RNA genomes are subsequently packaged into infectious VSV particles containing the ribonucleoprotein, matrix protein, and viral envelope GP. The virus particles are released from cells by budding. Initially, the rescued viruses were transferred into permissive cell lines, such as HEK293T, BHK21CI.13, or Vero. Several rounds of plate purification were performed before generating a seed virus pool using standard methods. Briefly, HEK293T, BHK21CI.13, or Vero cells were infected with serial 10-fold dilutions of the rescued preseeds. After approximately 2 hours, the cell monolayers were washed twice and layered with a medium containing 0.8% low-melting-point agarose. 24–48 hours post-infection, the plates were harvested, and the virus was used for an additional round of plate purification or to generate seed virus pools. Example 5.1 In vitro viral efficacy validation TCID5o (Figures 19A, 19B and 19-C) One day prior to infection, Vero, BHK21, and HEK293 cells were seeded in 6-well plates. The corresponding culture media were: (a) Vero cells: DMEM (Gibco, #31966-021) + 5% thermo-inactivated FBS (Gibco, #10500-064), (b) BHK21 cells: GMEM (Life Technologies, #21710-082 / 025) + 10% thermo-inactivated FBS (Gibco, #10500-064) + 5% tryptose phosphate culture TPB (Life Technologies, #18050-039), (c) HEK293 cells: Freestyle™ 293 Expression Medium (ThermoFisher Scientific, #12338018). On the day of infection, all cell lines had a confluence of 60-70%. One cavity per cell line was counted (CountessTM cell counter, Invitrogen) before infecting the other cavities with 0.005 MOI of one of the virus constructs VSV-GP (GP), VSV-GP-huCCL21 (21) or VSV-GPhuCCL21 (1-79) (21 k). Culture supernatants (3 ml total volume) were collected 0 h, 24 h, and 48 h after infection to determine viral replication competence by measuring TCIDso / ml. The TCIDso (median tissue culture infectious dose) was determined in 96-cell Vero plates seeded one day before infection. From all supernatants, 22 serial semi-algorithmic dilutions were prepared (ranging from 1E-1.0 to 1E-11.5) and titrated in quadruplicate. Six days post-infection, the cytopathic effect (CPE) was read by microscopic inspection of the plates. TCIDso / ml was calculated according to the Spearman-Karber formula M = x + d [0.5 - (1 / n) (r)] where x: positive exponent of highest dilution evaluated; d = space between dilutions; n = cavities per dilution; r = sum of the number of negative responses. Example 5.2 In vitro cargo expression ELISA / Western transfer (Figures 6A and 6B, Figures 12A and 12B and Figure 18) To confirm and quantify the expression of viral CCL21 cargoes (transgenes), as well as to better characterize different CCL21 variants, CCL21-specific ELISAs and Western blot assays were developed. As illustrated in Figure 6A and Figure 12A, supernatants from VSVGP-muCCL21 (Figure 6A; VSV-GP expressing full-length murine CCL21) infected HEK293 cells or VSV-GP-huCCL21 (Figure 12A; VSV-GP expressing full-length human CCL21) were analyzed at different time points after viral infection using mouse-specific and human-specific ELISAs, respectively. In addition, the variants of human CCL21 were characterized, namely the full-length human CCL21 and the C-terminus truncated version resembling the first 79 amino acids (without the signal sequence) of human CCL21 = CCL21 (1-79) using a Western blot specific for human CCL21.As illustrated in Figure 18 (from left), the supernatants of HEK293 cells transfected with plasmids encoding CCL21(1-79) or full-length CCL21 proteins were analyzed, as well as the supernatants of HEK293 cells infected with the indicated viruses. The chemokine variants were well expressed in both systems (plasmids and viruses). While the full-length CCL21 samples contained multiple CCL21 species and their respective breakdown / cleavage products, the CCL21(1-79) protein appeared as a single, clean band. Example 5.3 In vitro cargo activity Transwell (T / DC lymphocytes) (Figures 6A, 12A, 16 and 17) To further confirm and characterize the biological functionality of viral CCL21 cargoes (transgenes), their ability to