Compositions and methods for the treatment and / or prevention of an ILC2 rich cancer

Abstract

The present invention discloses compositions, such as pharmaceutical compositions, as well as methods for use in the treatment and / or prevention of cancer, preferably of an ILC2 rich cancer. The pharmaceutical composition of the invention comprises a Tropomyosin receptor kinase A inhibitor and is administered concomitantly, separately or staggered in time with an immune therapy.

Description

[0001] Unitec Ref: PCT Application Final PAT8297PC00Compositions and Methods for the treatment and / or prevention of an ILC2 rich cancer FIELD OF THE INVENTION The present invention discloses compositions, such as pharmaceutical compositions, aswell as methods for use in the treatment and / or prevention of cancer, preferably of an ILC2 richcancer. The pharmaceutical composition of the invention comprises a Tropomyosin receptorkinase A inhibitor and is administered concomitantly, separately or staggered in time with animmune therapy. BACKGROUND OF THE INVENTION Bladder cancer (BC) is the 10th most diagnosed cancer, characterized by a poor responseto conventional treatment and high relapse rate. Up to 40% of non-muscle invasive bladdercancer (NMIBC) patients fail to respond to intravesical bacillus Calmette-Guérin (BCG)therapy, and relapse or progress to the muscle invasive (MIBC) or metastatic state. Despiteencouraging clinical activity in multiple clinical settings and despite BC being consideredhighly immunogenic, immune checkpoint blockade (ICB, e.g., anti-PD-1 / PD-L1 therapies1) only produce durable benefit in a minority of BC patients2.BC is distinguished by a predominant immunosuppressive immune cell infiltrate unable tomount an adequate response to immunotherapies. The BC immunosuppressivemicroenvironment is sustained by different immune cells such as regulatory T cells (Tregs),tumor associated macrophages (TAMs) and type 2 innate lymphoid cells (ILC2s) that, via IL-13 secretion, modulate the T cell / monocytic myeloid-derived suppressors cell (M-MDSC) ratio in favor of immunotolerance3.ILC2s are a subset of innate lymphoid cells (ILCs) that release IL-5 and IL-13, driving a type2 immune response3-5, that is involved in tissue homeostasis, infection, inflammation andcancer3,4..ILC2s have divergent roles in tumor immunity, displaying either pro- or anti-tumoral features,depending on which factors are sustaining their activation and on the cancer type.Besides its typical role as inducer of neuronal growth, the neurotrophic factor Nerve GrowthFactor (NGF) is expressed in normal bladder, in human and mice. NGF has been shown toUnitec Ref: PCT Application Final PAT8297PC00regulate bladder function and to be involved in several bladder pathological conditions. In thecontext of cancer, neurotrophins, including NGF, and their receptors have recently gainedincreasing therapeutic attention as drivers of cancer neurogenesis, and for their direct effect ontumor cell growth and angiogenesis4. We have identified NGF, acting through its receptorTrkA, as a key driver of ILC2 pro-tumoral functions in BC patients. In vivo treatment withselective TrkA inhibitors improved survival in animals with orthotopic bladder cancer. Inpatients, NGF levels showed inverse correlation with survival in ILC2-rich tumors (e.g.,bladder, colorectal and gastric cancers), underscoring the clinical significance of this pathway.The blockade of TrkA+ILC2s might represent a targetable strategy to improve survival. There is an unmet need in the art for specific and effective treatments of cancer, in particular ILC2 rich cancer. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprising atherapeutically effective amount of at least one Tropomyosin receptor kinase A (TrkA)inhibitor for use in the treatment and / or prevention of an ILC2 rich cancer and at least onepharmaceutically acceptable carrier, diluent, excipient, and / or salt, wherein the TrkA inhibitoris administered concomitantly, separately or staggered in time with atherapeutically effective amount of at least one immune therapy.Also provided is a kit comprising a pharmaceutical composition of the invention. Further provided is a method of treatment and / or prevention of an ILC2 rich cancer,comprising administering a pharmaceutical composition of the invention to a subject in need thereof. Further provided is a method of treatment and / or prevention of an ILC2 rich cancer,comprising i) detecting whether the cancer is an ILC2 rich cancer and, if the cancer isdetermined as an ILC2 rich cancer, and ii) administering a pharmaceutical composition of theinvention to a subject in need thereof.Unitec Ref: PCT Application Final PAT8297PC00DESCRIPTION OF THE FIGURES Figure 1. NGF drives ILC2 functions via TrkA engagement(A) Relative expression of NTRK1 in ex vivo sorted ILC subsets from the peripheral blood ofHDs and BC patients. (B) Quantification of TrkA expression by ex vivo ILC2s from healthydonor (HDs) and bladder cancer patients (Patients). (C) IL-5 and (D) IL-13 secretion by short-term in vitro expanded ILC2s from HDs unstimulated (Ctrl), stimulated with NGF (+ NGF) for48 hours and pre-treated with GW441756 for 45 minutes prior NGF stimulation for 48 hours(GW441756 + NGF). Data are represented as the mean ± SEM. P values were determined bytwo-tailed Wilcoxon matched-pairs signed rank test (A, C and D) and by two-tailed unpaired t- test (B). Figure 2. Pharmacologic TrkA inhibition favors survival in an orthotopic bladder cancer model(A) Relative expression of Ntrk1 in ex vivo sorted mouse ILC subsets from healthy and tumor-infiltrated bladders at day 1 (Day 1 p.i.) and day 3 (Day 3 p.i.) post-MB49 instillation. Data are represented as the mean ± SEM and pooled from one to three independent experiments. (B) Survival curve of MB49 tumor-bearing WT mice treated with the TrkA inhibitor GW441756or the solvent control intraperitoneally twice per week. (C) Survival curve of MB49 tumor-bearing WT mice treated with the TrkA inhibitors (either GW441756, or