Long-acting il-15 agonist for treating bladder cancer

Abstract

A method of treating bladder cancer with an agonistic IL-15 complex, alone or in combination with BCG, is described.

Description

[0006] IL- 15 is a soluble protein, but endogenous IL- 15 is not readily detectable in serum or body fluids — instead, it occurs predominantly as a membrane-bound form that is expressed or acquired by several types of accessory cells (Fehniger et al., Blood, 2001, 97(1): 14-32). For instance, although IL- 15 mRNA is detected in cells of both hematopoietic and non-hematopoietic lineage, T cells do not produce IL- 15. Instead, IL- 15 binds to the IL-15Ra, forming cell-surface complexes on T cells. IL-15 specifically binds to the IL-15Ra with high affinity via the “sushi domain” in exon 2 of the extracellular domain of the receptor (Budagian et al., Cytokine & Growth Factor Reviews , 2006, 17(4): 259-80). After trans-endosomal recycling and migration back to the cell surface, these IL- 15 complexes acquire the property to activate bystander cells expressing the IL-15Rlow-affinity receptor complex, inducing IL- 15-mediated signaling via the Jak / Stat pathway. A naturally occurring soluble form of IL-15Ra (“sIL-15Ra”), which is cleaved at a cleavage site in the extracellular domain immediately distal to the transmembrane domain of the receptor has been observed (Lukic et al., Journal of Autoimmunity, 2003, 21(3): 239-46). Tumor necrosis factor-alpha-converting enzyme (TACE / ADAM17) has been implicated as a protease involved in this process.

[0007] Based on its multifaceted role in the immune system, various therapies designed to modulate IL- 15 -mediated function have been explored. For example, the administration of exogenous IL- 15 can enhance the immune function of patients infected with human immunodeficiency virus (HIV). Despite the amount of progress made in understanding the function of IL- 15, many challenges remain in IL- 15 based therapies, as further discussed infra. As such, there is strong interest in the further development of new IL- 15 based therapeutics.SUMMARY

[0008] The present disclosure discloses a method of treating bladder cancer in a subject in need thereof, comprising administering to the subject an agonistic interleukin 15 (IL- 15) complex comprising: (a) a fusion protein comprising an IL- 15 receptor a sushi domain fused to an Fc monomer, and (b) an IL- 15, wherein the IL- 15 receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6, and the method comprises administering to the human subject an effective amount of 50-1000 pg of the agonistic IL- 15 complex per administration.

[0009] In some embodiments, the subject has a non-muscle invasive bladder cancer (NMIBC).

[0010] In some embodiments, the subject has an intermediate and / or high risk NMIBC.

[0011] In some embodiments, the bladder cancer comprises at least one of stage Ta tumor, stage T1 tumor and / or carcinoma in situ (CIS).

[0012] In some embodiments, the bladder cancer is unresponsive to a Bacillus Calmette Guerin (BCG) therapy (BCG-unresponsive).

[0013] In certain embodiments, the subject has a BCG-unresponsive NMIBC comprising CIS with or without stage Ta tumor and / or stage T1 tumor.

[0014] In certain embodiments, the subject has a BCG-unresponsive NMIBC comprising highgrade Ta and / or T1 tumor.

[0015] In certain embodiments, the subject has never been treated with BCG, or the subject has not been treated with BCG for at least three years prior to the initial administration of the agonistic IL-15 complex, or the subject has a remission of at least 2 years after the last BCG treatment before a recurrence of the cancer.

[0016] In certain embodiments, the subject refuses or is ineligible for radical cystectomy.

[0017] In certain embodiments, the subject has a transurethral resection of bladder tumor (TURBT). In certain embodiments, the subject is clear of stage Ta and stage T1 tumor as shown by cystoscopy at least 12 weeks prior to the initial administration of the agonistic IL- 15 complex.

[0018] In certain embodiments, the subject meets one or more, preferably all, of the following criteria: the subject has a BCG refractory NMIBC, comprising of stage T1 papillary tumors at the initial tumor assessment (at 3 months); or high-grade Ta papillary tumors at enhanced induction phase or after first maintenance treatment phase (after 3 months and / or at 6 months); or CIS (no papillary tumors) at enhanced induction phase or after the first maintenance phase (at 3 months and persists at 6 months); or occurrence of high-grade tumors during the BCG maintenance phase; or the subject has a BCG relapsing NMIBC, with recurrent tumors after BCG therapy, comprising of recurrence of high-grade Ta / Tl papillary tumors within 6 months of completing adequate BCG therapy; or occurrence of CIS within 12 months of completing adequate BCG therapy.

[0019] In certain embodiments, the subject does not meet one or more, preferably all, of the following criteria:a) the subject had previous treatment(s) with IL-2 or IL- 15 agonists, including but not limited to rhIL-15 (NCI), ALT-803 (N-803), NKTR-214 (Nektar); orb) the subject has received any one of the following NMIBC-related treatments previously:has received local pelvic radiotherapy within 2 years before the first dose; orhas received NMIBC-targeted systemic treatment within 12 weeks, such as within 4 weeks, before the first dose, comprising radiotherapy, chemotherapy, immunosuppressive treatment, such as a treatment with an immune checkpoint inhibitor; orhas received transvesical instillation for the treatment of NMIBC, or a local therapy administered via transurethral intravesical delivery (including using a drug-device combination), with the proviso that a single immediate chemotherapy instillation beyond 2 weeks before the first dose, and / or transvesical instillation of mucosal protective agents (such as sodium hyaluronate) are allowed; orhas received surgical treatment for bladder lesions such as TURBT within 2 weeks before the first dose; orc) the subject has received any systemic anti-tumor investigational drugs and / or approved drugs (including drug-device combinations) within 4 weeks before the first dose, which comprises various types of drugs, such as large molecules, small molecules, and / or cell gene therapy;with the proviso that hormone replacement therapy [ HRT], testosterone or oral contraceptives, androgen deprivation therapy (ADT) for prostate cancer, endocrine therapy for breast cancer are allowed; andsubjects who have received radiation therapy within 2 weeks before the first dose, have recovered from all radiation therapy-related toxicities, don’t need corticosteroid treatment, and don’t have radiation pneumonitis are eligible for enrollment; andsubjects who have received Chinese medicines with anti -tumor indications within 2 weeks before the first dose are eligible for enrollment.

[0020] In certain embodiments, the method includes a first induction phase, which comprises administering to the subject an effective amount of the agonistic IL- 15 complex weekly for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks.

[0021] In certain embodiments, the method includes a second induction phase, which comprises administering to the subject an effective amount of the agonistic IL- 15 complex weekly for 3-8consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks. In certain embodiments, the second induction phase starts after the first induction phase, preferably the second induction phase starts about 3 months after the initial administration of the first induction phase.

[0022] In certain embodiments, the method includes a maintenance phase, which comprises administering to the subject an effective amount of the agonistic IL- 15 complex weekly for 2-4 consecutive weeks, such as for 2, 3 or 4 consecutive weeks, preferably for 3 consecutive weeks. In certain embodiments, the maintenance phase starts after the first or second induction phase, preferably the maintenance starts about 3 months after the initial administration of the first or second induction phase.

[0023] In certain embodiments, the method comprises repeating the maintenance phase one or more times. In certain embodiments, the subsequent maintenance phase starts after the previous maintenance phase, preferably the subsequent maintenance starts about 3 months after the initial administration of the previous maintenance phase.

[0024] In certain embodiments, the agonistic IL- 15 complex is administered by intravesical instillation.

[0025] In certain embodiments, the subject has an empty bladder before the intravesical instillation.

[0026] In certain embodiments, the agonistic IL-15 complex stays in the bladder for at least 1 hour, preferably the agonistic IL-15 complex stays in the bladder for 2 hours.

[0027] In certain embodiments, the carboxy 1-terminus of the IL- 15 receptor a sushi domain is fused to the amino-terminus of the Fc monomer via a linker comprising the amino acid sequence of SEQ ID NO: 7.

[0028] In certain embodiments, the linker consists of the amino acid sequence of SEQ ID NO: 8.

[0029] In certain embodiments, the IL-15 comprises the amino acid sequence of SEQ ID NO: 3.

[0030] In certain embodiments, the IL- 15 comprises the amino acid sequence of SEQ ID NO: 4.

[0031] In certain embodiments, the fusion protein comprises the amino acid sequence of SEQ IED NO: 2.

[0032] In certain embodiment, a method of the application further comprises administering to the subject another therapy, such as a BCG therapy. In certain embodiments, the subject is administered with an effective amount of BCG at 40 mg - 150 mg, such as 40, 50 mg, 60 mg, 70mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg per administration of BCG. In some embodiments, the effective amount of BCG is administered via intravesical instillation, such as weekly.

[0033] In certain embodiments, a method of treating bladder cancer in a subject in need thereof, comprises: (1) administering to the subject an effective amount of 50 - 1000 pg, such as 200-800 pg, per administration of an agonistic interleukin 15 (IL- 15) complex comprising: (a) a fusion protein comprising an IL- 15 receptor a sushi domain fused to an Fc monomer and having the amino acid sequence of SEQ ID NO: 1 or 2, and (b) an IL- 15 comprising the amino acid sequence of SEQ ID NO: 3 or 4; and (2) administering to the subject an effective amount of 40-150 mg, such as 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg per administration of a BCG.

[0034] In certain embodiments, the effective amount of IL- 15 complex is safely administered to the subject, as a monotherapy or in combination with another therapy, such as an effective amount of BCG.

[0035] In certain embodiments, the method does not induce Dose Limiting Toxicities (DLT) in the subject.

[0036] In certain embodiments, the method results in an effective treatment of the bladder cancer in the human subject as measured by one or more of Complete Response Rate (CRR), Objective Response Rate (ORR), Duration of Response (DoR), Disease Free Survival (DFS), Relapse Free Survival (RFS), time to cystectomy, radical cystectomy rate, Progression-free Survival (PFS) and Disease Control Rate (DCR).BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.

[0038] FIGs. 1 A-1D show the IL-6 and IFN- y levels in urine samples of patients treated with FL115 monotherapy: FIG. 1 A - IFN- y level on Day 1 (Week 1) of the treatment; FIG. IB -IFN- y level on Day 36 (Week 6) of the treatment; FIG. 1C - IL-6 level on Day 1 (Week 1) of the treatment; FIG. ID - IL-6 level on Day 36 (Week 6) of the treatment;

[0039] FIGs. 2A-2D show the IL-6 and IFN- Y levels in urine samples of patients treated with the combination therapy of FL115 and BCG: FIG. 2A - IFN- Y level on Day 1 (Week 1) of the treatment; FIG. 2B - IFN- Y level on Day 36 (Week 6) of the treatment; FIG. 2C - IL-6 level on Day 1 (Week 1) of the treatment; FIG. 2D - IL- 6 level on Day 36 (Week 6) of the treatment.DETAILED DESCRIPTION

[0040] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set in the specification. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein.

[0042] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0043] Unless otherwise stated, any numerical value, such as a % sequence identity or a % sequence identity range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a dosage of 10 mg includes 9 mg to 11 mg. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0044] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any oneof these options is understood to fall within the meaning and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning and therefore satisfy the requirement of the term “and / or.”

[0045] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0046] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having.”

[0047] When used herein “consisting of’ excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising,” “containing,” “including,” and “having,” whenever used herein in the context of an aspect or embodiment of the invention can be replaced with the term “consisting of’ or “consisting essentially of’ to vary scopes of the disclosure.

[0048] As used herein, the terms “antibody” and “antibodies” refer to molecules that contain an antigen binding site. Antibodies include, but are not limited to, monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, polyclonal antibodies, single domain antibodies, camelized antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked bispecific Fvs (sdFv), intrabodies, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id and anti-anti-Id antibodies to antibodies), and epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and TgA2) or subclass.

[0049] As used herein, the terms “disease” and “disorder” are used interchangeably to refer to a condition affected by IL- 15 signal transduction. In particular, a "disease" and "disorder" can be a pathological condition, and more particularly a disease affected by IL- 15 signal transduction.

[0050] The term “agonist” refers to a compound that binds to a receptor and elicits an agonistic intracellular response. Agonists mimic the effects of endogenous ligands, hormones, and produce physiological responses similar to those produced, for example, by endogenous ligands.

[0051] As used herein, “fragment crystallizable region” or “Fc” refers to a polypeptide containing an antibody heavy chain constant region excluding the first domain of the constant region CHI. Therefore, Fc can include the last two domains of the heavy chain constant region (CH2 and CH3) of an IgA, IgD or IgG antibody, the last three domains of the heavy chain constant region (CH2, CH3 and CH4) of an IgE and IgM antibody. The Fc can also include the flexible hinge region connected to the N-terminus of the CH2 domain. For IgA and IgM, Fc can include the J chain. For IgG, Fc contains immunoglobulin domains Cy2 and Cy3 and the hinge between Cyl and Cy2. Fc plays multiple roles in dimerization for the formation of Y-shaped structure of Ig and maintenance of the structure, and Fc-mediated effector functions and extension of serum half-life. The binding of Fc in IgG to its receptor Fc-gamma receptors (FcyRs) triggers antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis to kill and clear target cells (e.g., tumor cells). The binding of Fc to the serum complement molecule (Clq) can initiate the assembly of membrane attack complex formed by complement cascade proteins to destroy target cells, which is termed complementdependent cytotoxicity (CDC). Besides mediation of effector functions, Fc can also bind to neonatal Fc receptor (FcRn) in a pH-dependent manner, which can result in the extension of the serum half-life of IgG. In addition, binding of Fc to immune-related molecules such as Fc receptors can regulate immune response in vivo. Fc can refer to this region in isolation, or in the context of an antibody, antibody fragment, or Fc fusion. The Fc can be part of an antibody, an Fc fusion, or a protein or protein domain comprising Fc. The naturally occurring Fc forms a homodimer. Particularly preferred are Fc variants, which are non-naturally occurring Fc variants obtained using synthetic biology.

[0052] As used herein, “Fc monomer” or “monomeric Fc” refers to a Fc variant that no longer forms a homodimer under physiological conditions. Examples of Fc monomer include, but are not limited to, Fc monomers described in Wang et al., 2017, Front. Immunol., vol. 8, article1545, WO2022088484A1, and US20210206847, the content of each of which is hereby incorporated by reference in its entirety.

[0053] In some aspects, the Fc monomer of the present disclosure comprises an Fc polypeptide whose molecular weight is only half of the wild-type Fc dimer, and retains the FcRn binding performance and Protein A / G binding performance of the antibody Fc region, and can achieve high-efficiency expression in host cells, such as prokaryotic host cells, and can significantly decrease non-specific binding as compared to previously developed monomeric IgGl Fc mutants.

[0054] As used herein, the term “IL- 15 functional fragment” refers to a portion of IL- 15 that can serve to elicit or induce any degree of biological activity associated with IL-15. Such functional fragments include any mutated IL- 15 of any length and / or any truncated version of IL- 15 that retains a biological activity of IL-15. In some aspects, an IL-15 functional fragment comprises or consists of the sequence of SEQ ID NO: 3. In some aspects, an IL-15 functional fragment comprises or consists of the sequence of SEQ ID NO: 4. In some aspects, an IL-15 functional fragment comprises the sequence of any of the IL-15 sequences described throughout the present application.

[0055] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. “Oligonucleotide,” as used herein, refers to short, generally singlestranded, synthetic polynucleotides that are generally, but not necessarily, fewer than about 200 nucleotides in length. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides. Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5’ to the 5’ end of the RNA transcript are referred to as “upstream sequences”; sequence regions on the DNA strand havingthe same sequence as the RNA transcript that are 3’ to the 3’ end of the RNA transcript are referred to as “downstream sequences.”

[0056] As used herein, “subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been treated by a method according to an embodiment of the present disclosure. The term “mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non- human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human. A human subject can include a patient.

[0057] The terms “polypeptide” and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure may be based upon antibodies or other members of the immunoglobulin superfamily, in certain embodiments, a “polypeptide” can occur as a single chain or as two or more associated chains.

[0058] As used herein, the terms “treat”, “treating” and “treatment” in the context of the administration of a therapy to a subject refer to the beneficial effects that a subject derives from a therapy, such as, but not limited to, the reduction or inhibition of the progression, spread and / or duration of a disease or disorder, the reduction or amelioration of the severity of a disease or disorder, amelioration of one or more symptoms of a disease or disorder, and / or the reduction in the duration of one or more symptom of a disease or disorder resulting from the administration of one or more therapies. In specific embodiments, such terms in the context of cancer include, but are not limited to, one, two, or three or more results following the administration of a therapy to a subject: (1) a reduction in the growth of a tumor or neoplasm; (2) a reduction in the formation of a tumor; (3) an eradication, removal, or control of primary, regional and / or metastatic cancer; (4) a reduction in metastatic spread; (5) a reduction in mortality; (6) an increase in survival rate; (7) an increase in length of survival; (8) an increase in the number of patients in remission; (9) adecrease in hospitalization rate; (10) a decrease in hospitalization lengths; and (11) the maintenance in the size of the tumor so that it does not increase by more than 10%, or by more than 8%, or by more than 6%, or by more than 4%; preferably the size of the tumor does not increase by more than 2%.