attract T lymphocytes or monocyte-derived dendritic cells (moDCs) was analyzed in a Transwell migration assay. For this purpose, mouse and human CCL21 containing supernatants, respectively, as described in Example 5.2 (Figures 6A and 12A), migration medium alone (background control), recombinant CCL21 (positive control), or matched supernatants from VSV-GP-infected HEK293 cells (VSV-GP background control) were added to the background cavity of the Transwell migration assay setup, and CD3 / 28-stimulated mouse (Figure 6A; right site) or human (Figure 12A; right site) T lymphocytes were added to the upper chamber (Transwell insert). After incubation, the cells in the background cavity were quantified using the Promega® CelITiterGlo® cell viability assay.The results are illustrated as a “multiplier increase” compared to the migration medium-only control. Other experiments included the short cargo version of CCL21, CCL21(1-79) (aa 1-79 of human CCL21), and the shortest natural CCL21 fragment resulting from plasmin-mediated processing, CCL21(1-81) (aa 1-81 of human CCL21), using the assays described above (see Figure 15). For this purpose, supernatants from HEK293 cells transfected with expression plasmids were generated and analyzed (see Figure 16). In a final step, supernatants from VSV-GP-infected HEK293 cells, VSV-GP-huCCL21 (full length), and VSV-GP-huCCL21(1-79) were compared using the Transwell migration assays described above and moDC as the responding cells. In this assay, both full-length human CCL21 and CCL21(1-79) resulted in comparable moDC migration (see Figure 17). jzRQnn / ι ζηζ / E / γ Example 5.4 Cross-reactivity between species (human to mouse and rat) in vitro Transwell (T lymphocytes) (Figures 13A and 13B) To confirm the cross-species reactivity of human CCL21 with respect to the mouse and rat CCL21 receptor (CCR7), the previously described Transwell migration assay was used with mouse (left) or rat (right) T lymphocytes as responders (see Figures 13A and 13B). Migration assays were performed using recombinant human vs. mouse (left) and human vs. rat (right) chemokines at the indicated concentrations (background cavity). In conclusion, human CCL21 was as active in mouse and rat systems as the corresponding mouse and rat chemokines, respectively, indicating that the human molecule can be evaluated in preclinical rodent (mouse / rat) models. Example 6: Expression of Charge CCL21 in vivo ARNseq (Figure 10) Virally encoded CCL21 expression was analyzed / confirmed in rodent tumors under control or infected with VSV-GP or VSV-GP-muCCL21. For this purpose, C57BU6 mice with LLC1 IFNARKO tumors were used as controls or treated with a single intravenous injection of 1 x 10⁸ TCIDs of VSV-GP or VSV-GP-muCCL21. Seven days post-treatment, tumors were excised; whole RNA was extracted and analyzed using RNAseq. CD3 epsilon and CXCL10 were used as comparators. Virally encoded CCL21 was specifically detected using the codon-optimized DNA sequence as the read (see Figure 10). Example 6.1: Absence of neurotoxicity of VSV-GP and VSV-GP-CCL21 Survival (Figures 11A and 11B) Wild-type VSV infections can cause neurological symptoms when the virus reaches the brain. These neurological complications include severe encephalitis, which can be fatal. The advantage of using a chimeric VSV-GP is that neuronal infection has been shown to be almost entirely absent, thus making the VSV structure a safe oncolytic agent. The attenuated phenotype is thought to be due to altered viral tropism facilitated by the viral envelope glycoprotein. Although neuronal infection and spread of VSV-GP are not observed in the brain, it is unclear whether viral gene expression in other cell types, such as glial cells or astrocytes, is completely absent. Accidental expression of the CCL21 transgene by VSV-GP can attract immune cells that cause adverse effects in the brain; therefore, a neurotoxicity assessment of VSV-GP-muCCL21 was performed. Swiss CD-1 mice received a single intracranial injection of 3 pl containing 1x10⁶TCIDs via stereotactic injection into the right striatum. PBS was administered