Larotrectinib orDanusertib), or the solvent control intraperitoneally twice per week. (D) Survival curve ofMB49 tumor-bearing WT mice treated with the TrkA inhibitor GW441756 or the solventcontrol intravesically twice per week. P values were determined by Tukey's multiplecomparisons test (A) and by Log-rank (Mantel-Cox) test (B-D).Figure 3. Pharmacologic TrkA inhibition acts synergistically with ICB in an orthotopic bladder cancer model Survival curve of MB49 tumor-bearing WT mice treated with the TrkA inhibitor GW441756alone or in combination with anti-PD1 antibodies. P values were determined by Log-rank(Mantel-Cox) test.Unitec Ref: PCT Application Final PAT8297PC00DESCRIPTION OF THE INVENTION Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention. The term "comprise / comprising" is generally used in the sense of include / including, that is to say permitting the presence of one or more features or components. The terms "comprise(s)" and "comprising" also encompass the more restricted ones "consist(s)", "consisting" as well as "consist / consisting essentially of", respectively. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. As used herein, "at least one" means "one or more", "two or more", "three or more", etc.As used herein the terms "subject" / "patient", are well-recognized in the art, and are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some cases, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other aspects, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered. Preferably, the subject is a human, most preferably a human patient having a cancer, more preferably theUnitec Ref: PCT Application Final PAT8297PC00cancer is an ILC2-rich cancer, even more preferably the ILC2-rich cancer is not amenable, non-responsive and / or is resistant to one or more immune therapies.The present invention provides compositions and pharmaceutical compositions.In one aspect, the pharmaceutical composition comprises a therapeutically effective amount ofat least one Tropomyosin receptor kinase A (TrkA) inhibitor wherein the TrkA inhibitor isadministered concomitantly, separately or staggered in time with atherapeutically effective amount of at least one immune therapy. Preferably, thepharmaceutical composition is for use in the treatment and / or prevention of an ILC2 rich cancer.The term "therapeutically effective amount" as used herein means an amount of TrkA inhibitoror immune therapy, high enough to significantly positively modify the symptoms and / orcondition to be treated, but low enough to avoid serious side effects (at a reasonable risk / benefitratio), within the scope of sound medical judgment.The therapeutically effective amount of the TrkA inhibitor or immune therapy as describedherein is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient or subject; the severity of the condition or disease (e.g. cancer) to be treated; the route of administration; the renal and hepatic function of the patient or subject. A physician of ordinary skill in the art can readily determine and prescribethe effective amount of the TrkA inhibitor and immune therapy required to prevent, counter orarrest the progress of the disease, such as e.g. a cancer. In one aspect, the pharmaceutical composition also comprises at least one pharmaceuticallyacceptable carrier, diluent, excipient, and / or salt.“Pharmaceutically acceptable carrier or diluent” means a carrier or diluent that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes carriers or diluents that are acceptable for human pharmaceutical use. Such pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceuticalUnitec Ref: PCT Application Final PAT8297PC00composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Pharmaceutically acceptable excipients include starch, glucose, lactose, sucrose, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable salts such as, for example, a mineral acid salt such as a hydrochloride, a hydrobromide, a phosphate, a sulfate, etc.; and the salts of organic acids such as acetates, propionates, malonates, benzoates, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, buffers, pH buffering substances, gels or gelling materials, flavorings, colorants, microspheres, polymers, suspension agents, etc. may also be present herein. In addition, one or more other conventional pharmaceutical ingredients, such as preservatives, humectants, suspending agents, surfactants, antioxidants, anticaking agents, fillers, chelating agents, coating agents, chemical stabilizers, etc. may also be present, especially if the dosage form is a reconstitutable form. Suitable exemplary ingredients include macrocrystalline cellulose, carboxymethyf cellulosesodium, polysorbate 80, phenyletbyl alcohol, chiorobutanol, potassium sorbate, sorbic acid,sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, parachlorophenol, gelatin, albumin and a combination thereof. A thorough discussion of pharmaceutically acceptable excipients is available in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J.1991) which is incorporated by reference herein. Any of the compositions provided herein can be provided in any appropriate pharmaceuticalcomposition and be administered by any suitable route of administration. A physician ofordinary skill in the art can readily determine the suitable route of administration depending onthe compound to be administered, i.e. the TrkA inhibitor, the immune therapy of thecombination thereof and the cancer to be treated.Preferably, the pharmaceutical composition, or the compounds of the invention, is / are administered by a route of administration selected from the group comprising inhalation, intra- arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary,Unitec Ref: PCT Application Final PAT8297PC00instillation (e.g. intravesical instillation) and subcutaneous routes, or a combination of one or more thereof.By way of example, where the ILC2 rich cancer to be treated is a bladder cancer, the preferredroute of administration will be an intravesical instillation. In one