[0059] As used herein, the terms “prevent,” “preventing” and “prevention” in the context of the administration of a therapy to a subject refer to the inhibition of the onset or recurrence of a disease or disorder in a subject.

[0060] The phrases “percent (%) sequence identity” or “% identity” or “% identical to” when used with reference to an amino acid sequence describe the number of matches (“hits”) of identical amino acids of two or more aligned amino acid sequences as compared to the number of amino acid residues making up the overall length of the amino acid sequences. In other terms, using an alignment, for two or more sequences the percentage of amino acid residues that are the same (e.g. 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identity over the full-length of the amino acid sequences) may be determined, when the sequences are compared and aligned for maximum correspondence as measured using a sequence comparison algorithm as known in the art, or when manually aligned and visually inspected. The same determination may be made for nucleotide sequences. The sequences which are compared to determine sequence identity may thus differ by substitution(s), addition(s) or deletion(s) of amino acids. Suitable programs for aligning protein sequences are known to the skilled person. The percentage sequence identity of protein sequences can, for example, be determined with programs such as CLUSTALW, Clustal Omega, FASTA or BLAST, e.g., using the NCBI BLAST algorithm (Altschul SF, et al (1997), Nucleic Acids Res. 25:3389-3402).

[0061] As used herein, “cytokine release syndrome” refers to a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and / or other immune effector cells.

[0062] Cytokines of the invention are defined by any factor produced by cells that affect other cells and are responsible for any of multiple effects of cellular immunity. Examples of cytokines include but are not limited to the IL-2 family, interferon (IFN), IL- 10, IL-1, IL- 17, TGF and TNF cytokine families, and to IL-1 through IL-35, IFN-a, IFN-P, IFNy, TGF-P, TNF-a, and TNFp.

[0063] IL- la and IL- lb are secreted by macrophages and neutrophils. RANTES (also named CCL5) enhances antitumor immunity through the recruitment and activation of NK cells.

[0064] Bladder cancer (BCa) is one of the most common cancers in the world and one of the leading cause of death among solid tumors. It includes muscle- invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). NMIBC, also known as superficial bladder cancer, accounts for approximately 70% of newly diagnosed cases of bladder cancer. NMIBC includes various pathological stages, such as stage papillary noninvasive carcinomas (Ta) (confinement to the epithelium or mucosa), stage tumors infiltrating the lamina propria (Tl) (invasion of the subepithelial connective tissue or lamina propria) and carcinomas in situ (CIS) (Tis: Flat, high-grade, non-papillary carcinomas confined to the urothelium). The European Organization for Research and Treatment of Cancer (EORTC) developed risk tables to predict recurrence and progression in patients with NMIBC. Isharwal et al., Indian J Urol. 2015, 31(4): 289-296.

[0065] Radical cystectomy is the gold standard in the treatment of high-risk NMIBC. However, many patients with NMIBC are unwilling or unable to undergo radical cystectomy. The surgery can also result in poor quality of life. The current standard of care for high-risk (HR) NMIBC entails complete endoscopic resection with adjuvant induction and maintenance BCG therapy. BCG can delay recurrence and prolong the progression-free interval after initial tumor resection in patients with NMIBC. It exhibits a nonspecific immune response to reduce tumor burden by increasing the number of natural killer (NK) cells and CD8+T cells and by cytokine secretion, including that of interleukin (IL)-2, IL-12, IL-18, and interferon-gamma (INF-y). The risk of NMIBC tumor recurrence is very high. Around 40% of patients with HR NMIBC ultimately will experience treatment failure. In some embodiment, the subject has a BCG-unresponsive bladder cancer, many patients experience relapses and eventually develop resistance to BCG (i.e., they show no response). Such patients have to undergo cystectomy, which has a 9% mortality rate, have a poor quality of life, and bear high costs. Therefore, new therapies are urgently needed to prevent disease progression and allow bladder retention to maintain the patient’s quality of life.

[0066] As used herein, a bladder cancer that is “unresponsive to a BCG therapy,” “BCG-unresponsive” bladder cancer, “BCG refractory” bladder cancer, or “BCG resistant” bladder cancer, each refers to a bladder cancer that does not respond to a BCG therapy such that no improved outcome is observed after the bladder cancer is treated with the BCG therapy. In some embodiment, a subject has a BCG- unresponsive NMIBC. In some embodiments, a BCG-unresponsive NMIBC can have at least one of the following characteristics: (1) high-grade (HG) T1 disease at the first evaluation after induction BCG alone, (2) recurrent HG Ta / Tl disease within 6 months of completion of adequate BCG therapy, or (3) persistent or recurrent CIS alone with or without HG Ta / Tl disease within 12 months of completion of adequate BCG therapy. An adequate BCG therapy can include at least 5 or 6 induction doses and at least 2 of 3 maintenance or 2 of 6 second induction doses of the BCG treatment. See, e.g.,www. fda. gov / media / 101468 / download.

[0067] In some embodiment, a subject has a BCG-unresponsive NMIBC comprising CIS with or without stage Ta tumor and / or stage T1 tumor. In some embodiment, a subject has a BCG-unresponsive NMIBC comprising high-grade Ta and / or T1 tumor, but not CIS. In some embodiment, a subject responded to previous BCG treatment, but the bladder cancer recurred, and the subject is no longer responsive to BCG treatment or the subject is responsive to BCG treatment but the treatment is less effective than the previous BCG treatment.

[0068] As used herein, the term “induction phase” refers to an initial course of therapy with an agonistic IL- 15 complex described herein. According to embodiments of the application, an induction phase comprises a dosing period, wherein an effective amount of an agonistic IL- 15 complex described herein is administered to the subject once every week for3-8 consecutive weeks, such as for3 , 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks. In one embodiment, a method of the application comprises a single induction phase. In another embodiment, a method of the application comprises more than one induction phases, such as two induction phases.

[0069] As used herein, the term “maintenance phase” refers to a dosing period after the completion of one or more induction phases, where further doses of an agonistic IL- 15 complex described herein is administered. The effective amount and the dosing regimen administered in the maintenance phase can be the same or different from that used in the induction phase. In some embodiments, the maintenance phase is initiated in a subject who exhibits a complete response to the induction phase treatment. For example, a subject who exhibits no histological evidence of cancer or high-grade of cancer following the induction phase has exhibited a complete response to the induction phase. In some embodiments, subjects that enter the study with low grade T1 disease and do not experience a recurrence of T1 disease or do not have evidence of high-grade disease following the induction phase enter the maintenance phase. Insome embodiments, a subject who relapses with low-grade papillary tumor continues maintenance phase following tumor removal, unless the subject had low-grade T1 disease and relapses with low-grade T1 disease. For example, the maintenance phase is initiated in a subject who had high-grade Ta and exhibits a low-grade Ta after the induction phase treatment. Subjects with histologically confirmed evidence of high-grade disease following the induction phase will not enter the maintenance phase. In certain embodiments, maintenance therapy continues until disease recurrence (i.e., the subject recurs with histologically-confirmed CIS or high-grade papillary Ta or T1 disease, or low-grade T1 if that was the baseline disease) or disease progression (histologically-confirmed disease stage >T2), cystectomy, 24 or 36 months from start of study, or death, whichever comes first. The grades of disease can be evaluated using methods known in the art, such as biopsy. In one embodiment, a method of the application comprises a single maintenance phase. In another embodiment, a method of the application comprises more than one maintenance phase, such as two maintenance phases. In some embodiments, the effective amount of an agonistic IL- 15 complex is administered to the subject once every week for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks. In some embodiments, the effective amount of an agonistic IL- 15 complex is administered to the subject once every week for 3 consecutive weeks. In some embodiments, the effective amount of an agonistic IL-15 complex is administered to the subject once every week for 6 consecutive weeks.

[0070] The term “no evidence of high-grade disease,” as used herein, includes at least one of the following: a) normal cystoscopy and non-positive or non-suspicious urine cytology, or a negative biopsy or a biopsy revealing only low-grade papillary tumor; b) negative biopsy (or biopsy revealing only low-grade papillary tumor) and non-positive repeat urine cytology; or c) cystoscopy or biopsy revealing only low-grade papillary tumor that may be managed by transurethral resection of the bladder tumor (TURBT), and not requiring cystectomy.

[0071] As used herein, the term “recurrence” refers to the return of histologically-confirmed bladder cancer. CIS or high-grade papillary TA or T1 disease. As used herein, “time to disease recurrence” is defined as the interval from the date of the first documented no histological evidence of high-grade disease to the date of first recurrence of histologically-confirmed highgrade disease. In some embodiments, the time to disease recurrence in a subject that received oris receiving the immunoconjugate provided herein is delayed relative to the time to disease recurrence that would occur in a subject that received other available intravesicular therapy.

[0072] As used herein, the term “disease progression” refers to histologically-confirmed disease at a stage at or above the stage determined prior to the treatment. As used herein, “time to progression” is defined as the time from the date of first dose of the agonistic IL-15 complex to the date of histologically confirmed, invasive disease of stage > T2. In some embodiments, a method of the application delays the time to disease progression relative to the time to disease progression that would occur in a subject that had not received the agonistic IL-15 complex.

[0073] The application generally relates to a method of treating bladder cancer in a subject in need thereof, comprising administering to the subject an agonistic interleukin 15 (IL- 15) complex comprising: (a) a fusion protein comprising an IL- 15 receptor a sushi domain fused to an Fc monomer, and (b) an IL-15, wherein the IL-15 receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6, the method comprising administering to the human subject an effective amount of 50 -1000 pg of the agonistic IL-15 complex per administration.

[0074] A human IL-15, e.g., a 12-14 kD cytokine, was discovered by Grabstein et al. in 1994. It can play a role in the body’s normal immune response, such as promoting the proliferation of T cells, B cells and NK cells. It has been demonstrated that IL- 15 could be a useful therapeutic alternative treatment or combination treatment. For instance, IL- 15 has a more biased NK cell activation activity than IL-2. In addition, IL-2 stimulates the proliferation of Treg in addition to the proliferation of killer immune cells, and these Treg suppress the immune response, leading to a diminished antitumor effect. In contrast, the specific receptor for IL- 15 is IL-15Ra (CD 125), which does not activate Treg cells. Therefore, from the perspective of being an immune activator, IL- 15 has significant advantages over IL-2 and is expected to become a new generation of anti-tumor immune activator for 70-80% of tumor patients who do not respond to PD-1 monoclonal antibody, relying on its unique NK cell activation ability, with great market potential. As used herein, the term “IL- 15” encompasses a full-length IL- 15 or an IL- 15 functional fragment. An “IL-15” can be a wild-type IL-15 or a variant IL-15.

[0075] In spite of its potential, the wild-type IL- 15 has an extremely short half-life in vivo and very limited efficacy. In addition, IL- 15 has a trans delivery mechanism, and effective IL- 15 therapeutics need to consider the formation of complexes between IL- 15 and IL-15Ra, whichposes great difficulties. In addition to the short half-life and poor pharmacokinetics as factors limiting its clinical application, increasing the dosage of IL- 15 can also induce a cytokine storm, leading to strong toxic side effects, thereby greatly limiting its clinical dosage level. Therefore, improved IL- 15 therapies are of high interest and of great value.

[0076] The present disclosure generally relates to using a protein complex, i.e., an agonistic IL-15 complex, comprising an IL 15 and a monomeric IL- 15 receptor aSu / Fc fusion protein for treating bladder cancer, particularly NMIBC. The agonistic IL- 15 complexes described herein have a long half-life, have demonstrated good safety profiles, and have demonstrated higher antitumor activity as compared to other IL- 15 based treatments.

[0077] In certain embodiments, the fusion protein comprises an interleukin- 15 (IL-15) receptor a sushi domain fused to an Fc monomer, wherein the IL- 15 receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the carboxyl-terminus of the IL-15 receptor a sushi domain is fused to the amino-terminus of the Fc monomer via a linker comprising the amino acid sequence of GGGGS (SEQ ID NO: 7), such as a linker consisting of the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8. In certain embodiments, the fusion protein comprises or consists of the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the fusion protein comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0078] In some aspects, the IL- 15 receptor a sushi domain of the present disclosure comprises the extracellular domain of IL- 15 receptor a starts from the cysteine residue (Cl) encoded by the first exon 2 and ends at the fourth exon. The cysteine residue (C4), residues Cl and C4 encoded by sub-2 are all contained in the sushi domain. The amino acid sequence of the a sushi domain of IL- 15 receptor formed by the substitution, deletion or addition of one or more amino acid residues and having corresponding activity is also included in the present disclosure.

[0079] In some embodiments, the IL- 15 comprises a functional IL- 15 fragment having or consisting of the amino acid sequence of SEQ ID NO: 3. In some other embodiments, the IL-15 comprises a functional IL- 15 fragment having or consisting of the amino acid sequence of SEQ ID NO: 4.

[0080] In some embodiments, the agonistic IL- 15 complex enhances the tumor-killing activities of NK cells and CD8+T cells. In certain embodiments, the agonistic IL- 15 complex stimulates NK cells and CD8+T cells via the activation of IL-15Ra, IL-2RP (also named CD 122), and IL-2Ry (also named CD132), which share receptors with IL-2, IL-4, IL-7, IL-9, and IL-21, and thereby reduces tumor burden. In certain embodiments, the agonistic IL- 15 complex enhances the proliferation and activation of NK cells by stimulating the secretion of IL- la, IL- lb, and RANTES, which are Thl cytokines. In certain embodiments, the agonistic IL- 15 complex allows transpresentation selectively to only IL-2R0 and IL-2Ry chain of NK cells and CD8+T cells, without biding to Tregs, thus avoiding severe side effects. In certain embodiments, the agonistic IL- 15 complex has a longer half-life. In certain embodiments, the agonistic IL- 15 complex has surprisingly good tissue distribution. In certain embodiments, the agonistic IL- 15 complex has a small size.

[0081] In some embodiments, the agonistic IL- 15 complex has one or more of the following characteristics: 1) it binds tightly to FcRn under low pH conditions in lysosomes, protecting itself from degradation and extending its half-life time; 2) it does not bind to Fey receptors and Clq, and does not have ADCC or CDC activities; 3) it does not bind to the CD32a receptor and does not have ADCP activity; and / or 4) it stimulates immune cells (such as increases the CD8+T cell, CD4+T cell, and NK cell counts in a dose-dependent manner), which in turn kills tumor cells.

[0082] FL115 (also named FL115-V2), an agonistic interleukin 15 complex useful in an embodiment of the application, contains a monomeric IL- 15 receptor aSu / Fc fusion protein having the amino acid sequence of SEQ ID NO: 2 and a mutant IL15 having the amino acid sequence of SEQ ID NO: 3.

[0083] In some embodiments, FL115 can be administered once a week or weekly (QW), alone or together with BCG, 2-12 times per treatment phase. In some embodiments, the treatment phase is up to 12 weeks.

[0084] In some embodiments, the method comprises administering to the human subject an effective amount of 50 pg to 1000 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 50 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 75 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 100 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the humansubject an effective amount of 125 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 150 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 175 pg of the agonistic IL- 15 complex per administration.

[0085] In certain embodiments, the method comprises administering to the human subject an effective amount of 200 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 250 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 300 pg of the agonistic IL-15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 350 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 400 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 450 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 500 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 550 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 600 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 650 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 700 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 750 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 800 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 850 pg of the agonistic IL-15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 900 pg of theagonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 950 pg of the agonistic IL- 15 complex per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 1000 pg of the agonistic IL- 15 complex per administration.

[0086] In some embodiments, the agonistic interleukin 15 (IL- 15) complex composition is administered systemically, intravenously, subcutaneously, intramuscularly, intravesically, or by instillation.

[0087] In certain embodiments, the agonistic IL- 15 complex is administered intravesically. In certain embodiments, the agonistic IL- 15 complex is administered subcutaneously. In certain embodiments, the agonistic IL- 15 complex is administered by instillation. In certain embodiments, the agonistic IL- 15 complex is administered intravenously. In certain embodiments, the agonistic IL- 15 complex is administered by intravesical instillation.