intracytoplasmically in the control group. Animals were monitored daily for signs of neurotoxicity and overall well-being. Mouse survival in the PBS (circles), VSV-G DsRed (diamonds), VSV-GP (squares), and VSV-GP muCCL21 experimental groups was plotted as Kaplan curves. Meier (Figure 11B). Kaplan-Meier analysis indicated that none of the evaluated virus variants exhibited neurotoxicity in mice. Only the VSV-G DsRed control group, which contained wild-type VSV glycoprotein on the surface of the virus, showed increased weight loss (Figure 11A) and developed neurological signs that led to euthanasia within the first week of infection. Example 6.2 In vivo efficacy of VSV-GP and VSV-GP-CCL21 Tumor growth (Figure 14) The therapeutic potential of VSV-GP and VSV-GP-huCCL21 was evaluated / compared using the CT26.CL25-IFNARKO tumor model. For this purpose, established tumors were treated with two intravenous injections (days 0 and 3) of 2 x 10⁷ TCIDs of either VSV-GP or VSV-GP-huCCL21. The survival of the mice treated as described is illustrated in Figure 14. Example 6.3 In vivo efficacy of VSV-GP-huCCL21 and VSV-GP-CCL21 (1 -79) Tumor growth / survival (Figures 20, 21) The therapeutic potential of VSV-GP-huCCL21 and VSV-GP-huCCL21(1-79) was evaluated / compared using the CT26.CL25-IFNARKO tumor model. For this purpose, established tumors were treated with two IV injections (day 0 and 3) of 2x107TCIDs of VSV-GP-huCCL21 or VSV-GP-huCCL21(1-79). The cumulative tumor growth as well as the 30-day survival of mice treated as indicated are illustrated in Figures 20, 21. Treatment with the short CCL21 variant (CCL21(1-79)), corresponding to the fully plasmin-processed form (minus aa 80 / 81) and with free diffusion of human CCL21, achieved better control of tumor growth and improved survival compared to the full-length CCL21 having the VSV-GP variant. Example 6.4 MoA: T lymphocyte infiltration induced by VSV-GP-huCCL21 and VSV-GP-huCCL21 (1-79) IHC (Figures 22, 23) Tumors treated as in Example 6.3 were analyzed for T-cell infiltration. FFPE sections of tumors were stained to determine CD4 and CD8, as well as VSV-N and cleaved Caspase 3. Total T cells (CD4+ and CD8+) were quantified in viable (non-necrotic) tumor areas. As illustrated in Figure 22, the short CCL21 variant (CCL21(1-79)), corresponding to the fully plasmin-processed form (minus amino acids 80 / 81) and with free diffusion of human CCL21, attracted more T cells to the tumor, providing an explanation for the observed increased efficiency (Example 6.3). Additionally, virally expressed CCL21 was able to attract dendritic cells (expressing CD11c) to infected CT26.CL25 tumors. Established CT26.CL25 tumors were injected locally (it) with 2x107TCIDs of VSV-GP or VSV-GP-muCCL21 on days 0 and 3. FFPE sections of the respective tumors were analyzed to determine dendritic cell infiltration (tumor areas with active viral replication = necrotic margin) (see Figure 24). jzRQnn / ι ζηζ / E / γ Example 7 Efficacy: VSV-GP and VSV-GP-CCL21 combo with SMACm Tumor growth / survival (Figures 7A, 7B, 7C, 8A, 8B, 8Cy9) Based on encouraging data from the combination of VSV-GP and a PD5-blocking antibody (Example 2), other combinations of VSV-GP (Figures 7A, 7B, 7C, 8A, 8B, 8C, and 9) and VSV-GPmuCCL2 (Figures 8A, 8B, 8C, and 9) with a SMAC mimetic (SMACm), a modulator of cell death pathways that makes tumor cells more susceptible to stimuli / agents that induce cell death, were evaluated. The therapeutic interaction of the compounds was analyzed using the CT26.CL25-IFNARKO tumor model. For this purpose, Balb / c mice with established CT26.CL25-IFNARKO tumors received a single treatment. IV with 4x10⁶TCIDs of VSV-GP resp. VSV-GP-muCCL21 and / or 100 mg / kg of a daily SMACm (po) for a period of 2 weeks, starting on the same day as the VSV-GP resp. VSV-GP-muCCL21 treatment. The combination of VSV-GP and SMACm resulted in improved efficacy compared to the corresponding monotherapies. When VSV-GP-muCCL21 was combined with an SMACm, the combinatorial effects were even more pronounced, resulting in the cure of all treated animals.