preferred aspect of the invention, ILC2 rich cancer is not a TrkA fusion cancer.These typically arise from fusion of the 3’ region of an gene (containing a functionalkinase domain) and the 5’ region of an unrelated gene, either by intra- or inter chromosomalrearrangement. The resulting chimeric oncogenic gene fusion encodes a protein containing theN-terminus of the fusion partner joined to the C-terminus of the TRKA protein, including thecatalytic tyrosine kinase domain. This results in a protein that retains kinase activity, is ligand independent, and is constitutively activated to drive cell and tumor development. TrkA inhibitors are currently known to be effective and are clinically approved for cancers that exhibit TrkA fusion.Type 2 innate lymphoid cells (ILC2) refer to an integral part of the innate lymphoid cells (ILC)family, that are critical for orchestrating various immune responses. They lack antigen-specific receptors but are known for their versatility and ability to produce a range of cytokines in response to environmental cues. Predominantly, ILC2s are identified by their expression of thetranscription factor GATA3 (GATA3 positive), and the absence of the expression of CD3 (CD3negative) and their production of Th2 cytokines like IL-4, IL-5, IL-9, and IL-13 in response to signals such as IL-33, IL-25, and TSLP. This cytokine production is central to their role in various physiological processes, including tissue repair, metabolic homeostasis, and the defense against helminthic infections. The distribution of ILC2s across different tissues, including the lung, skin, gut, and adipose tissue, is notable for its impact on their functional characteristics. In the context of cancer, there is evidence suggesting their involvement in tumor-promoting processes. This pro-tumorigenic aspect of ILC2s is mediated through their secretion of type 2 cytokines, which can promote tumor progression and metastasis. Conversely, there is also emerging evidence indicating a potential anti-tumor role for ILC2s, particularly influenced by the tumor microenvironment. In one aspect of the invention, the TrkA inhibitor is administered concomitantly,separately or staggered in time with an immune therapy.Unitec Ref: PCT Application Final PAT8297PC00In one aspect, the TrkA inhibitor and the immune therapy are administeredconcomitantly, i.e. co-administered, at the same time. For example, the TrkA inhibitor and theimmune therapy are administered from the beginning and as long as necessary or only during aperiod of time. In some aspect, administration of the TrkA inhibitor is discontinued once one or moretherapeutic effects are detected whereas the immune therapy continues to be administered.In some aspect, administration of the immune therapy is discontinued once one or more therapeutic effects are detected whereas the TrkA inhibitor continues to be administered. In another aspect, the TrkA inhibitor is administered first, and the immune therapy isadministered thereafter, usually within weeks (e.g. about 1, about 2, about 3, about 4, about 5,about 10, about 20, about 30, weeks). In this case, administration of the TrkA inhibitor isdiscontinued once one or more therapeutic effects are detected, whereas the immune therapy continues to be administered. In another aspect, the immune therapy is usually administered first, and the TrkAinhibitor is administered thereafter, usually within weeks (e.g. about 1, about 2, about 3, about4, about 5, about 10, about 20, about 30, weeks). In this case, administration of the immunetherapy is discontinued once one or more therapeutic effects are detected, whereas the TrkAinhibitor continues to be administered.In another aspect, the TrkA inhibitor and the immune therapy are administeredstaggered in time, e.g. there is no overlap in the administration of the two therapies. The second therapy is administered about one hour, about 1 day, about 4 days, about one week, about 2 weeks, about 3 weeks, about 5 weeks, about 10 weeks, about 15 weeks, about 20 weeks or more, after the last administration of the first therapy. In one aspect of the invention, the immune therapy is an immune checkpoint blockade (ICB) therapy. Preferably, the ICB therapy is selected from the group comprising a PD-1 inhibitor, a PD-L1 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a TIGIT inhibitor, and a CTLA-4 inhibitor, or combination of one or more thereof.Unitec Ref: PCT Application Final PAT8297PC00In a preferred aspect, the ICB therapy comprises treatment with monoclonal antibodies (mAbs)specific to PD-1, PD-L1, TIM3, LAG3, TIGIT or CTLA-4, or a combination of one or morethereof (see e.g. Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. JExp Clin Cancer Res 38, 255 (2019); Twomey, J.D., Zhang, B. Cancer Immunotherapy Update:FDA-Approved Checkpoint Inhibitors and Companion Diagnostics. AAPS J 23, 39 (2021)).Non-limiting examples of mAbs specific to PD-1 comprise Nivolumab, Pembrolizumab,Dostarlimab, Tislelizumab, Retifanlimab, Toripalimab and Cemiplimab.Non-limiting examples of mAbs specific to PDL-1 comprise Atezolizumab, Avelumab, and Durvalumab.Non-limiting examples of mAbs specific to CTLA-4 comprise Ipilimumab and tremelimumab.A non-limiting example of mAb specific to LAG3 comprises relatlimab.A non-limiting example of mAb specific to LAG3 and PD-1 comprises opdualag.A non-limiting example of mAb specific to TIGIT comprises tiragolumab.In one aspect of the invention, the immune therapy is selected from the groupcomprising a 4-1BB agonist, a CD73 inhibitor, a CD40 agonist (e.g. APX005M, an agonistantibody), Bacillus Calmette-Guerin (BCG), and a live attenuated bacterial vaccine that protects against typhoid (such as e.g. Ty21a), or combination of one or more thereof. Non-limiting examples of agonists specific to 4-1BB comprise urelumab (BMS- 663513) , utomilumab (PF-05082566) as well as compounds listed in Table 1 of Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy. MAbs.2023 Jan-Dec;15(1):2167189. Non-limiting examples of CD73 inhibitor comprise antibodies selected from the groupcomprising Oleclumab, MEDI9447, AK119, HLX23, IPH5301, Sym042, CPI-0006, IBI325, PT199, JAB-BX102, TJ004309, NZV930, INCA00186 and BMS-986179, or combination of one or more thereof.Unitec Ref: PCT Application Final PAT8297PC00Non-limiting examples of agonists specific to CD40 comprise e.g. APX005M, as well as compounds listed in Table 1 of Jian CZ, Lin L, Hsu CL, Chen YH, Hsu C, Tan CT, Ou DL. A potential novel cancer immunotherapy: Agonistic anti-CD40 antibodies. Drug Discov Today. 