[0088] In some embodiments, for the treatment of bladder cancer, the agonistic IL- 15 complex is administered by instillation into the bladder. Methods of instillation are known. See, for example, Lawrencia, et al., Gene Ther 8, 760-8 (2001); Nogawa, et al., J Clin Invest 115, 978-85 (2005); Ng, et al., Methods Enzymol 391, 304-13 2005; Tyagi, et al., J Urol 171, 483-9 (2004); Trevisani, et al., J Pharmacol Exp Ther 309, 1167-73 (2004); Trevisani, et al., Nat Neurosci 5, 546-51 (2002)); (Segal, et al., 1975). (Dyson, et al., 2005). (Batista, et al., 2005; Dyson, et al., 2005). In certain embodiments, the agonistic IL-15 complex dosage for instillation can vary from about 50 and 1000 pg / dose. In other embodiments the intravesical doses of the agonistic IL- 15 complex can be 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 pg / dose, or any dose in between.

[0089] In certain embodiments, the agonistic IL- 15 complex is administered with other therapies. In certain embodiments, the agonistic IL- 15 complex is administered by instillation into the bladder in combination with other therapies, including but not limited to mitomycin C or Bacille Calmette-Guerin (BCG). In some embodiments, the agonistic IL-15 complex is administered in combination with any conventional therapy, including but not limited to, surgery, radiation therapy, chemotherapy, protein-based therapy or biological therapy. In some embodiments, the agonistic IL- 15 complex and the other therapy (or therapies) are administered simultaneously or sequentially. In certain embodiments, the agonistic IL- 15 complex and the other therapy (ortherapies) are administered simultaneously. In certain embodiments, the agonistic IL- 15 complex and the other therapy (or therapies) are administered sequentially.

[0090] In certain embodiments, the agonistic IL-15 complex is administered weekly. As used herein, “weekly” refers to every 7 days ± 1 day. In certain embodiments, the agonistic IL- 15 complex is administered more than once per week. In certain embodiments, the agonistic IL-15 complex is administered less frequently than weekly.

[0091] In some embodiments, the agonistic IL-15 complex is administered to the subject 1 to 60 times. In certain embodiments, the agonistic IL-15 complex is administered to the subject 1 to 30 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 3 to 27 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 6 to 27 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 3 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 6 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 9 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 12 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 15 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 18 times. In certain embodiments, the agonistic IL-15 complex is administered to the subject 21 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 24 times. In certain embodiments, the agonistic IL- 15 complex is administered to the subject 27 times.

[0092] In certain embodiments, the agonistic IL- 15 complex is administered to the subject weekly 3 times per treatment cycle. In certain embodiments, the agonistic IL- 15 complex is administered to the subject weekly 4 times per treatment cycle. In certain embodiments, the agonistic IL-15 complex is administered to the subject weekly 5 times per treatment cycle. In certain embodiments, the agonistic IL- 15 complex is administered to the subject weekly 6 times per treatment cycle.

[0093] In some embodiments, the agonistic IL- 15 complex is administered to the subject for 1 to 15 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 1 treatment cycle. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 2 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 3 treatment cycles. In certain embodiments, theagonistic IL-15 complex is administered to the subject for 4 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 5 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 6 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 7 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 8 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 9 treatment cycles. In certain embodiments, the agonistic IL-15 complex is administered to the subject for 10 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 11 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 12 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 13 treatment cycles. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 14 treatment cycles. In certain embodiments, the agonistic IL-15 complex is administered to the subject for 15 treatment cycles. In some embodiments, there are time gaps between treatment cycles.

[0094] In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 1 treatment cycle during the induction phase. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 2 treatment cycles during the induction phase. In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 3 treatment cycles during the induction phase.

[0095] In certain embodiments, the agonistic IL- 15 complex is administered to the subject for 0 treatment cycle during the enhanced induction phase. In certain embodiments, the agonistic IL-15 complex is administered to the subject for 1 treatment cycle during the enhanced induction phase. In certain embodiments, the agonistic IL-15 complex is administered to the subject for 2 treatment cycles during the enhanced induction phase.

[0096] In some embodiments, the agonistic IL- 15 complex is administered to the subject for 0 to 12 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 0 treatment cycle during the maintenance phase. In some embodiments, the agonistic IL-15 complex is administered to the subject for 1 treatment cycle during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 2 treatment cycles during the maintenance phase. In some1embodiments, the agonistic IL- 15 complex is administered to the subject for 3 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 4 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 5 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 6 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 7 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 8 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 9 treatment cycles during the maintenance phase. In some embodiments, the agonistic IL- 15 complex is administered to the subject for 10 treatment cycles during the maintenance phase.

[0097] In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 1, week 2, week 3, week 4, week 5, and week 6, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 13, week 14, and week 15, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 16, week 17, and week 18, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 28, week 29, and week 30, once a week. In some embodiments, the agonistic IL-15 complex is administered to the subject on week 41, week 42, and week 43, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 53, week 54, and week 55, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 79, week 80, and week 81, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on week 105, week 106, and week 107, once a week. In some embodiments, the agonistic IL- 15 complex is administered to the subject on weeks by any combinations of above weeks. The weeks for administering the agonistic IL- 15 complex can be modified depending on patients’ health conditions.

[0098] In some embodiments, the human subject has a solid tumor prior to the initial administration of the effective amount of the agonistic IL- 15 complex. In some embodiments, the tumor is a solid tumor, such as a carcinoma, a sarcoma, or a melanoma. In some embodiments, the solid tumor is selected from the group consisting of a bladder cancer, a lungcancer, a breast cancer, a colorectal cancer, a brain tumor, a prostate cancer, urothelial carcinoma, cholangiocarcinoma, a melanomas, a merkel cell carcinoma, a head and neck cancer, a small bowel cancer, a squamous cell carcinoma, metastatic solid tumor or a cervical cancer. In certain embodiments, the tumor is a bladder cancer. In certain embodiments, the tumor is a lung cancer, such as a non-small cell lung cancer (NSCLC). In certain embodiments, the tumor is a head and neck cancer. In certain embodiments, the tumor is a pancreatic cancer. In certain embodiments, the tumor is urothelial carcinoma. In certain embodiments, the tumor is a colorectal cancer. In certain embodiments, the tumor is incurable, unresectable, locally advanced or metastatic cancer that is refractory to standard therapies.

[0099] In certain embodiments, the cancer is Bladder cancer (BCa). In certain embodiments, the non-muscle-invasive bladder cancer (NMIBC) is tumors infiltrating the lamina propria (Tl). In certain embodiments, the non-muscle-invasive bladder cancer (NMIBC) is carcinomas in situ (CIS). In certain embodiments, the non-muscle-invasive bladder cancer (NMIBC) is papillary noninvasive carcinomas (Ta).

[0100] In certain embodiments, the human subject has a non-muscle-invasive bladder cancer (NMIBC) prior to the initial administration of the effective amount of the agonistic IL- 15 complex. In certain embodiments, the human subject has a BCG-unresponsive (BCGu) NMIBC. In certain embodiments, the human subject with non-muscle-invasive bladder cancer (NMIBC) is unwilling to undergo cystectomy. In certain embodiments, the human subject with non-muscle-invasive bladder cancer (NMIBC) is unable to undergo cystectomy. In certain embodiments, the subjects have BCG-unresponsive NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumor. In some embodiments, the subjects have BCG-unresponsive NMIBC with high-grade Ta / Tl papillary tumors. In some embodiments, the subjects have BCG-unresponsive NMIBC with high-grade Ta / Tl papillary tumors without CIS. In some embodiments, the subjects have BCG-naive NMIBC, including carcinoma in situ (CIS) or Ta / Tl papillary tumors.

[0101] BCG-naive disease as defined as either of the following: subjects have not received prior intravesical BCG; or previously received BCG, but stopped receiving more than 3 years before date of randomization.

[0102] In certain embodiments, the methods for treating cancer in a subject are carried out by administering to the subject a pharmaceutical composition comprising the agonistic IL- 15complex. In certain embodiments, the methods for treating cancer in a subject are carried out by administering to the subject BCG and a pharmaceutical composition comprising the agonistic IL-15 complex. In certain embodiments, the methods for treating cancer in a subject are carried out by administering to the subject a pharmaceutical composition comprising the agonistic IL- 15 complex and other therapies.

[0103] In some embodiments, the method comprises administering to the human subject an effective amount of 50 mg to 200 mg of BCG per administration. In some embodiments, the method comprises administering to the human subject an effective amount of 40 mg to 150 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 40 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 50 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 60 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 80 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 100 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 120 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 150 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 160 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 180 mg of BCG per administration. In certain embodiments, the method comprises administering to the human subject an effective amount of 200 mg of BCG per administration. This dosage amount may be adjusted upward or downward, as is routinely done in such treatment protocols, depending on the results of the initial clinical trials and the needs of a particular patient.

[0104] In some embodiments, BCG is administered systemically, intravenously, subcutaneously, intramuscularly, intravesically, or by instillation. In certain embodiments, BCG is administered intravesically. In certain embodiments, BCG is administered subcutaneously. In certain embodiments, BCG is administered by instillation. In certain embodiments, BCG isadministered intravenously. In certain embodiments, BCG is administered by intravesical instillation.

[0105] In some embodiments, the agonistic IL- 15 complex and BCG are administered simultaneously or sequentially. In certain embodiments, the agonistic IL- 15 complex and BCG are administered simultaneously. In certain embodiments, the agonistic IL- 15 complex and BCG are administered sequentially.

[0106] In certain embodiments, the BCG is administered weekly, bi-monthly, or monthly. In some embodiments, the BCG is administered weekly. As used herein, “weekly” refers to every 7 days ± 1 day.

[0107] In some embodiments, the BCG is administered to the subject for 1 to 15 treatment cycles. In certain embodiments, the BCG is administered to the subject for 1 treatment cycle. In certain embodiments, the BCG is administered to the subject for 2 treatment cycles. In certain embodiments, the BCG is administered to the subject for 3 treatment cycles. In certain embodiments, the BCG is administered to the subject for 4 treatment cycles. In certain embodiments, the BCG is administered to the subject for 5 treatment cycles. In certain embodiments, the BCG is administered to the subject for 6 treatment cycles. In certain embodiments, the BCG is administered to the subject for 7 treatment cycles. In certain embodiments, the BCG is administered to the subject for 8 treatment cycles. In certain embodiments, the BCG is administered to the subject for 9 treatment cycles. In certain embodiments, the BCG is administered to the subject for 10 treatment cycles. In certain embodiments, the BCG is administered to the subject for 11 treatment cycles. In certain embodiments, the BCG is administered to the subject for 12 treatment cycles. In certain embodiments, the BCG is administered to the subject for 13 treatment cycles. In certain embodiments, the BCG is administered to the subject for 14 treatment cycles. In certain embodiments, the BCG is administered to the subject for 15 treatment cycles. In some embodiments, there are time gaps between treatment cycles.

[0108] In some embodiments, the BCG is administered to the subject during the induction phase. In some embodiments, the BCG is administered to the subject during the enhanced induction phase. In some embodiments, the BCG is administered to the subject during the maintenance phase. In some embodiments, the BCG is administered to the subject during any combinations of above phases.

[0109] In some embodiments, the BCG is administered to the subject for 1 treatment cycle during the induction phase. In some embodiments, the BCG is administered to the subject for 2 treatment cycles during the induction phase. In some embodiments, the BCG is administered to the subject for 3 treatment cycles during the induction phase.

[0110] In some embodiments, the BCG is administered to the subject for 0 treatment cycle during the enhanced induction phase. In some embodiments, the BCG is administered to the subject for 1 treatment cycle during the enhanced induction phase. In some embodiments, the BCG is administered to the subject for 2 treatment cycles during the enhanced induction phase.

[0111] In some embodiments, the BCG is administered to the subject for 0 to 12 treatment cycles during the maintenance phase. In some embodiments, the BCG is administered to the subject for 0 treatment cycle during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 1 treatment cycle during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 2 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 3 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 4 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 5 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 6 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 7 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 8 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 9 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 10 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 11 treatment cycles during the maintenance phase. In certain embodiments, the BCG is administered to the subject for 12 treatment cycles during the maintenance phase.

[0112] In certain embodiments, the BCG is administered to the subject 1 time per treatment cycle. In certain embodiments, the BCG is administered to the subject 2 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 3 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 4 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 5 times per treatmentcycle. In certain embodiments, the BCG is administered to the subject 6 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 7 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 8 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 9 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 10 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 11 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 12 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 13 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 14 times per treatment cycle. In certain embodiments, the BCG is administered to the subject 15 times per treatment cycle.

[0113] In some embodiments, the BCG is administered to the subject on week 1, week 2, week 3, week 4, week 5, and week 6, once a week. In some embodiments, the BCG is administered to the subject on week 7, week 9, and week 11, once every two weeks. In some embodiments, the BCG is administered to the subject on months 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, once a month. In certain embodiments, the BCG is administered to the subject on month 4, once a month. In certain embodiments, the BCG is administered to the subject on month 5, once a month. In certain embodiments, the BCG is administered to the subject on month 6, once a month. In certain embodiments, the BCG is administered to the subject on month 7, once a month. In certain embodiments, the BCG is administered to the subject on month 8, once a month. In certain embodiments, the BCG is administered to the subject on month 9, once a month. In certain embodiments, the BCG is administered to the subject on month 10, once a month. In certain embodiments, the BCG is administered to the subject on month 11, once a month. In certain embodiments, the BCG is administered to the subject on month 12, once a month.

[0114] In some embodiments, the BCG is administered to the subject on months 3, 6, 12, 18, 24, and 36, weekly for three weeks in that month. In certain embodiments, the BCG is administered to the subject on month 3, weekly for three weeks in that month. In certain embodiments, the BCG is administered to the subject on month 6, weekly for three weeks in that month. In certain embodiments, the BCG is administered to the subject on month 12, weekly for three weeks in that month. In certain embodiments, the BCG is administered to the subject on month 18, weekly for three weeks in that month. In certain embodiments, the BCG isadministered to the subject on month 24, weekly for three weeks in that month. In certain embodiments, the BCG is administered to the subject on month 36, weekly for three weeks in that month.

[0115] The weeks and months for administering the BCG can be of any combination of above. The weeks and months for administering the BCG can be modified depending on patients’ health conditions.

[0116] In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 1, week 2, week 3, week 4, week 5, and week 6, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 13, week 14, and week 15, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 16, week 17, and week 18, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 28, week 29, and week 30, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 41, week 42, and week 43, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 53, week 54, and week 55, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 79, week 80, and week 81, once a week. In some embodiments, the agonistic IL- 15 complex and BCG are administered to the subject on week 105, week 106, and week 107, once a week. The weeks for administering the agonistic IL- 15 complex and BCG can be modified depending on patients’ health conditions.

[0117] In some embodiments, treatment of human patients or other animals is carried out using a therapeutically effective amount of a therapeutic identified herein in a physiologically -acceptable carrier. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin. The amount of the therapeutic agent to be administered varies depending upon the manner of administration, the age and body weight of the patient, and with the clinical symptoms of the neoplasia or infection. Generally, amounts will be in the range of those used for other agents used in the treatment of other diseases associated with bladder cancer.

[0118] In some embodiments, the administration of the agonistic IL- 15 complex for the treatment of bladder cancer may be by any suitable means that results in a concentration of thetherapeutic that, combined with other components, is effective in ameliorating, reducing, or stabilizing the cancer.

[0119] In some embodiments, pharmaceutical compositions are formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the therapeutic in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes. The agonistic IL- 15 complex may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for parenteral (e.g., subcutaneously, intravenously, intramuscularly, intravascularly or intraperitoneally) administration route. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

[0120] In some embodiments, compositions comprising the agonistic IL- 15 complex for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules, syringes or bags), or in vials containing several doses and in which a suitable preservative may be added. The composition may be in the form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. In some embodiments, the concentration of composition comprising the agonistic IL- 15 complex is 1 mL.

[0121] In some embodiments, a kit is provided for the treatment of cancer, the kit comprising an effective amount of the agonistic IL- 15 complex, and directions for the use of the kit for the treatment of cancer. Kits or pharmaceutical systems according to this aspect of the invention comprise a carrier means, such as a box, carton, tube, having in close confinement therein one or more container means, such as vials, tubes, ampoules, bottles, syringes, or bags.