Claims

1. A recombinant rhabdovirus characterized in that it encodes in its genome at least one CCL21 protein or a functional variant thereof, preferably human CCL21.

2. The recombinant rhabdovirus according to claim 1, further characterized in that the CCL21 protein or a functional variant thereof is selected from the group comprising: (i) a plasmin-processed CCL21 protein, (ii) a CCL21 protein truncated at the C-terminus, (iii) a protein comprising SEQ ID NO:2 or having at least 80% identity with SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80% identity with SEQ ID NO:3, (v) a protein comprising SEQ ID NO:4 or having at least 80% identity with SEQ ID NO:4, (vi) a protein according to any of (i) - (v) further comprising a signal peptide sequence, (vii) a protein comprising SEQ ID NO:1 or having at least 80% identity with SEQ ID NO:1, or (viii) a protein comprising SEQ ID NO:5 or having at least 80% identity with respect to SEQ ID NO:

5.

3. The recombinant rhabdovirus according to any of claims 1 to 2, further characterized in that it is a vesiculovirus.

4. The recombinant rhabdovirus according to claim 3, further characterized in that the vesiculovirus is selected from the group comprising: Alagoas vesicular stomatitis virus (VSAV), carajás virus (CJSV), chandipura virus (CHPV), cocal virus (COCV), Indiana vesicular stomatitis virus (VSIV), isfahan virus (ISFV), maraba virus (MARAV), New Jersey vesicular stomatitis virus (VSNJV), or Piry virus (PIRYV).

5. The recombinant rhabdovirus according to claim 3, further characterized in that it is a vesicular stomatitis virus, preferably an Indiana vesicular stomatitis virus (VSIV), or a New Jersey vesicular stomatitis virus (VSNJV).

6. The recombinant rhabdovirus according to any of claims 1 to 5, further characterized in that the rhabdovirus is competent for replication.

7. The recombinant rhabdovirus according to any of claims 1 to 6, further characterized in that the rhabdovirus (i) lacks a functional gene encoding glycoprotein G, and / or (ii) lacks a functional glycoprotein G.

8. The recombinant rhabdovirus according to claim 7, further characterized in that (i) the gene encoding glycoprotein G is replaced by the gene encoding glycoprotein GP of another virus, and / or (i) glycoprotein G is replaced by the glycoprotein GP of another virus.

9. The recombinant rhabdovirus according to claim 8, further characterized in that (i) the gene encoding glycoprotein G is replaced by the gene encoding glycoprotein GP of an arenavirus, and / or (ii) glycoprotein G is replaced by glycoprotein GP of an arenavirus.

10. The recombinant rhabdovirus according to any of claims 8 to 9, further characterized in that (i) the gene encoding the glycoprotein G is replaced by the gene encoding the glycoprotein GP of Dandenong virus or Mopeia virus, and / or (ii) the glycoprotein G is replaced by the glycoprotein GP of Dandenong virus or Mopeia virus.

11. The recombinant rhabdovirus according to any of claims 7 to 9, further characterized in that (i) the gene encoding glycoprotein G is replaced by the gene encoding the GP glycoprotein of lymphocytic choriomeningitis virus (LCMV), and / or (ii) the G glycoprotein is replaced by the GP glycoprotein of LCMV.