2024 Mar;29(3), or combination of one or more thereof Non-limiting examples of live attenuated vaccine are selected from mutants ofSalmonella comprising Ty21a, CVD 908-htrA, CVD 909, Ty800, M01ZH09, χ9633, χ9639 , χ9640, and χ8444, or combination of one or more thereof. Also envisioned are immune therapy combinations where a 4-1BB agonist, a CD73inhibitor, a CD40 agonist (e.g. APX005M, an agonist antibody), Bacillus Calmette-Guerin(BCG), or a live attenuated bacterial vaccine that protects against typhoid (such as e.g. Ty21a)are administered with anyone of the immune checkpoint blockade therapy selected from the group comprising a PD-1 inhibitor, a PD-L1 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a TIGIT inhibitor, and a CTLA-4 inhibitor, or combination of one or more thereof. As described herein, the ILC2-rich cancer is a solid cancer or a hematologic cancer. An "ILC2-rich cancer", as used herein, refers to a subtype of cancers in which ILC2 hastumor or angiogenic promoting activity. Preferably, ILC2 cells are determined or have been determined in one or more biological samples to be present. Determination of ILC2 rich cancers is well within the competences of one skilled in the art.ILC2s are identified or detected by their expression of the transcription factor GATA3 (GATA3positive), and the absence of the expression of CD3 (CD3 negative) and / or their production of Th2 cytokines like IL-4, IL-5, IL-9, and IL-13 in response to signals such as IL-33, IL-25, and TSLP. Any one of these characteristics can be used to determine or detect whether a specificcancer is an ILC2 rich cancer. For example, specific anti-GATA3 antibodies, such ascommercial antibodies (e.g., MAB6330, CB405, BSB2670) and anti-CD3 antibodies, such ascommercial antibodies (e.g. ab16669; MAB100) can be used in the techniques described herein.In some aspect, the ILC2 rich cancer displays high levels of Nerve Growth Factor (NGF).Unitec Ref: PCT Application Final PAT8297PC00As illustrated in more detail in the examples, the Inventors have also demonstrated thatNGF levels showed inverse correlation with survival in ILC2-rich tumors. Therefore, thedetermination or detection of NGF levels (using commercial kits, e.g. 93 / 556 MSD) in one ormore biological samples can be used to identify ILC2 rich cancers.The term “detection” as used herein includes quantitative or qualitative detections of NGFlevels as well as ILC2 specific markers (i.e. GATA3+ CD3- cells). Exemplary detectionmethods include, but are not limited to, immunofluorescence, immunocytochemistry, flowcytometry, fluorescence in situ hybridization, magnetic beads complexed with antibodymolecules, ELISA assay, and PCR technology (e.g., RT-PCR) etc.In some aspects, the biological sample includes body fluids, cells, or tissues. Biological samples may include, without limitation, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells), saliva, urine, stool (i.e., fecal material), tears, sweat, buccal smears, skin, sebum, nipple aspirate, ductal lavage, tumour exudates, tissue such as tumor tissue, cancer cells, synovial fluid, cerebrospinal fluid, lymph, fine needle aspirate, amniotic fluid, any other bodily fluid, cell lysates, cellular secretion products, inflammation fluid, semen and vaginal secretions, or a combination of one or more of thereof. In some aspects, the biological sample also includes extracellular vesicles such as, e.g. exosomes and microvesicles that are two major categories of extracellular vesicles released by almost all cell typesand are highly abundant in biological fluids.In one aspect, the sample may be whole blood or a fractional component thereof such as, e.g.,plasma, serum, a cell pellet or a tumor tissue (e.g. a biopsy). According to a specific aspect, the sample used in a method of detection according to the invention is whole blood or a fractional component thereof, such as e.g. white blood cells or peripheral blood mononuclear cells (PBMC) or tumor tissue. One may understand that the biological sample to be used will depend on the compound or marker to be detected (i.e. NGF levels as well as ILC2 specific markers such as GATA3+ CD3- cells) as well as on the technique to be used for detection. In one aspect, one may understand that the biological sample used for detection of NGF levelsmay be different from that used for the detection of GATA3+ CD3- cells.In one aspect, the biological sample used for detection of NGF levels is the same as that usedfor the detection of GATA3+ CD3- cells.Unitec Ref: PCT Application Final PAT8297PC00According to an aspect of the invention, the ILC2-rich solid cancer is selected from thenon-limiting group comprising prostate cancer, bladder cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, cholangiocarcinoma, lung adenocarcinoma, gastric cancer,breast cancer, and colorectal cancer, or combination of one or more thereof. In one aspect, thecancer is bladder cancer. In one aspect of the invention, the ILC2-rich hematologic cancer is chronicmyelogenous leukemia. In one aspect of the invention, the ILC2-rich cancer is a solid tumor, preferably a non-responsive tumor or resistant to one or more ICB. Resistance to ICB is usually determined bythe oncologist and is a clinical decision, that oncologists make depending on the response guidelines for each type of cancer. In one aspect of the invention, the ILC2-rich cancer is a hematologic tumor, preferablya non-responsive hematologic cancer not amenable, non-responsive and / or resistant to one ormore immune