[0122] As used herein, “safely administering" refers to an administration of an agonistic interleukin 15 (IL-15) complex to a human subject that does not result in an adverse event unacceptable to a regulatory agency. In certain embodiments, the method does not result in a treatment-related serious adverse event. Adverse events (AEs) include any adverse events thatcause Dose-limiting Toxicity, cytokine release syndrome (CRS), neurotoxicity, hematological toxicity including neutropenia, thrombocytopenia, and anemia, ocular toxicity, encephalopathy, myocarditis, fatigue that lasting over 7 days, nausea, vomiting, or diarrhea that persists for > 72 hours despite the use of optimal medical therapy, elevations in amylase or lipase, 4 electrolyte abnormalities that do not respond to replacement therapy and that persist for > 48 hours, endocrinopathies, including hypothyroidism and adrenal insufficiency, that cannot be adequately supplemented with hormone replacement therapy, rash with ulceration or bullae formation that does not resolve within 7 days, and hypertension that does not respond to medical therapy within 24 hours. As used herein, “serious adverse event” or “SAE” is defined as any adverse experience that meets any of the following criteria: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization (additionally, complications occurring during hospitalization are also considered AEs); results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; important medical events that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. As used herein, “suspected unexpected serious adverse reactions (SUS AR)” is defined as when an adverse event is unexpected, serious, and may be related to the clinical trial drug, it can be regarded as a suspected unexpected serious adverse reaction. “Unexpected” refers to the nature, specificity, severity or outcome of an adverse event that exceeds the existing information such as the investigator’s manual of the clinical trial drug and / or the instructions for the marketed drug. The main adverse reactions of BCG intravesical administration include bladder irritation, hematuria, influenza-like syndrome, and fever.Dose-limiting Toxicity (DLT)

[0123] In certain embodiments, the method does not induce Dose Limiting Toxicities (DLT) in the subject. As used herein, “dose-limiting toxicity” or “DLT” refers to the occurrence of any adverse events that are at least possibly related to the study drug.

[0124] As used herein, dose-limiting toxicity will be evaluated during Cycle 1 (21 days) of treatment. Adverse events that occur after Cycle 1 will be considered when determining whether the dose should be escalated.

[0125] Adverse events, other than those associated with CRS and related neurotoxicity events, will be graded according to the NCI CTCAE version 5.0. For AEs associated with CRS and neurotoxicity events, the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading will be used. (Lee et. al., 2019)

[0126] Dose-limiting toxicity is defined as the occurrence of any of the following adverse events that are, as determined by the Investigator, at least possibly related to the study drug.

[0127] Bladder Local Adverse Events

[0128] Bladder local adverse events are Grade 3 or 4 bladder toxicity lasting more than 1 week. Bladder toxicity is usually characterized by severe symptoms that are not relieved by standard medical treatments, such as dysuria, urinary urgency, urinary frequency, and / or frequent urination, obvious hematuria leading to urethral obstruction, bladder spasm, urinary incontinence, etc.

[0129] Hematological Toxicity

[0130] Hematologic toxicity is defined as:• Febrile neutropenia, defined as: neutrophil count <0.5-1.0xl09 / L, and a single body temperature >38.3 °C or continuous body temperature >38°C for more than 1 hour• Grade 4 anemia lasting > 7 days despite adequate medical intervention• Grade 4 neutropenia lasting > 7 days despite adequate medical intervention• Grade 4 thrombocytopenia that persists for >3 days despite adequate medical intervention• Grade 3 thrombocytopenia with clinically significant bleeding (i.e., requiring hospitalization, transfusion of blood products, or other emergency medical intervention)

[0131] Non-hematological Toxicity

[0132] Grade 4 non-hematological toxicity or any Grade 3 non-hematologic toxicity AEs with the following exceptions:• Grade 3 fatigue lasting no more than 7 days• Grade 3 nausea, vomiting, or diarrhea that persists for no more than 3 days despite medical treatment.• Grade 3 rash with ulceration or bullae formation that lasts no more than 7 days.• Grade 3 endocrinopathies, including hypothyroidism and adrenal insufficiency, that can be treated with hormone replacement therapy.• Grade 3 or 4 hypertension that responds to medical therapy within 24 hours.• Cytokines Releasing Syndromes (CRS) symptoms that are relieved within 3 days of medical treatment.

[0133] Any Grade 3 or Grade 4 non-hematology abnormal laboratory result that meets the following criteria:• Clinically significant medical intervention is needed, and the abnormality lasts more than 7 days• Abnormalities leading to hospitalization.• Abnormalities leading to drug-induced liver injury (DILI): serum ALT or AST > 3 x ULN, accompanied by an increase in serum total bilirubin > 2 x ULN; without evidence of cholestasis (ALP > 2 x ULN); and after excluding other potential causes of concurrent elevations in ALT / AST and total bilirubin (e.g., viral hepatitis, excessive alcohol [ethanol] consumption, etc.).• Any deaths, except disease progression, with known underlying cause, and unrelated to study drugs.

[0134] In addition to the safety data collected during the dose- finding phase of the study, the occurrence of late toxicity (i.e., safety data from all patients for up to 30 days from the last dose of FL115) will be considered in the determination of the RP2D and schedule to be taken forward into the cohort expansion phase of the study.MTD / MAD / RP2D

[0135] The maximum tolerated dose (MTD) is defined as the highest dose level at which < 1 out of 6 patients experience DLT during the DLT observation period. During the DLT observation period, if the number of patients with DLT in a dose group is > 2 out of 6 patients, then this dose level exceeds the MTD and is considered the maximum tolerated dose (MAD), and the dose escalation will be terminated. If the MTD is not reached at the tested maximum dose of 800 pg / dose, then the MAD would be 800 pg / dose or a higher dose that can continue to be escalated after a comprehensive evaluation by SMC.

[0136] If the terminated dose is the lowest dose group, additional dose levels may be added below this (e.g., < 200 pg / dose). If the terminated dose level is not the lowest dose group, the previous dose level will be expanded to 6 patients and will define the MTD if < 1 of 6 patients experiences a DLT.

[0137] The Recommended Phase 2 Dose (RP2D) will be determined based on the SMC’s evaluation of the study data, including safety and tolerance / PK / PD / preliminary anti-tumor activity, etc. More than one dose may be selected as RP2D.

[0138] Progressive disease that is not complicated by other adverse events should not be reported as an SAE.Assessments and AnalysisPharmacokinetics

[0139] Blood samples will be collected at specific time points from all patients to determine the serum concentration FL115 using a validated immunoassay for PK analyses. The actual time of each blood collection will be recorded. After preparation, samples will be stored at -70°C before shipment to the laboratories.

[0140] The main PK parameters will be calculated using a noncompartmental model using WinNonlin (version 6.4 or above) software to comprehensively reflect the characteristics of drug absorption, distribution, metabolism, and excretion in humans. The main PK parameters will be: AUC, Cmax, Tmax, t'A, Vss, CL, etc. Descriptive statistical analysis will be performed for PK parameters in different dose groups or cohorts, and arithmetic mean, standard deviation, coefficient of variation, median, maximum, minimum values and geometric mean of PK parameters will be calculated for each dose group or cohort.

[0141] According to the PK data, the concentration data will be tabulated and descriptive statistics will be performed based on dose group, for the Phase I dose escalation phase. The mean and median drug concentration versus time curves (linear and semi-logarithmic) at planned blood collection times will be plotted. If data permits, the PK parameters, including but not limiting to AUCo-last, Cmax, Ctrough, Tmax, ti / 2, CL / F, Va / F, etc will be calculated. The relationship between the main PK parameters (such as AUC, Cmax, etc.) and the dose ratio will be explored. In addition, descriptive statistics of PK parameters will be performed based on dose level. Descriptive statistics will include the number of cases, arithmetic mean, standard deviation, coefficient of variation (CV%), and minimum and maximum values. AUCo-iastand Cmax, Ctrough will also provide geometric mean and geometric CV%. Depending on the available urine data, the drug recovery rate in the urine 0-4 hours after administration will be evaluated based on the urine volume, theoretical dosage, and detected drug concentration.Immunogenicity

[0142] Blood samples for analysis of the incidence and titer of anti-drug antibodies (AD As) to FL115 will be collected at the scheduled time points. Samples with an increased titer to FL115 will be assessed for the presence of neutralizing antibodies (Nabs).

[0143] The changes of ADA and NAb produced by patients after treatment will be assessed. The potential immunogenicity of FL115 will be assessed by summarizing the number according to dose cohorts and percentage of patients with detectable AD As. The impact of AD As on PK will be assessed if data permit. Samples will be collected for later evaluation of neutralizing capacity for AD As.

[0144] If data permits, the incidence of anti-FLl 15 antibodies will be summarized. The key PK, safety, and efficacy data will be collected and analyzed, based on dose level / cohort in ADApositive and -negative populations, to evaluate the association of ADA with PK, safety, and efficacy.Pharmacodynamics and Biomarker

[0145] For pharmacodynamic analyses of NK cells, T cells (CD8, CD4, Treg), macrophages, monocytes, etc., and cytokines (interferon gamma, GM-CSF, IL-1, IL-2, IL-6, IL- 12, IL- 18 and TNF-a), PD-L1 and serum PD-1, blood samples will be collected and analyzed.

[0146] If data permits, changes of cytokines (including IL-2, IL-4, IL-6, IL-8, IL- 10, IL- 13, IL-1 P, IL-12p70, TNFa, IFN-y, etc.) before and after administration will be summarized and evaluated. Relationship between peripheral blood and urine cytokine levels and FL115 singleagent exposure, safety and efficacy will also be gathered and assessed.

[0147] If applicable, predictive biomarkers such as PD-L1 expression status, percentage of CD56 / CD4 / CD8 / panck-positive cells, or other potentially relevant biomarker assays (DNA, RNA, or proteomics), and their correlation with efficacy, will be explored, summarized, and evaluated.Anti-tumor Response

[0148] The Phase I secondary objectives and Phase II primary objectives of this study are to evaluate the preliminary antitumor activity of FL115.

[0149] The efficacy endpoints include: complete response rate (CRR) at any time point; CRR at 3 / 6 / 12 / 15 / 18 / 21 / 24 / 30 / 36 months; duration of response (DoR, for CIS only); 6 / 12 / 18 / 24 / 30 / 36-month disease-free survival (DFS) rate; disease-free survival time (DFS, for Ta or T1 without CIS); time to cystectomy; and rate of radical cystectomy.

[0150] Within the first two years following the initial intravesical instillation, cystoscopy and urine cytology examinations will be performed every 3 months; starting from year 3, they will be conducted every 6 months. TURBT / biopsy will be performed as clinically indicated.

[0151] Upper urinary tract evaluation will be conducted annually, with additional assessments as needed during the study.

[0152] Urine Cytology

[0153] Urine and / or bladder irrigation fluid samples will be collected, processed, and analyzed at the study center for cytological examination. At least 30 mL of voided urine or bladder irrigation fluid is required. If cytology results become positive or suspicious for malignancy after initiation of study treatment, the subject will undergo a bladder biopsy.

[0154] If urine cytology is positive or suspicious, bladder biopsy is required. Any suspicious lesion should be biopsied. If the site of the suspected lesion cannot be identified, random biopsies should be taken from the trigone, dome, right and left lateral walls, and posterior wall. In addition, subjects with a history of CIS should undergo a biopsy of the prostatic urethra.

[0155] If all bladder biopsies are negative, an upper urinary tract evaluation is recommended.

[0156] Cystoscopy

[0157] Subjects undergo cystoscopic examination according to the study center’s standard operating procedure. It is recommended that the light source type (white light / blue light / narrow-band imaging) remain consistent with that used during the screening period.

[0158] During diagnostic cystoscopy, the investigator should perform a comprehensive inspection of the entire urethra and bladder (including the prostate in males) to assess and record tumor size, location, morphology, number, and mucosal abnormalities, as well as bladder filling status.

[0159] After completion, the bladder should be re-examined after partial emptying to confirm absence of residual tumor. Recommended procedural steps include: insert a flexible or rigid cystoscope under direct vision into the urethra and guide it into the bladder; use sterile saline for visualization and bladder irrigation (which may also be used for urine cytology assessment); identification of key landmarks — ureteral orifices and the bladder dome — is essential; systematically examine the bladder; identify the trigone, bladder neck, and both ureteral orifices. Examine the bladder base and posterior wall and identify the dome; examine both lateral walls(right and left); examine the prostatic urethra for abnormalities; and / or examine the entire urethra systematically.

[0160] If cystoscopy suggests malignancy, bladder biopsy is required. If a mass or abnormality is detected, bladder biopsy must be performed.

[0161] Transurethral Resection of Bladder Tumor (TURBT) / Biopsy: endoscopic TURBT is performed to resect papillary (Ta and Tl) lesions. CIS areas may be treated with cauterization or fulguration.

[0162] Screening Period: Confirm diagnosis of Ta / Tl or CIS based on urine cytology, cystoscopy, and biopsy. For Tl disease, postoperative pathology must demonstrate presence of detrusor muscle. If muscle is absent, a second resection at the original tumor site should be performed 2-6 weeks after initial TURBT, and pathology must confirm presence of muscle tissue and absence of invasive disease.

[0163] Treatment Period: All CIS subjects must undergo biopsy at Week 12. CIS subjects receiving enhanced induction therapy must undergo biopsy at Month 6.

[0164] If urine cytology is positive or suspicious but cystoscopy is normal, bladder biopsy is recommended. If no visible lesion is identified, random biopsies should be taken from the trigone, dome, right and left lateral walls, and posterior wall.

[0165] Ta / Tl subjects should undergo TURBT; for Tl or high-grade high-risk Ta tumors, repeat TURBT within 6 weeks (preferably 4 weeks) is recommended.

[0166] Upper Urinary Tract Evaluation: upper tract evaluation should include the following options, with CT urography (CTU) as the preferred method; alternatives may be used as appropriate: CTU (CT urography, preferred); MRU (MR urography) — recommended for patients with iodine contrast allergy, renal insufficiency, or other contraindications to CT contrast; non-contrast CT — if neither CTU nor MRU can be performed.Tumor Response Evaluation.

[0167] Definition of Complete Response (CR): CR is defined as meeting any of the following criteria: (1) Negative urine cytology and negative cystoscopy; @ Negative urine cytology with positive cystoscopy but biopsy shows benign or low-grade Ta lesion; (3) Negative cystoscopy with positive urine cytology indicating upper tract or prostatic urethral origin, and random bladder biopsies are negative.31

[0168] Definition of Disease-Free Survival (DFS): DFS is defined as absence of any of the following events: (1) High-grade Ta (excluding low-grade Ta); @ Any T1 lesion; (3) Persistent CIS > 6 months; (4) New CIS; (5) Disease progression to muscle-invasive disease (> T2), lymph node metastasis (N+), or distant metastasis (Ml); @ Cystectomy; @ Change of treatment (e.g., systemic chemotherapy or radiotherapy) indicating disease progression; or ® Death from any cause after the first intravesical instillation.Statistical Analysis

[0169] After the trial protocol is finalized, the statistical analysis plan (SAP) will be developed by the statistician. Statistical analysis will be descriptive in nature and will be performed using SAS statistical software. Measurement data will be described using mean, standard deviation, median, maximum, and minimum values. Categorical data will be described using frequency, or constituent ratio (%).Efficacy Analyses

[0170] In certain embodiments, the method results in an effective treatment of the solid tumor in the human subject as measured by, e.g., one or more of Complete Response Rate (CRR) at any time, CRR on any or all month(s) of 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, Objective Response Rate (ORR), Duration of Response (DoR), Disease Free Survival (DFS) at any time, DFS on any or all month(s) of 6, 12, 18, 24, 30, 36, Relapse Free Survival (RFS), time to cystectomy, radical cystectomy rate, Progression-free Survival (PFS) and Disease Control Rate (DCR).

[0171] Definition of Complete Response Rate (CRR) at any time:a. Phase I: The proportion of subjects whose best overall response is complete response (CR) at any time point, divided by the total number of subjects in the full analysis set or in the efficacy-evaluable population.b. Phase II: The proportion of subjects whose best overall response is CR at any time point, calculated separately for Cohorts 1 and 3, divided by the number of efficacy-evaluable subjects with CIS in each respective cohort.The 95% exact confidence interval will be calculated using the Clopper-Pearson method, if data permit.

[0172] Definition of Duration of Response (DoR): DoR is defined as the time interval from the first assessment of CR to the date when the subject no longer meets the criteria for CR. Themedian DoR and its 95% confidence interval will be estimated, if data permit, and the Kaplan-Meier (KM) method will be used to generate the survival curve.

[0173] As used herein, “objective response rate” or “ORR” is the percentage of people in a study or treatment group who have a partial response (PR) or complete response (CR) to the treatment within a certain period of time. As used herein, “complete response” is a disappearance of all target lesions. As used herein, “partial response” is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0174] Tumor response (objective response rate [ORR] and disease control rate [DCR]) will be evaluated according to iRECIST or RECIST 1.1; duration of response (DOR) and progression-free survival (PFS) will also be evaluated.Complete Response (CR)

[0175] Complete response (CR) is defined as the lack of detectable evidence of tumor. It is also called complete remission. Imaging studies and / or histopathology are normally used to measure CR.

[0176] For patients with NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumors, CR includes but is not limited to any one of the following: negative urine cytology; negative cystoscopy; negative urine cytology, with positive cystoscopy and biopsy result of benign or low-grade Ta; and negative cystoscopy, with positive urine cytology but suggesting tumor in the upper urinary tract or prostatic urethra, and negative random bladder biopsy.Complete Response Rate (CRR)

[0177] A complete response rate (CRR) is the percentage of patients who show no evidence of cancer after treatment. If data permits, the Clopper-Pearson method will be used to calculate the 95% confidence interval.