12. A recombinant vesicular stomatitis virus characterized in that it encodes in its genome at least one CCL21 protein or a functional variant thereof, preferably human CCL21, selected from the group comprising: (i) a plasmin-processed CCL21 protein, (ii) a C-terminus truncated CCL21 protein, (iii) a protein comprising SEQ ID NO:2 or having at least 80% identity with SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80% identity with SEQ ID NO:3, (v) a protein comprising SEQ ID NO:4 or having at least 80% identity with SEQ ID NO:4, (vi) a protein according to any of (i) - (v) further comprising a signal peptide sequence, (vii) a protein comprising SEQ ID NO:1 or having at least 80% identity with SEQ ID NO:1, (viii) a protein comprising SEQ ID NOS or having at least 80% identity with SEQ ID NOS,wherein the gene encoding the glycoprotein G of recombinant vesicular stomatitis virus is replaced by the gene encoding the glycoprotein GP of lymphocytic choriomeningitis virus (LCMV), and / or the glycoprotein G is replaced by the LCMV glycoprotein GP.

13. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a plasmin-processed CCL21 protein.

14. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a CCL21 protein truncated at the C terminus.

15. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising SEQ ID NO:2 or having at least 80% identity with respect to SEQ ID NO:

2.

16. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising SEQ ID NO:3 or having at least 80% identity with respect to SEQ ID NO:

3.

17. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising SEQ ID NO:4 or having at least 80% identity with respect to SEQ ID NO:

4.

18. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising a protein according to any of (i) - (v) further comprising a signal peptide sequence.

19. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising SEQ ID NO:1 or having at least 80% identity with respect to SEQ ID NO:

1.

20. The recombinant vesicular stomatitis virus according to claim 12, further characterized in that the genome encodes a protein comprising SEQ ID NO:5 or having at least 80% identity with respect to SEQ ID NO:

5.

21. A recombinant vesicular stomatitis virus characterized in that it encodes in its genome at least one nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G) of the vesicular stomatitis virus and at least one CCL21 protein or a functional variant thereof, preferably human CCL21.

22. The recombinant vesicular stomatitis virus according to claim 21, further characterized in that the nucleoprotein (N) comprises an amino acid sequence as indicated in SEQ ID NO:7 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:

7.

23. The recombinant vesicular stomatitis virus according to any of claims 21 or 22, further characterized in that the phosphoprotein (P) comprises an amino acid sequence as indicated in SEQ ID NO:8 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:

8.

24. The recombinant vesicular stomatitis virus according to any of claims 21 to 23, further characterized in that the large protein (L) comprises an amino acid sequence as indicated in SEQ ID NO:9 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:

9.

25. The recombinant vesicular stomatitis virus according to any of claims 21 to 24, further characterized in that the matrix protein (M) comprises an amino acid sequence as indicated in SEQ ID NQ:10 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 7 7RQnn / l 7P7 / E / Y 96%, 98% identical to SEQ ID NQ:

10.

26. The recombinant vesicular stomatitis virus according to any one of claims 21 to 25, further characterized in that: - the nucleoprotein (N) comprises an amino acid sequence as indicated in SEQ ID NO:7 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:7 - wherein the phosphoprotein (P) comprises an amino acid sequence as indicated in SEQ ID NO:8 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:8 - wherein the large protein (L) comprises an amino acid sequence as indicated in SEQ ID NO:9 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:9, and - the matrix protein (M) comprises an amino acid sequence as indicated in SEQ ID NQ:10 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NQ:

10.

27. The recombinant vesicular stomatitis virus according to any of claims 21 to 26, further characterized in that it is competent for replication.

28. The recombinant vesicular stomatitis virus according to any of claims 21 to 27, further characterized in that (i) it lacks a functional gene encoding glycoprotein G, and / or (ii) it lacks a functional glycoprotein G.

29. The recombinant vesicular stomatitis virus according to any of claims 21 to 28, further characterized in that (i) the gene encoding glycoprotein G is replaced by the gene encoding glycoprotein GP of another virus, and / or (ii) glycoprotein G is replaced by glycoprotein GP of another virus.

30. The recombinant vesicular stomatitis virus according to any of claims 21 to 29, further characterized in that (i) the gene encoding glycoprotein G is replaced by the gene encoding the GP glycoprotein of lymphocytic choriomeningitis virus (LCMV), and / or (ii) the G glycoprotein is replaced by the GP glycoprotein of LCMV.