therapies.Usually, the TrkA inhibitor is selected from the non-limiting group comprisingGW441756, Larotrectinib, Danusertib, Entrectinib, Selitrectinib, Repotrectinib, Taletrectinib,Belizatinib, and VMD-928, or a combination of one or more thereof (for a review see Hala B.El-Nassan, Mustafa A. Al-Qadhi, Recent advances in the discovery of tropomyosin receptorkinases TRKs inhibitors: A mini review, European Journal of Medicinal Chemistry, Volume258, 2023,115618).The pharmaceutical composition of the invention and be administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral,pulmonary, instillation and subcutaneous routes. Pharmaceutical compositions of the presentinvention are preferably formulated for intravenous or instillation administration.In one aspect, the pharmaceutical composition is formulated to comprise at least onetherapeutically effective amount of Tropomyosin receptor kinase A (TrkA) inhibitor and atUnitec Ref: PCT Application Final PAT8297PC00least one therapeutically effective amount of an immune therapy, optionally with at least onepharmaceutically acceptable carrier, diluent, excipient, and / or salt. Preferably, thepharmaceutical composition is for use in the treatment and / or prevention of an ILC2 rich cancer. The present invention further contemplates methods of treatment and / or prevention ofan ILC2 rich cancer.In one aspect, the method of treatment and / or prevention of an ILC2 rich cancer comprisesadministering a pharmaceutical composition described herein to a subject in need thereof.In one aspect of the invention, the method of treatment and / or prevention of the invention comprises a step of detecting whether the cancer is an ILC2 rich cancer. It is understood thatthis detection can be determined by any suitable method known in the art (see e.g. the examplesand description herein). In a further aspect, the invention contemplates a kit for comprising the pharmaceutical composition of the invention. Preferably, the kit is for the treatment and / or prevention of an ILC2 rich cancer. The kits of the invention may also comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. Thecontainer holds a composition which is effective for treating the disease of disorder of theinvention and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).Alternatively, or additionally, the kits may further comprise a second (or third) containercomprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection(BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may furtherinclude other materials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.The label or package insert may comprise instructions for use thereof. Instructions included may be affixed to packaging material or may be included as a package insert. While theinstructions are typically written or printed materials they are not limited to such. Any mediumUnitec Ref: PCT Application Final PAT8297PC00capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. In some aspects, the kit comprises, alternatively or additionally, one or more ICB therapy described herein. Referring in more details to the examples, the Inventors identified NGF as a trigger ofILC2 activation in the context of bladder cancer, both in an orthotopic mouse model and inpatients. They found that ILC2s specifically express the NGF high affinity receptor TrkA andrespond to NGF stimulation by secreting IL-5 and IL-13. Moreover, they identified mast cellsas source of NGF in the bladder and Tregs as key players in sustaining the pro-tumoral role ofILC2s. Further, they showed that blockade of NGF-TrkA signaling reduces ILC2 effectorfunctions and results in survival advantage in an orthotopic mouse model of bladder cancer, asmonotherapy and in synergy with immune checkpoint blockade (ICB). This work dissected the NGF-TrkA-ILC2s axis in BC development and progression anddemonstrates TrkA blockade as a novel potential therapeutic strategy for BC patients,particularly in ICB-resistant patients. Lastly, the association of NGF levels with reduced patients’ survival across ILC2-rich tumor types underscores the clinical significance of this axisin human cancer (see Falquet M. et al, PhD thesis manuscript deposited at the University ofGeneva Archives). It is common practice to attempt to combine different cancer therapies. Many such combinations include immune checkpoint blockade. Despite the fact that bladder cancers are known not to respond well to ICB, the inventors have shown that combining TrkA inhibitionwith ICB surprisingly improved the response to ICB, in a synergistic manner. Considering theknown expression of immune checkpoint molecules, including PD-1 on ILC2s, the inventors were worried that additional treatment with ICB might lead to the expansion and functional activation of pro-tumoral ILC2, thereby promoting deleterious Type 2 immunity which might in fact reduce the effect of TrkA inhibition. To the inventors’ surprise, not only did the combination between TrkA inhibition and PD-1 inhibition not reduce the effect of TrkA inhibition alone, but instead resulted in a synergistic effect.Unitec Ref: PCT Application Final PAT8297PC00Usually, the synergistic effect results in an increase in the survival rate of the subject administered with a pharmaceutical composition of the invention.In one aspect, the survival rate improved of at least about 2% or more, at least about 5% ormore, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, or at least about 50% or more is detectedwith the administration of the pharmaceutical composition of the invention when comparedto the survival rate detected when only either a TrkA inhibitor or ICB therapy is administered.Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which comewithin the meaning and range of equivalency are intended to be embraced therein. Variousreferences are cited throughout this Specification, each of which is incorporated herein by reference in its entirety. The foregoing description will be more fully understood with reference to the following Examples.