[0178] For patients with NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumors, CRR during Phase I clinical trial refers to the percentage of patients who show no evidence of cancer after treatment, compared to the total analysis population or the number of people whose efficacy can be evaluated. For patients with NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumors, CRR during Phase II clinical trial refers to the percentage of patients who show no evidence of cancer after treatment, compared to the number of subjects in cohort 1 and cohort 3 who can be evaluated for the efficacy of CIS treatment.Objective Response Rate (ORR)

[0179] Objective response rate (ORR) is a measure of how a specific treatment impacts tumor burden in a patient with a history of solid tumors. It is defined as the proportion of patients that respond either partially or fully to therapy.Duration of Response (DoR)

[0180] The duration of overall response will be evaluated by dose cohort and overall response. The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or confirmed progression (iCPD) is objectively documented.

[0181] iCPD is confirmed if further increase in tumour burden, compared to the last assessment. iCPD is a category that does not meet criteria for iUPD but meets the criteria for RECIST 1.1 progression. Prefix “i” indicates immune responses assigned using iRECIST. iUPD is defined as unconfirmed progression.

[0182] In some embodiments, DoR refers to the time from when the subject is first evaluated as CR to when the treatment efficacy no longer meets the CR definition. The Kaplan-Meier (KM) method will be used to plot a curve, estimate the median CR duration, and calculate the 95% confidence interval, if data permits.Disease Free Survival (DFS)

[0183] Disease- free survival (DFS) is defined as the time from randomization until evidence of disease recurrence. In some embodiments, Disease- free survival (DFS) is defined as the time from the start of treatment until disease recurrence or progression. The KM method will be used to plot a curve, estimate the median disease-free survival time, and calculate the 95% confidence interval, if data permits.

[0184] For patients with NMIBC high-grade Ta / Tl papillary tumors without CIS, disease-free is defined as the absence of any of the following since the start of treatment: recurrence of highgrade Ta (except low-grade Ta); any grade Tl; CIS persisting for 6 months; new CIS; disease progression (progression to > T2, N+ or Ml); radical cystectomy; change of treatment method (including systemic chemotherapy or radiotherapy, etc.) suggesting disease progression or death from any cause.

[0185] For patients with NMIBC high-grade Ta / Tl papillary tumors without CIS, the disease-free survival rate (DFS rate) is defined as the percentage of subjects from the start of treatment to the disease recurrence / progression compared to the number of safety population or the number ofefficacy evaluable population. For the primary efficacy endpoint of Phase II, the 12-month DFS rate, is defined as the proportion of subjects with disease recurrence / pr egression at 12 months after the start of treatment to the Ta / Tl efficacy evaluable population in cohort 2 and cohort 3, respectively. KM analysis method will be used to provide estimations and its 95% confidence interval, if data permits.Relapse Free Survival (RFS)

[0186] For patients with NMIBC high-grade Ta / Tl papillary tumors without CIS, relapse-free survival (RFS) is defined as the time from the start of treatment until disease recurrence (such as high-grade Ta recurrence, any grade Tl, or new CIS). The KM method will be used to plot a curve, estimate the median recurrence-free survival, and calculate the 95% confidence interval, if data permits.Time to Cystectomy

[0187] The time to cystectomy surgery is defined as the time from the start of treatment to the time the subject undergoes cystectomy surgery. The time to cystectomy surgery will be drawn using the KM method, the median time to cystectomy surgery will be estimated, and the 95% confidence interval will be calculated, if data permits.Radical Cystectomy Rate

[0188] Radical cystectomy rate is defined as the proportion of subjects who underwent radical cystectomy surgery. The analysis method of radical cystectomy rate is the same as the above CRR analysis method. If data permits, the Clopper-Pearson method will be used to calculate its 95% confidence interval.Progression-free Survival (PFS)

[0189] PFS will be evaluated by dose cohort and overall response using Kaplan-Meier methods. The KM method will be used to draw the curve, estimate the median disease- free survival time, and calculate the 95% confidence interval, if data permits. PFS is defined as the time from the date of first treatment to the date of iCPD or death (any cause) whichever occurs first. Patients who do not have disease progression or have not died at the end of follow up will be censored at the last known date the patient was progression free.Overall survival (OS)

[0190] Overall survival (OS) is defined as the time from the start of treatment to death. The analysis method of OS is the same as the PFS analysis method mentioned above.Disease Control Rate (DCR)

[0191] Disease control rate (DCR) is a percentage that measures the number of patients who achieve tumor relief or stable disease after treatment for advanced or metastatic cancer. Disease control rate (DCR) describes the percentage of patients with advanced cancer whose therapeutic intervention has led to a complete response, partial response, or stable disease. DCR is related to ORR and has the greatest utility in evaluating cancer therapies that have predominating tumoristatic effects rather than tumoricidal effects.Objective Tumor Response and Disease Control Rate

[0192] The percentage of patients who achieve an objective confirmed complete or partial overall tumor response using iRECIST-informed RECIST 1.1 or RECIST 1.1 will be evaluated by dose cohort and overall response. The 95% confidence interval of the response rate will be evaluated. Disease control (confirmed response or SD lasting for at least 6 months) will be analyzed in a similar manner.

[0193] Traditional 3 + 3 dose-escalation rules in clinical trial:• Three patients will be enrolled for each dose cohort.• If none of the initial 3 patients experiences a DLT at that dose level, dose escalation will move to the next cohort.• If > 2 of the initial 3 patients experience a DLT, dose escalation will stop, and the dose level will be lowered.• If 1 of the initial 3 patients experiences a DLT, 3 additional patients will be enrolled for the cohort or dose escalation will be stopped.• If none of the additional 3 patients experiences a DLT, escalation to the next cohort will proceed.• If > 1 of the additional 3 patients experience a DLT, dose escalation will stop, and the dose level will be lowered.• If a certain dose level exceeds the MTD, 3 more subjects will be enrolled at the previous lower dose level (if 6 subjects have been enrolled, there is no need to enroll additional subjects). If the DLT incidence rate among the 6 patients tested at this dose level is < 1 / 6, this dose level is regarded as MTD.• The above escalation / stop rules also apply to subsequent dose level escalations.SEQUENCE LISTINGNumbered Embodiments

[0194] Subject matter described in this application includes, but is not limited to, the following numbered embodiments:1. A method of treating bladder cancer in a subject in need thereof, comprising administering to the subject an agonistic interleukin 15 (IL-15) complex comprising: (a) a fusion protein comprising an IL-15 receptor a sushi domain fused to an Fc monomer, and (b) an IL- 15, wherein the IL- 15 receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6, and the method comprises administering to the human subject an effective amount of 50 -1000 pg of the agonistic IL-15 complex per administration.2. The method of embodiment 1, wherein the subject has a non- muscle invasive bladder cancer (NMIBC).3. The method of embodiment 2, wherein the subject has an intermediate and / or high risk NMIBC.4. The method of any of the foregoing embodiments, wherein the bladder cancer comprises at least one of stage Ta tumor, stage T1 tumor and carcinoma in situ (CIS).5. The method of any of the foregoing embodiments, wherein the bladder cancer is unresponsive to a Bacillus Calmette Guerin (BCG) therapy (BCG-unresponsive).6. The method of embodiment 5, wherein the subject has a BCG-unresponsive NMIBC comprising CIS with or without stage Ta tumor and / or stage T1 tumor.7. The method of embodiment 5, wherein the subject has a BCG-unresponsive NMIBC comprising high-grade Ta and / or T1 tumor.8. The method of any of embodiments 1-3, wherein1) the subject has never been treated with a BCG therapy,2) the subject has not been treated with a BCG therapy for at least three years prior to the initial administration of the agonistic IL- 15 complex, or3) the subject has a remission of at least 2 years after the last BCG treatment before a recurrence, optionally, there is evidence of complete response within two years after BCG treatment.9. The method of any of the foregoing embodiments, wherein the subject is refused or ineligible for radical cystectomy.The method of any of the foregoing embodiments, wherein the subject has a transurethral resection of bladder tumor (TURBT), preferably the subject is clear of stage Ta and stage T1 tumor as shown by cystoscopy at least 12 weeks prior to the initial administration of the agonistic IL- 15 complex.The method of embodiment 1, wherein the subject has BCG-unresponsive high-grade NMIBC, preferably the subject has BCG refractory NMIBC, which comprises of stage T1 papillary tumors detected at the initial tumor assessment (at 3 months); or high-grade Ta papillary tumors detected at enhanced induction phase or after first maintenance phase (after 3 months and / or at 6 months); or CIS (no papillary tumors) detected at the enhanced induction phase or after the first maintenance phase (detects at 3 months and persists at 6 months); or occurrence of high-grade tumors during the BCG maintenance phase; or BCG relapsing NMIBC, with recurrent tumors after adequate BCG therapy, comprising of recurrence of high-grade Ta / Tl papillary tumors within 6 months of completing adequate BCG therapy; or occurrence of CIS within 12 months of completing adequate BCG therapy.The method of any one of the foregoing embodiments, wherein the subject does not meet one or more, preferably all, of the following criteria:1) previous anti-tumor treatments:a) Patients who previously received IL-2 or IL- 15 agonist therapies, including but not limited to rhIL-15 (NCI), ALT-803 (N-803), and NKTR-214 (Nektar);b) Patients who have previously received any of the following NMIBC-related treatments:• extensive pelvic radiotherapy (irradiation of >30% of bone marrow area) within 2 years prior to the first dose;• systemic treatments intended for NMIBC (including radiotherapy, chemotherapy, immune checkpoint inhibitors, etc.) within 4 weeks prior to the first dose;• transvesical instillation or other local intravesical treatments (including drugdevice combinations) for NMIBC within 4 weeks prior to the first dose; however, a single immediate post-operative intravesical chemotherapy instillation performed more than 2 weeks prior to the first dose is allowed, andintravesical instillation of mucosal protective agents (e.g., sodium hyaluronate) is also permitted; and / or• surgical interventions for bladder lesions such as TURBT within 2 weeks prior to the first dose;) Other previous treatments and recovery from medication toxicities:a) Patients with known or suspected hypersensitivity to FL115 or its excipients; patients with a history of Grade 3-4 allergic reactions to interleukin-based therapies or fusion proteins; patients with known or suspected hypersensitivity or significant intolerance to BCG (applicable to Phase lb and II);b) Patients who received systemic immunomodulatory therapy within 4 weeks prior to the first dose, except for any of the following:• corticosteroids at a dose equivalent to <10 mg / day of prednisone;• topical, inhaled, or intranasal corticosteroids;• adrenal replacement steroid therapy at a dose equivalent to <7.5 mg / day of prednisone;• prophylactic one-time corticosteroid use for contrast-agent allergy prior to imaging procedures;c) Patients with a history of allogeneic organ transplantation or allogeneic PBSC / bone marrow transplantation;d) Patients who have received live attenuated vaccines within 4 weeks prior to the first dose;e) Patients who experienced Grade >3 immune-related adverse events (irAEs) or irAEs leading to discontinuation of immunotherapy. Exceptions include: previous hypothyroidism, type 1 diabetes, or dermatologic irAEs (excluding Stevens- Johnson syndrome, toxic epidermal necrolysis, or other severe dermatitis); and / or f) Patients whose adverse events from prior anti-tumor treatments have not resolved to baseline or <Grade 1 (according to NCI CTCAE v5.0 or ASTCT) prior to the first dose. Exceptions include: alopecia (any grade), peripheral sensory neuropathy (<Grade 2), hypothyroidism well controlled with hormone replacement therapy, or other situations explicitly permitted by inclusion / exclusion criteria. Subjects with other AEs <Grade 2 may be enrolled ifdeemed appropriate by the investigator after consultation with the sponsor’s medical representative;) Past medical and surgical history:a) Patients with a history or current presence of muscle-invasive disease (T2-T4), locally advanced disease (T3 / T4, any N), or metastatic bladder cancer;b) Patients with concomitant upper urinary tract malignancies (renal pelvis, ureter, kidney) or prostatic urethral tumors. Subjects with Ta / Tl / CIS of the upper tract who have undergone curative nephroureterectomy more than 2 years prior to first dose may be considered eligible. Subjects with low-grade Ta disease of the prostatic urethra may be eligible. Tumor involvement of prostatic ducts is not permitted regardless of histology;c) Patients with documented vesicoureteral reflux or bladder perforation;d) Patients with confirmed urinary tract infection — particularly bladder infection — or gross hematuria judged by the investigator to be unsuitable for study entry.Subjects whose infection can be controlled with antibiotics and resolve after discontinuation of antibiotics may be eligible;e) Patients who discontinued prior BCG therapy due to BCG-related sepsis, infection requiring systemic therapy, urinary incontinence, or other BCG-related adverse reactions (applicable to Phase lb and II);f) Patients who developed post-TURBT complications that, in the investigator’s judgment, preclude intravesical instillation therapy;g) Patients with clinically significant polyuria (documented 24-hour urine output >4,000 mL);h) Patients with other malignancies that have progressed or required active treatment within 2 years prior to screening. Subjects with curatively treated localized cancers (such as basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) may be eligible; gastrointestinal tumors limited to the mucosa and completely removed via endoscopy are allowed; low-risk prostate cancer under active surveillance may be eligible per investigator assessment;i) Patients with active autoimmune disease or a history of autoimmune disease requiring systemic steroids or immunosuppressive therapy, including but notlimited to rheumatoid arthritis, systemic lupus erythematosus, Wegener’s granulomatosis, Sjogren’s syndrome, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, myositis, autoimmune hepatitis, vasculitis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, and glomerulonephritis. Exceptions include endocrine disorders manageable with hormone replacement therapy (e.g., hypothyroidism, type 1 diabetes, adrenal or pituitary insufficiency);j) Patients with any of the following pulmonary toxicities:• severe clinically significant pulmonary disease within 12 weeks prior to the first dose, including but not limited to pulmonary embolism, severe asthma, severe COPD, idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or drug-induced pneumonitis;• active interstitial lung disease (ILD) or interstitial pneumonia;• a history of ILD or non-infectious pneumonitis requiring corticosteroids or other immunosuppressive therapy;k) Patients with evidence of active tuberculosis infection within 1 year prior to screening, or a remote history of active tuberculosis without evidence of adequate treatment;l) Patients with uncontrolled pleural effusion, pericardial effusion, or ascites (e.g., requiring repeated drainage more than once per month), as judged by the investigator, m) Patients with clinically significant cardiovascular disease, including but not limited to: myocardial infarction, uncontrolled angina, viral myocarditis, stroke, or other Grade >3 cardiovascular / cerebrovascular events within 6 months prior to the first dose; any supraventricular or ventricular arrhythmias requiring intervention; congestive heart failure of NYHA Class III / IV; uncontrolled hypertension [systolic BP >160 mmHg and / or diastolic BP >100 mmHg despite standard therapy, or history of hypertensive crisis or encephalopathy]; and / orn) Patients who have undergone major surgery within 4 weeks prior to signing the informed consent form;4) Past history of infectious diseases:a) Patients with severe infections within 4 weeks prior to the first dose, including but not limited to bacteremia requiring hospitalization or severe pneumonia; or patients with active infections of CTCAE Grade >2 requiring systemic antibiotics within 1 week before first dose. Subjects may be re-screened after complete resolution of infection. Exceptions include localized bacterial (e.g., skin), localized viral, or localized fungal infections not requiring systemic therapy; b) Patients with any known history of active HBV, HCV, HIV infection, or active tuberculosis:• Non-active HBV-infected subjects may be eligible if they meet the following:controlled HBV infection (>4 weeks of antiviral therapy prior to screening and HBV DNA <1000 copies / mL or <200 ZU / mL at screening). Subjects on antiviral therapy should continue treatment during the study; and / or • Evidence of active HCV infection is defined as: positive HCV antibody test together with positive HCV RNA test;5) Other situations:a) Pregnant or breastfeeding women;b) Patients with known, documented, or suspected drug abuse requiring exclusion.Exceptions include: opioid analgesics prescribed by physicians. Enrollment may be permitted if clinically justified per investigator judgment and after discussion with the sponsor’s medical representative; and / orc) Any other condition that, in the investigator’s judgment, renders the subject unsuitable for participation in the study.The method of any one of the foregoing embodiments, comprising a first induction phase, which comprises administering to the subject an effective amount of the agonistic IL- 15 complex weekly for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks.The method of embodiment 13, further comprising a second induction phase, which comprises administering to the subject an effective amount of the agonistic IL-15 complex weekly for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks, wherein the second induction phase startsafter the first induction phase, preferably the second induction phase starts about 3 months after the initial administration of the first induction phase.. The method of embodiment 13 or 14, further comprising a maintenance phase, which comprises administering to the subject an effective amount of the agonistic IL-15 complex weekly for 2-4 consecutive weeks, such as for 2, 3 or 4 consecutive weeks, preferably for 3 consecutive weeks, wherein the maintenance phase starts after the first or second induction phase, preferably the maintenance phase starts about 3 months after the initial administration of the first or second induction phase.. The method of embodiment 15, further comprising repeating the maintenance phase one or more times, wherein the subsequent maintenance phase starts after the previous maintenance phase, preferably the subsequent maintenance starts about 3 months after the initial administration of the previous maintenance phase.. The method of any one of the foregoing embodiments, wherein the agonistic IL- 15 complex is administered by intravesical instillation.. The method of embodiment 17, wherein the subject has an empty bladder before the intravesical instillation.. The method of embodiment 17 or 18, wherein the agonistic IL- 15 complex stays in the bladder for at least 1 hour, preferably the agonistic IL- 15 complex stays in the bladder for 2 hours.. The method of any one of the foregoing embodiments, wherein the effective amount is 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 pg of the agonistic IL-15 complex per administration.a. The method of embodiment 20, wherein the effective amount is 200 pg of the agonistic IL- 15 complex per administration.b. The method of embodiment 20, wherein the effective amount is 300 pg of the agonistic IL- 15 complex per administration.c. The method of embodiment 20, wherein the effective amount is 400 pg of the agonistic IL- 15 complex per administration.d. The method of embodiment 20, wherein the effective amount is 500 pg of the agonistic IL- 15 complex per administration.e. The method of embodiment 20, wherein the effective amount is 600 pg of the agonisticIL- 15 complex per administration.f. The method of embodiment 20, wherein the effective amount is 700 pg of the agonistic IL- 15 complex per administration.g. The method of embodiment 20, wherein the effective amount is 800 pg of the agonistic IL- 15 complex per administration.h. The method of embodiment 20, wherein the effective amount is 900 pg of the agonistic IL- 15 complex per administration.i. The method of any one of embodiments 20-2h, wherein the effective amount of the agonistic IL- 15 complex is administered weekly.j . The method of any one of embodiments 20-2i, wherein the effective amount of the agonistic IL- 15 complex is administered by intravesical instillation.. The method of any one of embodiments 15-20j, wherein the same effective amount is used in the induction phase and the maintenance phase.. The method of any one of embodiments 15-20j, wherein the effective amount used in the maintenance phase is different from that of the induction phase.. The method of any one of the foregoing embodiments, wherein the carboxy 1-terminus of the IL-15 receptor a sushi domain is fused to the amino-terminus of the Fc monomer via a linker.. The method of embodiment 23, wherein the linker comprises the amino acid sequence of SEQ ID NO: 7.. The method of embodiment 24, wherein the linker consists of the amino acid sequence of SEQ ID NO: 8.. The method of any one of the foregoing embodiments, wherein the IL- 15 comprises the amino acid sequence of SEQ ID NO: 3.. The method of any one of embodiments 1-25, wherein the IL- 15 comprises the amino acid sequence of SEQ ID NO: 4.. The method of any one of embodiments 1-23, wherein the fusion protein comprises the amino acid sequence of SEQ IED NO: 2.. The method of any of the foregoing embodiments, further comprising administering to the subject another therapy, such as a BCG therapy.a. The method of embodiment 29, further comprising administering to the subject aneffective amount of a BCG.0. The method of embodiment 29a, wherein the effective amount of BCG is 120 mg per administration.0a.The method of embodiment 29a, wherein the effective amount of BCG is 50-150 mg per administration.0b. The method of embodiment 29a, wherein the effective amount of BCG is 50 mg per administration.0c. The method of embodiment 29a, wherein the effective amount of BCG is 60 mg per administration.0d.The method of embodiment 29a, wherein the effective amount of BCG is 70 mg per administration.0e.The method of embodiment 29a, wherein the effective amount of BCG is 80 mg per administration.0f.The method of embodiment 29a, wherein the effective amount of BCG is 90 mg per administration.0g. The method of embodiment 29a, wherein the effective amount of BCG is 100 mg per administration.Oh. The method of embodiment 29a, wherein the effective amount of BCG is 110 mg per administration.0i.The method of embodiment 29a, wherein the effective amount of BCG is 130 mg per administration.0j. The method of any one of embodiments 30-30i, wherein the effective amount of the agonistic IL- 15 complex is administered weekly.0k.The method of any one of embodiments 30-30j, wherein the effective amount of BCG is administered by intravesical instillation.1. A method of treating bladder cancer in a subject in need thereof, comprising:(1) administering to the subject an effective amount of 50 - 1000 pg per administration of an agonistic interleukin 15 (IL- 15) complex comprising: (a) a fusion protein comprising an IL-15 receptor a sushi domain fused to an Fc monomer and having the amino acid sequence of SEQ ID NO: 1 or 2, and (b) an IL-15 comprising the amino acid sequence of SEQ ID NO: 3 or 4; and(2) administering to the subject an effective amount of 40-150 mg per administration of a BCG.1a. The method of embodiment 31 , wherein the effective amount of 200 pg per administration of the agonistic IL- 15 complex was administered to the subject once every week via intravesical instillation.1b. The method of embodiment 31, wherein the effective amount of 400 pg per administration of the agonistic IL- 15 complex was administered to the subject once every week via intravesical instillation.1c. The method of embodiment 31 , wherein the effective amount of 600 pg per administration of the agonistic IL- 15 complex was administered to the subject once every week via intravesical instillation.1 d. The method of embodiment 31 , wherein the effective amount of 800 pg per administration of the agonistic IL- 15 complex was administered to the subject once every week via intravesical instillation.1 e. The method of embodiment 31 , wherein the effective amount of 1000 pg per administration of the agonistic IL- 15 complex was administered to the subject once every week via intravesical instillation.If. The method of any one of embodiments 31-31e, wherein the effective amount of 50 mg per administration of the BCG was administered to the subject once every week via intravesical instillation.1g. The method of any one of embodiments 31-31e, wherein the effective amount of 80 mg per administration of the BCG was administered to the subject once every week via intravesical instillation.1h. The method of any one of embodiments 31-31e, wherein the effective amount of 100 mg per administration of the BCG was administered to the subject once every week via intravesical instillation.1 i. The method of any one of embodiments 31-31e, wherein the effective amount of 120 mg per administration of the BCG was administered to the subject once every week via intravesical instillation.Ij . The method of any one of embodiments 31-31e, wherein the effective amount of 150 mg per administration of the BCG was administered to the subject once every week via intravesical instillation.1k. The method of any one of embodiments 31 -3 Ij, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 1 and the IL- 15 comprises the amino acid sequence of SEQ ID NO: 3.11. The method of any one of embodiments 31 -3 Ij, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 2 and the IL-15 comprises the amino acid sequence of SEQ ID NO: 3.Im. The method of embodiment 31 , comprising:(1) administering to the subject the effective amount of 400 pg per administration of the agonistic IL- 15 complex comprising: (a) the fusion protein having the amino acid sequence of SEQ ID NO: 1, and (b) the IL-15 comprising the amino acid sequence of SEQ ID NO: 3; and(2) administering to the subject an effective amount of 120 mg per administration of the BCG.In. The method of embodiment 31 , comprising:(1) administering to the subject the effective amount of 800 pg per administration of the agonistic IL- 15 complex comprising: (a) the fusion protein having the amino acid sequence of SEQ ID NO: 1, and (b) the IL-15 comprising the amino acid sequence of SEQ ID NO: 3; and(2) administering to the subject an effective amount of 120 mg per administration of the BCG.1o.The method of embodiment 31, comprising:(1) administering to the subject the effective amount of 400 pg per administration of the agonistic IL- 15 complex comprising: (a) the fusion protein having the amino acid sequence of SEQ ID NO: 2, and (b) the IL-15 comprising the amino acid sequence of SEQ ID NO: 3; and(2) administering to the subject an effective amount of 120 mg per administration of the BCG.Ip. The method of embodiment 31, comprising:(1) administering to the subject the effective amount of 800 pg per administration of the agonistic IL- 15 complex comprising: (a) the fusion protein having the amino acid sequence of SEQ ID NO: 2, and (b) the IL-15 comprising the amino acid sequence of SEQ ID NO: 3; and(2) administering to the subject an effective amount of 120 mg per administration of the BCG.q. The method of any one of embodiments 31 -3 Ip, wherein the subject has a non-muscle invasive bladder cancer (NMIBC).r. The method of embodiment 31 q, wherein the subject has an intermediate and / or high risk NMIBC.s. The method of embodiment 31q, wherein the subject has a BCG-unresponsive NMIBC comprising high-grade Ta and / or T1 tumor.. The method of any of the foregoing embodiments, wherein the method does not induce Dose Limiting Toxi cities (DLT) in the subject.. The method of any of the foregoing embodiments, wherein the method results in an effective treatment of the solid tumor (bladder cancer) in the human subject as measured by one or more of Complete Response Rate (CRR), Objective Response Rate (ORR), Duration of Response (DoR), Disease Free Survival (DFS), Relapse Free Survival (RFS), time to cystectomy, radical cystectomy rate, Progression-free Survival (PFS) and Disease Control Rate (DCR).. The method of any one of the foregoing embodiments, wherein the method does not result in a treatment related serious adverse event.a. The method of any one of the foregoing embodiments, wherein the effective amount of the IL- 15 complex is safely administered to the subject, as a monotherapy or in combination with another therapy, such as in combination with the effective amount of BCG.. An agonistic interleukin 15 (IL- 15) complex for use in a method of any of the foregoing embodiments, wherein the complex comprises: (a) a fusion protein comprising an IL- 15 receptor a sushi domain fused to an Fc monomer, and (b) an IL-15, wherein the IL-15receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6.EXAMPLESExample 1: Half Maximal Effective Concentration (ECso) of FL115 Against Multiple Cell Lines