31. The recombinant vesicular stomatitis virus according to any one of claims 21 to 30, further characterized in that the CCL21 protein or a functional variant thereof is selected from the group comprising: (i) a plasmin-processed CCL21 protein, (ii) a CCL21 protein truncated at the C-terminus, (iii) a protein comprising SEQ ID NO:2 or having at least 80% identity with SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80% identity with SEQ ID NO:3, (v) a protein comprising SEQ ID NO:4 or having at least 80% identity with SEQ ID NO:4, (vi) a protein according to any one of (i) - (v) further comprising a signal peptide sequence, (vii) a protein comprising SEQ ID NO:1 or having at least 80% identity with SEQ ID NO:4 SEQ ID NO:1, (viii) a protein comprising SEQ ID NO:5 or having at least 80% identity with SEQ ID NO:5.

32. A recombinant vesicular stomatitis virus characterized in that it encodes in its genome a vesicular stomatitis virus nucleoprotein (N), large protein (L), phosphoprotein (P), matrix protein (M), glycoprotein (G), and at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the CCL21 protein or functional variant thereof is selected from the group comprising: (i) a plasmin-processed CCL21 protein, (ii) a CCL21 protein truncated at the C terminus, (iii) a protein comprising SEQ ID NO:2 or having at least 80% identity with SEQ ID NO:2, (iv) a protein comprising SEQ ID NO:3 or having at least 80% identity with SEQ ID NO:3, (v) a protein comprising SEQ ID NO:4 or having at least 80% identity with SEQ ID NO:4, (vi) a protein of in accordance with any of (i) - (v) further comprising a signal peptide sequence,(vii) a protein comprising SEQ ID NO:1 or having at least 80% identity with SEQ ID NO:1, (viii) a protein comprising SEQ ID NO:5 or having at least 80% identity with SEQ ID NO:5, wherein the gene encoding the vesicular stomatitis virus glycoprotein G is replaced by the gene encoding the lymphocytic choriomeningitis virus (LCMV) glycoprotein GP, ​​and / or the glycoprotein G is replaced by the LCMV glycoprotein GP, ​​and wherein - the nucleoprotein (N) comprises an amino acid as indicated in SEQ ID NO:7 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:7 - wherein the phosphoprotein (P) comprises an amino acid as indicated in SEQ ID NO:8 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:8 - wherein the large protein (L) comprises an amino acid as indicated in SEQ ID NO:9 or a functional variant at least 80%, 85%, 90%, 92%, 94%, 96%,98% identical to SEQ ID NO:9 - the matrix protein (M) comprises an amino acid as indicated in SEQ ID NO:10 or a functional vahant at least 80%, 85%, 90%, 92%, 94%, 96%, 98% identical to SEQ ID NO:

10.

33. A pharmaceutical composition, characterized in that the composition comprises a recombinant rhabdovirus as claimed in any of claims 1 to 20, or a recombinant vesicular stomatitis virus as claimed in any of claims 21 to 32.

34. A recombinant rhabdovirus as claimed in any of claims 1 to 20, a recombinant vesicular stomatitis virus as claimed in any of claims 21 to 32, or a pharmaceutical composition as claimed in claim 33 for use as a medicament.

35. A recombinant rhabdovirus as claimed in any of claims 1 to 20, a recombinant vesicular stomatitis virus as claimed in any of claims 21 to 32, or a pharmaceutical composition as claimed in claim 33 for use in the treatment of cancer, preferably solid cancer types.

36. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to claim 35, wherein the solid cancer is selected from the list comprising: reproductive system tumor, ovarian tumor, testicular tumor, endocrine tumor, gastrointestinal tumor, pancreatic tumor, liver tumor, kidney tumor, colon tumor, colorectal tumor, bladder tumor, prostate tumor, skin tumor, melanoma, respiratory tumor, lung tumor, breast tumor, head and neck tumor, head and neck squamous cell carcinoma (HNSCC), and bone tumor.

37. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus or the pharmaceutical composition for use according to any of claims 34 to 36, wherein the recombinant rhabdovirus, the recombinant vesicular stomatitis virus or the pharmaceutical composition are adapted to be administered intratumorally or intravenously.

38. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus or the pharmaceutical composition for use according to any of claims 35 to 37, wherein the recombinant rhabdovirus, the recombinant vesicular stomatitis virus or the pharmaceutical composition are adapted to be administered at least once intratumorally and then intravenously.

39. The recombinant rhabdovirus, recombinant vesicular stomatitis virus or the pharmaceutical composition for use according to claim 38, wherein the subsequent intravenous administration is administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or 31 days after the initial intratumoral administration.

40. A composition characterized in that it comprises a recombinant rhabdovirus or a recombinant vesicular stomatitis virus as claimed in any of the preceding claims and additionally a PD-1 pathway inhibitor or a SMAC mimetic.

41. The composition according to claim 40, further characterized in that the PD-1 pathway inhibitor is an antagonistic antibody, which is directed against PD-1 or PD-L1.

42. The composition according to claim 40, further characterized in that the SMAC mimetic is selected from the group consisting of any of compounds 1 to 26: jzRQnn / ι ζηζ / E / γ jzRQnn / ι ζηζ / E / γίΛΐ 7 7RQnn / l 7Π7 / Β / ΥΙΛΙ 7 7RQnn / l Ζηζ / E / ΥΙΛΙ jzRQnn / ι ζηζ / E / γίΛΐ or a pharmaceutically acceptable salt of one of these compounds.

43. The composition according to claim 40, further characterized in that the PD-1 pathway inhibitor is an antagonist selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, atezolizumab, avelumab, durvalumab, PDR-001, PD1-1, PD1-2, PD1-3, PD1-4 and PD15.

44. A kit of parts characterized in that it comprises: a) a recombinant rhabdovirus, a recombinant vesicular stomatitis virus or a pharmaceutical composition as defined in any of the preceding claims, and b) a PD-1 pathway inhibitor or SMAC mimetic as defined in any of the preceding claims.

45. A recombinant rhabdovirus, a recombinant vesicular stomatitis virus, or a pharmaceutical composition for use according to any of claims 34 to 36 in combination with a PD-1 pathway inhibitor or a SMAC mimetic.

46. ​​The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to claim 45, wherein the recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition are adapted to be administered concomitantly, sequentially, or alternately with the PD-1 pathway inhibitor or the SMAC mimetic.

47. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to claims 45 to 46, wherein the SMAC mimetic is selected from the group consisting of any one of compounds 1 to 26 claimed in claim 42 or a pharmaceutically acceptable salt of one of these compounds.

48. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to claims 45 to 46, wherein the PD-1 pathway inhibitor is selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, atezolizumab, avelumab, durvalumab, PDR-001, PD1-1, PD1-2, PD1-3, PD1-4, and PD1-5.

49. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to any of claims 45 to 47, wherein the recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition are adapted to be administered by a route of administration other than the PD-1 pathway inhibitor or the SMAC mimetic.

50. The recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition for use according to any of claims 45 to 47, wherein the recombinant rhabdovirus, the recombinant vesicular stomatitis virus, or the pharmaceutical composition are adapted to be administered at least once intratumorally, and the PD-1 pathway inhibitor or the SMAC mimetic are adapted to be administered intravenously.

51. A virus-producing cell, characterized in that the cell produces a recombinant rhabdovirus or recombinant vesicular stomatitis virus as claimed in any of the preceding claims.

52. The virus-producing cell according to claim 51, further characterized in that the cell is a Vero cell, a HEK cell, a HEK293 cell, a Chinese hamster ovary cell (CHO), or a baby hamster kidney cell (BHK).

53. A recombinant rhabdovirus characterized in that it encodes in its RNA genome at least one CCL21 protein or a functional variant thereof, preferably human CCL21, wherein the RNA genome of the recombinant rhabdovirus comprises or consists of a coding sequence that is at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 24.