[0002] Unitec Ref: PCT Application Final PAT8297PC00EXAMPLES Material and Methods Human peripheral blood cell collection Venous blood was collected from healthy donors (HDs) at the local blood transfusion center, Geneva, Switzerland, upon informed consent. Peripheral blood mononuclear cells (PBMCs) were freshly isolated by Lymphoprep (Promega) centrifugation (1800 rpm, 20 minutes, without break, room temperature). Red blood cell lysis was performed using red blood lysis buffer (Qiagen) and platelets were removed by centrifugation (1000 rpm, 10 minutes without break, room temperature). Cells were counted and immediately used or cryopreserved. Bladder cancer patient samples Blood and tumor specimens were freshly obtained from bladder cancer patients from the University Hospital of Geneva in the frame of the EC 2020-02375 protocol approved by thelocal Ethical Committee and upon written informed consent. Blood samples were collectedprior the surgery and tumor samples were excised by surgeons in the frame of trans urothelial resection of the bladder tumor (TURBT) or during cystectomy. Samples were immediately processed and used or cryopreserved. Patients’ clinical information is summarized in Table 1. All subjects gave written informed consent in accordance with the Declaration of Helsinki. PBMCs were freshly isolated by Lymphoprep (Promega) centrifugation (1800 rpm, 20 minutes, without break, room temperature). Red blood cell lysis was performed using red blood lysis buffer (Qiagen) and platelets were removed by centrifugation (1000 rpm, 10 minutes without break, room temperature). Cells were counted and immediately used or cryopreserved. Tumor biopsies were freshly collected in Leibovitz’s L-15 medium (Gibco), supplemented with Hepes (Gibco), Glucose (Sigma) and penicillin-streptomycin (Gibco). Small tumor pieces were cut and digested in complete Leibovitz’s L-15 medium containing 2.5mg / ml of Liberase TM (Roche) for 30 minutes at 37°C. For big tumor pieces, tumors were dissociated in complete Leibovitz’s L-15 medium containing 2.5mg / ml of Liberase TM (Roche) using thegentleMACS™ dissociator instrument (Miltenyi), following the manufacturer’s protocol. Cellsuspension was filtered using a 70µm strainer and red blood cells lysis was performed using red blood cell lysis Buffer (Qiagen). Cells were then ready to be stained for flow cytometry analysis or were cryopreserved.Unitec Ref: PCT Application Final PAT8297PC00Isolation and flow cytometry analyses of ILC2 from PBMCs ILCs were isolated from fresh PBMCs using a FACS Aria II (BD Biosciences). Human ILCs were identified as lineage (Lin) negative and CD127 positive cells. Lineage markers, all FITC- conjugated, include: anti-human CD3 (UCHT1, Biolegend), anti-human CD4 (RPA-T4, Biolegend), anti-human CD8 (Sp954, Immunotools), anti-human CD14 (HCD14, Biolegend), anti-human CD15 (HI98, Biolegend), anti-human CD16 (3G8, Biolegend), anti-human CD19 (HIB19, Biolegend), anti-human CD20 (2H7, Biolegend), anti-human CD33 (HIM3-4, Biolegend), anti-human CD34 (581, BD Pharmingen, 1:100), anti-human CD203c (NP4D6, Biolegend) and anti-human FcεRIα (AER-37, Biolegend). Additional markers used for ILC subsets’ identification include: PE anti-human TrkA (REA430, Miltenyi), Brilliant Ultraviolet 395 (BUV395) anti-human CD45 (HI30, BD Biosciences), Brilliant Violet 421 anti-human CD127 (IL-7Rα) (A019D5, Biolegend), Brilliant Violet 605 anti-human CD117 (c-Kit) (104D2, Biolegend), PerCP-Cyanine5.5 anti-human CD3 (UCHT1, Biolegend), PerCP- Cyanine5.5 anti-human CD8 (SK1, Biolegend), PerCP-Cyanine5.5 anti-human CD14 (HCD14, Biolegend), PerCP-Cyanine5.5 anti-human CD16 (3G8, Biolegend) and PerCP-Cyanine5.5 anti-human CD19 (H1B19, Biolegend), Alexa Fluor 647 anti-human CRTH2 (CD294) (BM16, Biolegend), PE-Cyanine7 TCRα / β (IP26, Biolegend) and PE-Cyanin7 TCRγ / δ (B1, Biolegend). Dead cells were excluded using the viability Zombie Green Dye (Biolegend).Samples used for quantification of TrkA expression were acquired on LSR Fortessa FlowCytometer (BD Biosciences) and data were analyzed using FlowJo (v.10.7.1).Human ILC2 cultureSorted human ILC2s were short-term expanded in RPMI 1640 (Gibco), supplemented with 8% human serum (HS), 1% penicillin-streptomycin (Gibco), 1% L-Glutamine (Gibco), 10mMHepes (Gibco), 1% Kanamycin (Gibco), 0.1% β-mercaptoethanol (Gibco), 1% non-essentialamino acide and 1% Na-Pyruvate with the addition of with 250U / ml recombinant humaninterleukin (IL)-2 (Roche), 10ng / ml of recombinant human IL-7 (Peprotech) and 1µg of Phytohaemagglutinin (PHA) at day 0 (Sigma). The medium was changed every 2 days. Cells were grown at 37°C with 5% CO2. Human bladder cell line (HCV29) and bladder cancer cell lines (RT-4, J82, TCC-Sup) were cultured in RPMI 1640 (Gibco), supplemented with 10% FCS (Gibco), 1% penicillin-streptomycin (Gibco), 10mM Hepes (Gibco), 0,05mg cyproxin (Bayer) and a mix of L-Arginine, L-Asparagine and L-glutamine (AAG). Cells were grown at 37°C with 5% CO2.Unitec Ref: PCT Application Final PAT8297PC00For NGF stimulation