[0195] When the effect target ratio (peripheral blood mononuclear cell (PBMCs) counts over tumor cell counts) is 20:1, the in vitro half maximal effective concentration ofFL115 (ECso) against T24-Luc cell lines, NCI-H460-Luc cell lines, and SW480-Luc cell lines are 0.0002884 pg / mL, 0.0006258 pg / mL, and 0.0003695 pg / mL, respectively.

[0196] When the effect target ratio (peripheral blood mononuclear cell (PBMCs) counts over tumor cell counts) is 5:1, the in vitro half maximal effective concentration of FL115 (ECso) against T24-Luc cell lines, NCI-H460-Luc cell lines, and SW480-Luc cell lines are 0.0002329 pg / mL, 0.0003055 pg / mL, and 0.0006265 pg / mL, respectively.Example 2: Pharmacology of FLU 5 in Animal ModelsA. Antitumor Activity of FL115 in Mice Bearing Orthotopic Bladder Tumors

[0197] Bladder cancer has been established in mice (subcutaneous transplantation model of cancer cell MB49). The experiments demonstrated that FL115 administered by different routes of administration (intravenous injection or subcutaneously) all has significant anti -tumor effects, and can induce tumor-infiltrating killer NK cells and CD8+T cells to secrete more granzymes.

[0198] The antitumor activity of FL115 was evaluated in mice bearing orthotopic MB49 bladder tumors. C57BL / 6 mice were instilled intravesically with MB491uc cells, following polylysine pretreatment of the bladders, FL115 (10 mg / kg, i.v.), FL115 (10 mg / kg, instilled intravesically), and BCG (135pg / injection, instilled intravesically) were administered separately on post MB491uc tumor cell instillation. The mice were maintained to assess survival rate among the treatment groups as the efficacy endpoint. FL115 treatment significantly prolonged the survival of the MB491uc bearing mice compared with BCG, no matter it was injected intravenously or instilled intravesically.B. Antitumor Activity of ELI 15 with BCG in Mice Bearing Orthotopic BladderTumors

[0199] The antitumor activity of FL115 in combination with BCG was evaluated in mice bearing orthotopic MB491uc bladder tumors. C57BL / 6 mice were instilled intravesically with MB491uc cells (3 104cells / bladder), following polylysine pretreatment of the bladders. Low, medium, and high dosage of FL115 (25 pg / inj ection, 75 pg / inj ection, or 225 pg / inj ection, instilled intravesically), together with fixed dosage BCG (lOOpg / inj ection, instilled intravesically) were administered to the post MB491uc tumor cell instillation. The mice were maintained to assess survival rate among the treatment groups as the efficacy endpoint.

[0200] FL115 and BCG combination treatment showed better antitumor activity in the MB491uc bearing mice compared with BCG treatment alone. However, while low and medium dosage agonistic FL115 (25 pg / inj ection, 75 pg / inj ection) and BCG combination treatment demonstrated better antitumor activity than FL115 treatment alone, high dosage FL115 (225 pg / inj ection) and BCG combination therapy didn’t exhibit any advantage in antitumor activity than high dosage FL115 treatment alone. This might be due to the good antitumor activity obtained through high dosage FL115 treatment.Example 3: Toxicity, Pharmacodynamics (PD), and Pharmacokinetics (PK) of FLU 5 in Mice and Cynomolgus MonkeysA. Toxicity of FL115 in Mice and Cynomolgus Monkeys

[0201] A study was performed under Good Laboratory Practice regulations to evaluate the safety effects of i.v. administration of FLU 5 in animal models.

[0202] The safety and pharmacodynamic profiles of FL115 were assessed in healthy C57BL / 6N mice injected i.v. with 3.0 mg / kg to 9 mg / kg dose, no adverse effects on mice’s respiratory system were observed.

[0203] The safety and pharmacodynamic profiles of FL115 was also assessed in healthy cynomolgus monkeys injected i.v. with 0.2 mg / kg to 2 mg / kg FL115, no adverse effects on the cardiovascular, respiratory and central nervous system were observed in cynomolgus monkeys.B. Pharmacodynamics (PD), Pharmacokinetics (PK) of FL115 in Mice and Cynomolgus Monkeys

[0204] The Pharmacodynamics (PD), and Pharmacokinetics (PK) of single dose i.v.(intravenous) administration of FL115 in cynomolgus monkeys were performed. Monkeys were administered with 0.23 to 1.02 mg / kg FLU 5 as i.v. injection. The Cmax, AUCo-t, and AUCo-® values all increased with the increasing dosage. The increase ratio is nearly the same as the doseincrease ratio, indicating a linear pharmacokinetic characteristic. There is no distinguishable difference of the PK data between male and female cynomolgus monkeys, with T1 / 2 ranging from 2.81 hours to 5.45 hours, and distribution volume Vd from 112 mL / kg to 231 mL / kg. The absolute bioavailability is 54.7% to 65.8%, when 0.43 mL / kg of FL115 was administered s.c. (subcutaneous).

[0205] Toxicological studies of SD rats for 5 weeks (intravenous injection, once a week, 5 times in total) demonstrated that FL115 has good drug exposure (Cmax and AUCo-t). No difference of PK data was observed between male and female mice, and drug exposure increased in a dose-ratio manner. After the fourth dose (D22), compared with the first dose (DI), there was no obvious accumulation of AUCo-t in the low-dose group. There was visible accumulation of AUCo-t in the medium-dose and high-dose groups, but the accumulation ratio was not large (2.5 times). Under repeated dosing conditions, although more individual rats were ADA positive, drug exposure was not significantly affected.

[0206] Toxicological studies accompanied by repeated intravenous administration of cynomolgus monkeys for 4 weeks (once a week, 5 times in total) showed that there was no difference in drug exposure between male and female cynomolgus monkeys within the dose range of 0.2-2 mg / kg of FL115. The drug exposure ((Cmax and AUCo-t) of each dose group increased in a dose-ratio manner; the drug exposure ratios (Cmax ratio, and AUCo-t ratio) after D22 administration and DI administration were both within the range of 2.0, and no accumulation of the drug was observed. Under repeated dosing conditions, only a very small number of individual cynomolgus monkeys became ADA positive, and drug exposure was not adversely affected.C. Toxicities of FL115 in Mice

[0207] Toxicokinetic studies of the 6- week repeated dose in SD rats showed that FL115 was not detected in any PK samples, after intravesical instillation of 0.5, 1.5 or 5 mg / kg of FL115. The bioavailability is 0.

[0208] The toxicity study in SD rats after 6 weeks of intravesical instillation of FLU 5 showed that after intravesical administration of 0.5, 1.5 or 5 mg / kg of FL115, the rats demonstrated no obvious clinical symptoms, no body weight, food intake, eye examination, local irritation from administration, hematology, blood coagulation, plasma biochemistry (including electrolytes), urinalysis, anatomical gross morphological observation, organ weight and pathologicalhistological changes. There was no systemic exposure or systemic toxicity observed, which is consistent with the result of zero bioavailability. The non-toxicity dose (NOAEL) is 5 mg / kg. No irritation related to FL115 was found at the administration site.Example 4: Clinical Study of the FLU 5 in Patients with Bladder Cancer

[0209] A multi-center, open-label, clinical study of FL115, or FL115 in combination with BCG in patients with NMIBC is carried out. Specifically, a first-time phase la, phase lb, phase II, dose-escalation, and cohort-expansion clinical study of intravesical instillation of FLU 5 alone, as well as FL115 in combination with BCG are conducted. The study helps to evaluate the MTD, MAD, RP2D, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary antitumor activity and efficacy of FL115 alone, as well as FL115 in combination with BCG in patients with NMIBC. The study includes three parts: a single dose-escalation phase of FLU 5 (Phase la), a dose-escalation phase of FL115 plus BCG (Phase lb), and a cohort expansion phase of FL115 plus BCG (Phase II).

[0210] Each patient is treated with FL115 alone, or FL115 in combination with BCG. There are three major treatment periods (induction phase, enhanced induction phase / maintenance phase 1, and maintenance phase 2), with the maximum times for dosages of 24 to 27. All participants have their bladder emptied, then are administered with FL115 (alone or together with BCG) via a urinary catheter in the bladder. The medication stays in the bladder for two hours (at least one hour, optionally two hours).Clinical Study Plan:

[0211] First Treatment Period (Induction Phase): FL115 alone or in combination with BCG, is administered once a week or weekly (QW) by intravesical instillation, 6 times per treatment period (QW*6).

[0212] Second Treatment Period (Enhanced Induction Phase or Maintenance Phase 1): it evaluates patients’ bladder tumor three months after the first dosage.1) If the assessment result is no cancer residue or a low-grade Ta, patients then receive a 3-week maintenance course, which is administered once a week (QW / 3).2) If the assessment result is the existence of carcinoma in situ (CIS) residue or highgrade Ta or low-grade Tl, then patients receive a re- induction, which is administered once a week or weekly (QW) by intravesical instillation, 6 times per treatment period (QW*6). Prior to this, a TURBT surgery should be performed for Ta / Tl lesions.3) If the assessment result is > high-grade T1 tumor or new occurrence of CIS, the treatment is deemed as a failure and is terminated. For subjects receiving FL115 monotherapy, if they meet the inclusion criteria for combination therapy based on the investigator's assessment, they may be switched to FL115 in combination with BCG treatment.

[0213] Third Treatment Period (Maintenance Phase 2): evaluate patients’ bladder tumor 6, 9, 12, 18, and 24 months after the first dosage.1) If the assessment result is no existence of cancer or a low-grade Ta tumor, patients then receive five 3-week maintenance courses at months 7, 10, 13, 19, and 25, which are administered once a week (QW*3). Prior to this, a TURBT surgery should be performed for Ta lesions.2) If the assessment result is > low-grade Ta or existence of carcinoma in situ (CIS) residue, then the treatment is deemed as a failure, and terminated. For subjects receiving FL115 monotherapy, if they meet the inclusion criteria for combination therapy based on the investigator's assessment, they may be switched to FL115 in combination with BCG treatment.

[0214] Table 1. Clinical Study Objectives and EndpointsDose Escalation I

[0215] Single Dose-Escalation Phase of FL115 (Phase la).In this open-label, multicenter study, patients with BCG-unresponsive NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumors are treated with intravesical FL115 alone. Patients with BCG-unresponsive NMIBC high-grade Ta / Tl papillary tumors without CIS are also treated with intravesical FL115 single therapy. This study uses an accelerated titration design and a traditional 3 + 3 dose-escalation design, which is shown in the following Table 2.

[0216] Table 2: Dose-escalation for FL115 Single Therapy

[0217] One to six subjects are enrolled and administered with 200 to 800 pg / dose FL115 alone by intravesical instillation. In the traditional 3 + 3 dose-escalation design, there are at least three days’ gap between the first dose of the first subject and the first dose of subsequent subjects at each dosage group. Enrollment at the next higher dose level are opened only after SMC has assessed the safety, when at least 1-3 subjects evaluable for DLT at the current dose level. If the subject stops receiving treatment due to non-DLT reasons (such as poor compliance, disease progression / relapse, comorbidities, other non-trial drug-related adverse events, etc.) and fails to complete the DLT observation period (21 days) or fails to receive at least 2 treatments, the subject must be replaced. Those who suspend the use of trial drugs, delay medication, or permanently discontinue medication during the DLT observation period due to DLT-related reasons are DLT evaluable subjects and not replaced.

[0218] Dose-limiting toxicity is evaluated during Cycle 1 (21 days) of treatment. Dose escalation decisions are mainly based on safety data observed during the DLT period. If necessary, other safety and PK / ADA / cytokine data can be used as a reference for escalation evaluation.

[0219] Escalating dose level can be adjusted (e.g., reducing or increasing certain dose levels or other dosing intervals) based on data collected on FL115 treated patients, to explore optimal dosing regimens. If a certain dose level shows some efficacy signals (for example: >1 case of CR or DFS>3 months), after evaluation by SMC and the sponsor, expansion at that dose level (up to 9 cases) can be considered, while dosing at higher dose levels is continued.

[0220] Dose escalation continues until one of the MTD, MAD or RP2D is reached. If the MTD is still not reached when the dose is escalated to 800 pg / time, the SMC discusses and decideswhether to ramp up to a higher dose group. After the RP2D is determined, subjects who are still in the study during the escalation period can be considered to switch to the RP2D dose and continue administration based on the comprehensive judgment of the investigator and the sponsor.Dose Escalation II

[0221] Dose-Escalation Phase of FL115 and BCG Combination Therapy (Phase lb).

[0222] After SMC determines the MID, MAD or RP2D of FL115 as a single therapy based on Phase la dose-escalation data, this dose-escalation study of FL115 and BCG combination therapy are open for enrollment.

[0223] In this study, patients with BCG-unresponsive NMIBC carcinoma in situ (CIS) with or without Ta / Tl papillary tumors are enrolled. Patients with BCG-unresponsive NMIBC highgrade Ta / Tl papillary tumors without CIS are also subjects of this study. Traditional 3 + 3 doseescalation with two dose levels is shown in the following Table 3.

[0224] Table 3: Dose-escalation of FL115 and BCG Combination Therapy

[0225] Dose-limiting toxicity can be evaluated during Cycle 1 (21 days) of treatment. The definition of DLT is the same as Phase la.

[0226] Further dose escalation decisions can be mainly based on safety data observed during the DLT period. If necessary, other safety and PK / ADA / cytokine data may be used as a reference for escalation evaluation.

[0227] There can be two dosage groups. Three to six subjects are enrolled in each group, and administered with FL115 plus BCG by intravesical instillation. In the traditional 3 + 3 dose-escalation design, there must be at least three days between the first dose of the first case in each dose group and subsequent subjects. Enrollment at the next higher dose level is open only after SMC has assessed safety, when at least 3 subjects evaluable for DLT at the current dose level. If the subject stops treatment due to non-DLT reasons (such as poor compliance, disease progression / relapse, comorbidities, other non-trial drug-related adverse events, etc.) and fails to complete the DLT observation period (21 days) or fails to complete at least 2 treatments, the subject must be replaced. Those who suspend the use of trial drugs, delay medication, or permanently discontinue medication during the DLT observation period due to DLT-related reasons are DLT evaluable subjects and not replaced.

[0228] Escalating dose level can be adjusted (e.g., reducing or increasing certain dose levels or other dosing intervals) based on the collected data of ELI 15 and BCG combination therapy, to explore optimal dosing regimens. If a certain dose level demonstrates some efficacy signals (for example: > 1 case of CR or DFS >3 months), after evaluation by SMC and the sponsors, expansion at that dose level (up to 9 cases) is considered, while dosing at higher dose levels can be performed.

[0229] Dose escalation continues until one of the MTD, MAD or RP2D is reached. If the MTD is not reached when the dose is escalated to 800 pg / time, the SMC discusses and decides whether to escalate to a higher dose group. After the RP2D is determined, subjects who are still in the study during the dose-escalation period can be switched to the RP2D dose and continue administration based on the comprehensive judgment of the investigators and the sponsors.Cohort Expansion

[0230] Cohort Expansion Phase of FL115 and BCG Combination Therapy (Phase II).

[0231] After SMC determines RP2D based on FL115 combined with BCG intravesical instillation data, the cohort expansion phase study can be conducted at this dose level. If necessary, SMC may discuss and decide to explore other intravesical instillation dosages and / or other dosage intervals. Based on the results of the Phase lb combination dose-escalation, the SMC determined to add a 600 pg cohort for further exploration. This cohort will not be included in the DLT evaluation population, as subjects at a higher dose level (800 pg) have already completed DLT assessment and the dose has been confirmed to be safe.

[0232] The subjects in this study need to meet the following criteria:• Cohort 1 (n=20): subjects with BCG-unresponsive NMIBC CIS with or without Ta / Tl papillary tumors.• Cohort 2 (n=20): subjects with BCG-unresponsive NMIBC high-grade Ta / Tl papillary tumors without CIS.• Cohort 3 (n=15): subjects with BCG-naive, intermediate to high risk NMIBC, including carcinoma in situ (CIS) with or without Ta / Tl or Ta / Tl papillary tumors.

[0233] The above cohort subjects and sample sizes can be adjusted (adding or reducing cohorts, pausing or stopping cohort expansions) based on the study data for FL115. During Phase II, SMC holds meetings regularly after the first six subjects complete at least one tumor evaluation.

[0234] BCG-naive disease as defined as one of the following: a subject has not received prior intravesical BCG treatment; or previously received BCG treatment, but stopped receiving for more than 3 years; or the subject has a remission of at least 2 years after the last BCG treatment before a recurrence of the cancer.

[0235] If the investigator believes that the subject can continue to benefit from the treatment, after the DLT observation period, the subject can continue to receive FL115 treatment alone or in combination with BCG, preferably in combination with BCG, until a maximum of 24-27 total doses. At the same time, during the treatment period, tumor evaluation can be performed every 3 months for the first 2 years after the first treatment, and every 6 months starting from the third year. The evaluation includes cystoscopy / urine cytology, trans urethral resection of bladder tumor (TURBT) / biopsy / upper urinary tract evaluation. The evaluations are performed when necessary, until the subject starts new anti-tumor treatment (e.g.: radical cystectomy), dies, withdraws informed consent, lost to follow-up, the sponsor terminates the study, or 3 years after the first dose, whichever comes first. For subjects whose disease progression / relapse leads to permanent discontinuation of treatment, relevant tumor assessments are still required according to the scheduled assessment time, unless the tumor assessment time is within 4 weeks after the decision to permanently discontinue or suspend treatment.

[0236] All subjects undergo safety evaluations during treatment with the FL115 (alone, or in combination with other drugs), preferably during the treatment with FL115 in combination with BCG, and 28 days (± 7 days) after the last dose.

[0237] After the subject finishes the last dose (withdraws early or completes all doses), the subject’s disease recurrence / progression, the subject’s start of new anti-tumor treatment andsurvival status are followed up every 3-6 months as scheduled 3 years after treatment, until initiation of new anti-tumor treatment, death, withdrawal of informed consent, loss to follow-up, or study termination by the sponsor, whichever comes first.Inclusion Criteria

[0238] Patients must meet all of the following criteria to be eligible for participation in this study:1. Male or female > 18 years.2. Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures.3. Pathological tissue biopsy diagnosis within 12 weeks before the first dose is NMIBC comprising CIS (with or without Ta and / or T1 papillary tumor); or NMIBC comprising highgrade Ta and / or T1 papillary tumors without CIS (based on the WHO pathological diagnostic criteria for bladder cancer 2004 version). Other minor histological variant subtypes are allowed, but urothelium must be the predominant histological type (>50%).Phase I and Phase II clinical trial subjects also must meet the following criteria:a) Phase la and lb: BCG-unresponsive high risk NMIBC patients, comprising CIS with or without Ta tumor and / or T1 tumor, or high-grade Ta and / or T1 papillary tumors without CIS. b) Phase II:• Cohort 1: BCG-unresponsive NMIBC subjects comprising CIS with or without Ta / Tl papillary tumors.• Cohort 2: BCG-unresponsive NMIBC subjects comprising high-grade Ta / Tl papillary tumors without CIS.• Cohort 3: BCG-naive intermediate to high-risk NMIBC subjects, including CIS with or without Ta / Tl, or Ta / Tl papillary tumors without CIS. BCG-naive disease is defined as one of the followings: a subject has not received prior intravesical BCG treatment; or one previously received BCG treatment, but stopped receiving for more than 3 years; or the subject has a remission of at least 2 years after the last BCG treatment before a recurrence of the cancer.Note: The definition of NMIBC risk is based on the “Bladder Cancer Diagnosis and Treatment Guidelines 2022.”4. Patient refuses or is deemed to be unsuitable for radical cystectomy by the researcher.5. Subjects have transurethral resection of the bladder (TURBTj / cystoscopy within 12 weeks before the first dose, which shows removal of all papillary tumors (Ta / Tl), or the residual disease is only CIS. For stage T1 patients, the postoperative pathology needs to show the presence of bladder muscle tissue. For those who meet the requirements for a second-time resection, 2-6 weeks after the first TURBT, their primary tumor sites should be resected for the second time, and the presence of bladder muscle tissue and absence of invasive tumors need to be confirmed by pathological examination.Note: Indications for suitability of a second-time resection include: confirmed or suspected incomplete resection of tumor by the first TURBT, no bladder muscle tissue was observed in the first resection tumor specimen (except for low-grade Ta and pure CIS), and stage T1 tumors.6. For BCG unresponsive high-risk NMIBC, BCG unresponsive therapy needs to meet any of the following definitions (based on the 2023 European Society of Urology Guidelines for NMIBC):• BCG refractory: including detection of stage T1 papillary tumors at the initial tumor assessment (at 3 months); or detection of high-grade Ta papillary tumors at enhanced induction phase or after first maintenance phase (after 3 months and / or at 6 months); or detection of CIS (no papillary tumors) at the enhanced induction phase or after the first maintenance phase (detect at 3 months and persist at 6 months); or occurrence of high-grade tumors during the BCG maintenance phase.• BCG relapsing: recurrent tumors after adequate BCG therapy, including recurrence of high-grade Ta / Tl papillary tumors within 6 months of completing adequate BCG therapy; or occurrence of CIS within 12 months of completing adequate BCG therapy.Note: Adequate BCG treatment is defined as: completing at least 5 of the 6 consecutive doses at the induction phase; and completing at least 2 of the 3 consecutive doses in the maintenance phase, or completing at least 2 of the 6 consecutive doses in the enhanced induction phase. In addition, detection of high-grade Ta / Tl at 6-9 months also meets the requirement if the subject’s first tumor evaluation is delayed until months 6-9.7. Eastern Cooperative Oncology Group (ECOG) performance status is 0, 1 , or 2.8. Patient’s life expectancy > 2 years (evaluated by the investigator).9. Adequate organs function by meeting all of the following requirements:• Hematological function: absolute neutrophil count (ANC) > l.5 / IO9 / L; platelet count > 90x109 / L; hemoglobin > 90 g / L (No transfusion of whole blood, blood components, or colonystimulating factor is acceptable within 14 days prior to the screening examinations, such as Granulocyte colony-stimulating factor G-CSF, granulocyte macrophage colony-stimulating factor GM-CSF, erythropoietin (EPO) or thrombopoietin (TPO) and other medical treatments.• Liver function (no hepatoprotective treatment within 7 days before the screening examinations): total bilirubin (TBIL) < 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5xULN.• Renal function: serum creatinine < 1.5xULN, or serum creatinine > 1.5xULN but endogenous creatinine clearance > 50ml / min (calculated according to the Cockroft-Gault formula).• Echocardiography: left ventricular ejection fraction (LVEF) > 50%.• Coagulation function: activated partial thromboplastin time (aPTT) <1.5xULN, international normalized ratio (INR) <1.5xULN, prothrombin time PT <1.5xULN, or the subject is receiving anticoagulant therapy and the PT / aPTT / INR values are maintained within the therapeutic range for the anticoagulant’s intended use.10. Subjects (male and female) of childbearing potential and their spouses, starting from their willingness to sign the informed consent form (ICF), for the entire duration of treatment and for at least 5 half-lives or 4 months (120 days) after the last dose, whichever is longer, must use a contraceptive method that is available and considered effective by the researcher.Postmenopausal women must have had amenorrhea for at least 12 months to be considered not potentially fertile.Exclusion Criteria