experiment, ILC2s were seeded at 2000 cells per well and stimulated with10ng / ml of recombinant human NGF (Peprotech). Supernatants was collected after 48 hours ofstimulation. For TrkA inhibition experiments, ILC2s were pre-treated with 10µM of GW441756 (Selleckchem) for 45 minutes, washed and then stimulated with 10ng / ml of NGF for 48 hours. Quantitative Polymerase Chain Reaction (qPCR) Total RNA was isolated from cells using the TRIZOL reagent according to the manufacturer’s instructions (Invitrogen) and was reverse-transcribed with the iScript Reverse Transcription Supermix for RT-qPCR (Bio-Rad). The quantitative real-time PCR was carried out in the Applied Biosystems 7900HT Fast Real-Time PCR Sequence Detection System (Applied Biosystems) with specific commercially available primers: human beta-2-microglobulin (β2M), human tropomyosin receptor kinase A (NTRK1), using KAPA SYBR® FAST qPCR Kits (Roche). Samples were amplified simultaneously in duplicate and the Ct value for each samplewas determined. The housekeeping genes human β2M was used as an internal control tonormalize the Ct values, using the 2−ΔCtformula. Cytokine quantification The concentrations of various cytokines in cell supernatants, healthy donors’ and patients’ serawere determined using the multiplex immunoassay LEGENDplex™ (Biolegend) human ThPanel (13-plex). Samples were acquired using the Attune NxT instrument and data wereanalyzed with the LEGENDplex™ Data Analysis software (v. 8.0).Mice Wild-type mice C57BL / 6 were purchased from the Jackson laboratory. Mice used in this studywere 8-12 weeks old. All mice were bred and maintained in accredited animal facilities and allanimal experiments were performed in compliance with relevant ethical guidelines for the use and the care of laboratory animals. This study was approved by the Veterinary Authority of the Swiss Geneva Canton (authorization GE4). Mouse cell culture The murine MB49 bladder tumor cell line was cultured in DMEM GlutaMAX (Gibco), supplemented with 10% fetal calf serum (Gibco) and 5% penicillin-streptomycin (Gibco). Cells were grown at 37°C with 5% CO2.Unitec Ref: PCT Application Final PAT8297PC00MB49 tumor instillation Mice were deeply anesthetized with a solution of ketamine (50mg / ml) and xylazine (20mg / ml)and were urethral catheterized using a 24-gage catheter (BD Insyte). After a 15 minutes pre-treatment with 50µl of a 22% ethanol solution and a wash with 50µl of PBS, 0.5 x 106MB49bladder tumor cells (Merck) were instilled in 50µl of PBS. The catheter was removed 15minutes after the instillation. Mice were observed and weighted every 2 days and scored based on pre-defined criteria. Mice were either monitored for survival studies, or scarified at the indicated time points for immune cell phenotyping. When indicated, 10mg / kg per mouse of the TrkA inhibitor GW441756 (Selleckchem), 50mg / kg per mouse of the TrkA inhibitor Larotrectinib (Selleckchem), or 50 mg / kg per mouse ofthe TrkA inhibitor Danusertib (Selleckchem), or the solvent control was intraperitoneallyinjected twice a week. Anti-PD1 (BioXcell, clone RMP1-14) treatment was doneintraperitoneally using 200^g / mouse at day 5 post-engraftment, combined with 10mg / kg of GW441756 intraperitoneally twice per week, when indicated. For the intravesical instillationof the TrkA inhibitor GW441756 (Selleckchem), mice were anesthetized with isoflurane andurethral catheterized using a 24-gage catheter (BD Insyte). 50µl of 15,6µM of GW441756 orthe DMSO control solutions were instilled. The catheter was removed 5 minutes after theinstillation. Isolation of murine ILCsMurine ILCs were isolated from bladders and lungs. Bladder were cut in pieces and digestedwith Liberase TM (Roche) and DNAse I (Invitrogen) at 37°C for 20 minutes, followed by thelysis of the red blood cells with a lysis buffer (Qiagen). For lung ILC isolation, lungs were cutin pieces and digested with Liberase TM (Roche) and DNAse I (Invitrogen) at 37°C for 30 minutes, followed by a Lymphoprep (Promega) centrifugation (1800 rpm, 20 minutes, without break, room temperature). The lysis of the red blood cells with a lysis buffer (Qiagen) wasadditionally performed. Cell suspension was filtered using a 70µm strainer and then stained forcell sorting. ILCs were sorted using a FACS Aria II (BD Biosciences) and were identified as lineage negative, CD90.2 positive cells. Lineage markers, all FITC-conjugated include: anti-mouse CD3e (REA641, Miltenyi), anti-mouse CD5 (53-7.3, Miltenyi), anti-mouse CD8a (53-6.7, Miltenyi), anti-mouse CD11b (M1 / 70.15.11.5, Miltenyi), anti-mouse CD11c (REA754, Miltenyi), anti-mouse CD19 (6D5, Miltenyi), anti-mouse B220 (RA3-6B2, Miltenyi), anti-Unitec Ref: PCT Application Final PAT8297PC00mouse TCRδ / γ (GL3, Miltenyi, anti-mouse TCRα / β (REA318, Miltenyi), anti-mouse TER119 (Ter-119, Miltenyi) and FcεRIα (36951, Miltenyi).Additional markers used for ILC subsets’ identification include Brilliant Ultraviolet 737 anti-mouse CD45 (30-F11, BD Biosciences), Brilliant Violet 605 anti-mouse CD90.2 (53-2.1, Biolegend), PE-Cyanine7 