[0239] Patients will be excluded from participating this clinical trial if they meet any one of the following criteria:1. Previous anti-tumor treatments:a) Patients who previously received IL-2 or IL- 15 agonist therapies, including but not limited to rhIL-15 (NCI), ALT-803 (N-803), and NKTR-214 (Nektar);b) Patients who have previously received any of the following NMIBC-related treatments:• extensive pelvic radiotherapy (irradiation of >30% of bone marrow area) within 2 years prior to the first dose;• systemic treatments intended for NMIBC (including radiotherapy, chemotherapy, immune checkpoint inhibitors, etc.) within 4 weeks prior to the first dose;• transvesical instillation or other local intravesical treatments (including drug-device combinations) for NMIBC within 4 weeks prior to the first dose; however, a single immediate post-operative intravesical chemotherapy instillation performed more than 2 weeks prior to the first dose is allowed, and intravesical instillation of mucosal protective agents (e.g., sodium hyaluronate) is also permitted;• surgical interventions for bladder lesions such as TURBT within 2 weeks prior to the first dose.2. Other previous treatments and recovery from medication toxicities:a) Patients with known or suspected hypersensitivity to FL115 or its excipients; patients with a history of Grade 3-4 allergic reactions to interleukin-based therapies or fusion proteins; patients with known or suspected hypersensitivity or significant intolerance to BCG (applicable to Phase lb and II);b) Patients who received systemic immunomodulatory therapy within 4 weeks prior to the first dose, except for any of the following:• corticosteroids at a dose equivalent to <10 mg / day of prednisone;• topical, inhaled, or intranasal corticosteroids;• adrenal replacement steroid therapy at a dose equivalent to <7.5 mg / day of prednisone;• prophylactic one-time corticosteroid use for contrast-agent allergy prior to imaging procedures.c) Patients with a history of allogeneic organ transplantation or allogeneic PBSC / bone marrow transplantation;d) Patients who have received live attenuated vaccines within 4 weeks prior to the first dose;e) Patients who experienced Grade >3 immune-related adverse events (irAEs) or irAEs leading to discontinuation of immunotherapy. Exceptions include: previous hypothyroidism,type 1 diabetes, or dermatologic irAEs (excluding Stevens- Johnson syndrome, toxic epidermal necrolysis, or other severe dermatitis);f) Patients whose adverse events from prior anti-tumor treatments have not resolved to baseline or <Grade 1 (according to NCI CTCAE v5.0 or ASTCT) prior to the first dose.Exceptions include: alopecia (any grade), peripheral sensory neuropathy (<Grade 2), hypothyroidism well controlled with hormone replacement therapy, or other situations explicitly permitted by inclusion / exclusion criteria. Subjects with other AEs <Grade 2 may be enrolled if deemed appropriate by the investigator after consultation with the sponsor’s medical representative.3. Past medical and surgical history:a) Patients with a history or current presence of muscle-invasive disease (T2-T4), locally advanced disease (T3 / T4, any N), or metastatic bladder cancer;b) Patients with concomitant upper urinary tract malignancies (renal pelvis, ureter, kidney) or prostatic urethral tumors. Subjects with Ta / Tl / CIS of the upper tract who have undergone curative nephroureterectomy more than 2 years prior to first dose may be considered eligible. Subjects with low-grade Ta disease of the prostatic urethra may be eligible. Tumor involvement of prostatic ducts is not permitted regardless of histology;c) Patients with documented vesicoureteral reflux or bladder perforation;d) Patients with confirmed urinary tract infection — particularly bladder infection — or gross hematuria judged by the investigator to be unsuitable for study entry. Subjects whose infection can be controlled with antibiotics and resolve after discontinuation of antibiotics may be eligible;e) Patients who discontinued prior BCG therapy due to BCG-related sepsis, infection requiring systemic therapy, urinary incontinence, or other BCG-related adverse reactions (applicable to Phase lb and II);f) Patients who developed post-TURBT complications that, in the investigator’s judgment, preclude intravesical instillation therapy;g) Patients with clinically significant polyuria (documented 24-hour urine output >4,000 m );h) Patients with other malignancies that have progressed or required active treatment within 2 years prior to screening. Subjects with curatively treated localized cancers (such asbasal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) may be eligible; gastrointestinal tumors limited to the mucosa and completely removed via endoscopy are allowed; low-risk prostate cancer under active surveillance may be eligible per investigator assessment;i) Patients with active autoimmune disease or a history of autoimmune disease requiring systemic steroids or immunosuppressive therapy, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, Wegener’s granulomatosis, Sjogren’s syndrome, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, myositis, autoimmune hepatitis, vasculitis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, and glomerulonephritis. Exceptions include endocrine disorders manageable with hormone replacement therapy (e.g., hypothyroidism, type 1 diabetes, adrenal or pituitary insufficiency);j) Patients with any of the following pulmonary toxicities:• severe clinically significant pulmonary disease within 12 weeks prior to the first dose, including but not limited to pulmonary embolism, severe asthma, severe COPD, idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or drug-induced pneumonitis;• active interstitial lung disease (ILD) or interstitial pneumonia;• a history of ILD or non-infectious pneumonitis requiring corticosteroids or other immunosuppressive therapy;k) Patients with evidence of active tuberculosis infection within 1 year prior to screening, or a remote history of active tuberculosis without evidence of adequate treatment;l) Patients with uncontrolled pleural effusion, pericardial effusion, or ascites (e.g., requiring repeated drainage more than once per month), as judged by the investigator, m) Patients with clinically significant cardiovascular disease, including but not limited to: myocardial infarction, uncontrolled angina, viral myocarditis, stroke, or other Grade >3 cardiovascular / cerebrovascular events within 6 months prior to the first dose; any supraventricular or ventricular arrhythmias requiring intervention; congestive heart failure of NYHA Class III / IV; uncontrolled hypertension [systolic BP >160 mmHg and / or diastolic BP >100 mmHg despite standard therapy, or history of hypertensive crisis or encephalopathy], n) Patients who have undergone major surgery within 4 weeks prior to signing the informed consent form.4. Past history of infectious diseases:a) Patients with severe infections within 4 weeks prior to the first dose, including but not limited to bacteremia requiring hospitalization or severe pneumonia; or patients with active infections of CTCAE Grade >2 requiring systemic antibiotics within 1 week before first dose. Subjects may be re-screened after complete resolution of infection. Exceptions include localized bacterial (e.g., skin), localized viral, or localized fungal infections not requiring systemic therapy;b) Patients with any known history of active HBV, HCV, HIV infection, or active tuberculosis:• Non-active HBV-infected subjects may be eligible if they meet the following: controlled HBV infection (>4 weeks of antiviral therapy prior to screening and HBV DNA <1000 copies / mL or <200 ZU / mL at screening). Subjects on antiviral therapy should continue treatment during the study;• Evidence of active HCV infection is defined as: positive HCV antibody test together with positive HCV RNA test.5. Other situations:a) Pregnant or breastfeeding women;b) Patients with known, documented, or suspected drug abuse requiring exclusion.Exceptions include: opioid analgesics prescribed by physicians. Enrollment may be permitted if clinically justified per investigator judgment and after discussion with the sponsor’s medical representative;c) Any other condition that, in the investigator’s judgment, renders the subject unsuitable for participation in the study.

[0240] The study is ongoing. It is currently being conducted at 12 clinical sites. The first dosing of monotherapy was 200 pg / dose of FL115, and the first dosing of the combination therapy was 400 pg / dose of FL115 + 120 mg / dose of BCG. Each of FL115 and BCG was administered via intravesical instillation, once weekly. FL115 or the combination of FL115 and BCG was administered to the subject 24-27 times.

[0241] As of September 15, 2025, a total of 28 patients have been enrolled and treated in the study (male = 22; female = 6; age range 42 - 81 years):1• FL115 monotherapy (n = 10): 200 pg / dose (n = 1), 400 pg / dose (n = 3), and 800 pg / dose (n = 6); and• FL115 + BCG combination therapy (n = 18): 400 pg / dose (n = 7), 600 pg / dose (n = 2), and 800 pg / dose (n = 9) of FL115 + 120 mg / dose of BCG.

[0242] All 28 patients had BCG-unresponsive high-risk NMIBC: five patients with CIS (with or without Ta / Tl) and twenty -three patients with Ta / Tl without CIS. All patients had previously received BCG intravesical therapy (5-34 instillations).Preliminary Results

[0243] As the study is ongoing, data are still being collected from the study participants and analyzed.Safety:

[0244] The preliminary safety data set includes results from 28 patients. The data obtained thus far indicate that most of the adverse events (AEs) were Grade 1-2, mainly local urinary tract irritation matched the safety profile of intravesical instillation or BCG, and laboratory abnormalities consistent with elderly NMIBC patients.Efficacy:A. Monotherapy group (n = 10):

[0245] 3-month evaluation: among the nine evaluable patients (1 x 200 pg / dose, 2 x 400 pg / dose, 6 x 800 pg / dose), two patients (800 pg / dose) had recurrence (high-grade T1 and / or T2), while seven patients showed no progression or recurrence.

[0246] 6-month evaluation: among the six evaluable patients (1 x 200 pg / dose, 2 x 400 pg / dose, 3 x 800 pg / dose): one patient (200 pg / dose) developed new CIS; one (400 pg / dose) progressed, one (400 pg / dose) was identified as Lg Ta at 6-month assessment and switched to combination therapy; two (800 pg / dose) had no progression or recurrence, and one (800 pg / dose) had recurrence (Hg Tl).

[0247] 9-month evaluation: both evaluable patients (800 pg / dose) had no progression or recurrence during a treatment period of 9 months.B. Combination group (n = 18):

[0248] 3-month evaluation: among the thirteen evaluable patients (7 X 400 pg / dose + BCG, 6 X 800 pg / dose + BCG), one had recurrence (Hg Tl); one had residual CIS requiring reinduction; and eleven patients showed no progression or recurrence.

[0249] 6-month evaluation: all three evaluable patients (400 pg + BCG) remained progression-free and recurrence-free during a 6 month treatment.

[0250] In the present study, among the six subjects who received FL-115 monotherapy at a higher dose (800 pg / dose), tumor assessments at 3 months showed that four of the six evaluable subjects were progression-free / recurrence-free; at 6 months, two of the three evaluable subjects remained progression-free / recurrence-free; and at 9 months, both of the two evaluable subjects maintained a progression-free / recurrence-free status.

[0251] In comparison, among the ten subjects who received N-803 monotherapy, only two achieved a complete response (CR), with just one case maintaining CR for >6 months, indicating a non-progressive / recurrence-free status. The remaining eight subjects did not achieve CR. Pharmacokinetics and Cytokine Profile:

[0252] As shown in FIG. 1A - FIG. ID, FL115 monotherapy increased the levels of IFN-y and IL-6 in urine samples up to about 50 pg / ml as measured on Day 1 and Day 36 with the treatment of 200 -800 pg / dose of FL115. The monotherapy did not alter the level of plasma cytokines. In comparison, the reported urine levels of IFN-y and IL-6 induced by the N-803 monotherapy were much higher, e.g., more than 1000 pg / ml or 20,000 ph / ml, respectively, as described in Center for Drug Evaluation and Research Application No. 7613360rigls00, Multi-Discipline Review, which is available from the World Wide Web (www) at: accessdata.fda.gov / drugsatfda_docs / nda / 2024 / 761336Origls000MultidisciplineR. pdf (“N-803 Study Report”). The markedly lower IL-6 induction by FL115 relative to that of N-803 suggests a distinct immune activation cluster, potentially translating to improved tolerability and clinical benefit.

[0253] As shown in FIG. 2A - FIG. 2D, the combination therapy of FL115 with BCG increased the levels of IFN-y in urine samples up to about 1300 pg / ml, and the levels of IL-6 in urine samples up to about 280 pg / ml as measured on Day 1 and Day 36 with the treatment of 400 -800 pg / dose of FL115 in combination with 120 mg / dose of BCG. The combination therapy did not alter the level of plasma cytokines. It is noted that the IL-6 levels were markedly lower than that of IFN-y. IFN-y, mainly produced by NK and T cells, serves as a positive biomarker for antitumor immune activation, reflecting enhanced CD8+T cell and NK cell function (see, e.g., Kwon, Cell Mol Immunol. 2018; 15:531-532). IL-6, secreted by monocytes / macrophages, T cells, fibroblasts, and endothelial cells, is more often associated with inflammatory toxicity thandirect antitumor effect (see, e.g., Hunter et al., Nat Immunol. 2015; 16:448-457). The urine levels of IL-6 induced by the FL115 and BCG combination therapy were significantly lower than the IL-6 values reported in previous N-803 studies, while the urine levels of IFN-y are significantly higher (see, the N-803 Study Report).

[0254] It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

[0255] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.

[0256] All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains.

[0257] The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising,” “consisting essentially of,” and “consisting of’ may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Other embodiments are within the following claims.

Claims

CLAIMSWe claim:

1. A method of treating bladder cancer in a human subject in need thereof, comprising(1) administering to the human subject an effective amount of 50 -1000 pg per administration of an agonistic interleukin 15 (IL-15) complex comprising: (a) a fusion protein comprising an IL-15 receptor a sushi domain fused to an Fc monomer, and (b) an IL- 15, wherein the IL- 15 receptor a sushi domain comprises the amino acid sequence of SEQ ID NO: 5 and the Fc monomer comprises the amino acid sequence of SEQ ID NO: 6; and(2) administering to the human subject an effective amount of 40-150 mg per administration of a Bacillus Calmette Guerin (BCG).

2. The method of claim 1, wherein the subject has a non- muscle invasive bladder cancer (NMIBC), such as an intermediate and / or high risk NMIBC.

3. The method of any of the foregoing claims, wherein the bladder cancer comprises at least one of stage Ta tumor, stage T1 tumor and carcinoma in situ (CIS).

4. The method of any of the foregoing claims, wherein the bladder cancer is unresponsive to a Bacillus Calmette Guerin (BCG) therapy (BCG-unresponsive), such as a BCG-unresponsive NMIBC comprising CIS with or without stage Ta tumor or stage T1 tumor.

5. The method of any one of the foregoing claims, comprising a first induction phase, which comprises administering to the subject an effective amount of the agonistic IL-15 complex and an effective amount of BCG weekly for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks.

6. The method of claim 5, further comprising a second induction phase, which comprises administering to the subject an effective amount of the agonistic IL-15 complex and an effective amount of BCG weekly for 3-8 consecutive weeks, such as for 3, 4, 5, 6, 7, or 8 consecutive weeks, preferably for 6 consecutive weeks, wherein the second induction phase starts after the first induction phase, preferably the second induction phase starts about 3 months after the initial administration of the first induction phase.

7. The method of claim 5 or 6, further comprising a maintenance phase, which comprises administering to the subject an effective amount of the agonistic IL-15 complex and an effective amount of BCG weekly for 2-4 consecutive weeks, such as for 2, 3 or 4 consecutive weeks, preferably for 3 consecutive weeks, wherein the maintenance phase starts after the first or secondinduction phase, preferably the maintenance phase starts about 3 months after the initial administration of the first or second induction phase.

8. The method of claim 7, further comprising repeating the maintenance phase one or more times, wherein the subsequent maintenance phase starts after the previous maintenance phase, preferably the subsequent maintenance starts about 3 months after the initial administration of the previous maintenance phase.

9. The method of any one of the foregoing claims, wherein the agonistic IL- 15 complex is administered to the human subject by intravesical instillation weekly.

10. The method of any one of the foregoing claims, wherein the effective amount of the agonistic IL-15 complex is 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 pg of the agonistic IL-15 complex per administration.

11. The method of any one of claims 5-10, wherein the same effective amount of the agonistic IL- 15 complex is used in the induction phase and the maintenance phase.

12. The method of any one of claims 5-10, wherein the effective amount of the agonistic IL- 15 complex used in the maintenance phase is different from that of the induction phase.

13. The method of any one of the foregoing claims, wherein the carboxy 1-terminus of the IL- 15 receptor a sushi domain is fused to the amino-terminus of the Fc monomer via a linker.

14. The method of claim 13, wherein the linker comprises the amino acid sequence of SEQ ID NO: 7, or the linker consists of the amino acid sequence of SEQ ID NO: 8.

15. The method of any one of the foregoing claims, wherein the IL- 15 comprises the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4.

16. The method of any one of the foregoing claims, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 1 or SEQ IED NO: 2.

17. The method of any of the foregoing claims, wherein the effective amount of BCG is 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 mg per administration.

18. The method of claim 17, wherein the effective amount of BCG is administered via intravesical instillation weekly.19 The method of any of the foregoing claims, wherein the method does not induce Dose Limiting Toxi cities (DLT) in the subject.

20. The method of any of the foregoing claims, wherein the method results in an effective treatment of the bladder cancer in the human subject as measured by one or more of CompleteResponse Rate (CRR), Objective Response Rate (ORR), Duration of Response (DoR), Disease Free Survival (DFS), Relapse Free Survival (RFS), time to cystectomy, radical cystectomy rate, Progression-free Survival (PFS) and Disease Control Rate (DCR).

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