anti-mouse KLRG1 (2F1 / KLRG1, Biolegend), PE anti-mouse ST2 (RMST2-2, Invitrogen), Brilliant Violet 711 anti-mouse NK1.1 (PK136, BD Biosciences) and Brilliant Violet 650 NKp46 (29A1.A, Biolegend). Statistical analysisStatistical analysis was performed using GraphPad Prism software (v. 10.0.0.). The normalitywas first assessed with the Shapiro-Wilk test, then adequate statistical analysis was performed based on the dataset. Data are shown by plotting individual data points and the mean ± SEM. A p-value less than 0.05 was considered as statistically significant. Results NGF drives ILC2 functions via TrkA engagement TrkA is the high affinity receptor for NGF, and NGF signaling modulates inflammatory responses in the bladder and in other tissues. Given the role of ILC2s in BC recurrence in patients3and their responsiveness to neural peptides, neurotrophins and neurotransmitters in inflammatory settings, we reasoned that ILC2s might express the NGF receptors. To confirmthis hypothesis, the Inventors sorted the 3 main ILC subsets from the peripheral blood of HDsand bladder cancer patients and compared the neurotrophic receptors’ transcriptional levels by qPCR (NTRK1, encoding for TrkA; p75NTR, encoding for the NGF low-affinity receptor p75;NTRK2, encoding for Tropomyosin receptor kinase B, TrkB; NTRK3, encoding forTropomyosin receptor kinase C, TrkC, Figure 1A). The Inventors found that NTRK1 waspreferentially expressed by ILC2s both in HDs and in BC patients (Figure 1A) and itsexpression was confirmed at protein level, with a trend for an increase in BC patients’ ILC2s(Figure 1B). The main function of ILC2s is the secretion of Type-2 cytokines. To define a putative role forNGF in ILC2s, the Inventors stimulated short-term expanded human ILC2s with recombinanthuman NGF and analyzed cytokine secretion. NGF-stimulated ILC2s secreted high levels of the Type-2 cytokines (Figure 1C-D). To assess the specificity of the NGF effect, the Inventors pretreated ILC2s with non-toxic concentrations of GW441756, a selective TrkA inhibitor. UponUnitec Ref: PCT Application Final PAT8297PC00treatment with the inhibitor, the NGF-mediated secretion of IL-5 and IL-13 was reverted to basal levels (Figure 1C-D), demonstrating that NGF triggers ILC2 cytokine production viaTrkA engagement. Thus, the Inventors demonstrate that NGF is a potent and fast ILC2activator. Pharmacologic TrkA inhibition favors survival in synergy with ICB in an orthotopic BC modelTo assess the in vivo relevance of these findings, the Inventors established an orthotopic mousemodel of bladder cancer relying on the intravesical instillation of the MB49 bladder cancer cell line. ILC2s isolated from healthy bladders and tumor-infiltrated bladders at day 1 and day 3post MB49 instillation expressed high levels of Ntrk1 (Figure 2A).Therefore, the Inventors in vivo blocked the NGF-TrkA signaling by injecting the TrkAinhibitor GW441756 intraperitoneally and evaluated mouse survival. They observed asignificant survival advantage when MB49 tumor-bearing mice were treated with GW441756 (Figure 2B), demonstrating that TrkA-blockade is sufficient to dampen tumor cell growth. No effect of the inhibitor was observed when administered in ILC2KO tumor bearing animals, arguing for an ILC2-dependent NGF-TrkA effect. Similar results were observed using otherTrkA inhibitors, i.e., Larotrectinib and Danusertib (Figure 2C). Moreover, to reduce potentialsystemic toxicity, increase local delivery and be closer to the clinical setting, in which theconventional BCG therapy is intravesically delivered, the Inventors administered GW441756intravesically (Figure 2D), at concentrations not affecting tumor cell survival in vitro andmonitored animal survival. Similar to the previous experiment (Figure 2B), mice receiving theTrkA inhibitor showed a survival advantage, supporting the therapeutic potential for TrkA-blockade in BC patients resistant to current treatment (Figure 2D). Interestingly, by mining theTCGA BC patients’ dataset the Inventors observed significantly higher expression of immunecheckpoint molecules in the NGFhighcompared to NGFlowcohort and low NGF concentrationspredicted better response to immunotherapy, as indicated by the lower Tumor immunedysfunction and exclusion (TIDE) score of these patients. Therefore, the Inventors reasonedthat by alleviating the local NGF-TrkA immune suppressive axis, ICB therapy would showsuperior efficacy. To test this, they treated tumor-bearing mice with GW441756 and anti-PD1antibody (BioXcell, clone RMP1-14) and observed synergy of the two treatments, as compared to either of the monotherapies, with important clinical implications for resistant / relapsing patients (Figure 3).Unitec Ref: PCT Application Final PAT8297PC00Discussion In the bladder, NGF has been identified as a key regulator of organ function and is involved inseveral bladder inflammatory pathologies. Here, the Inventors highlighted NGF as a novelregulator of tumor immunity in BC, both in patients and tumor bearing animals, and theInventors demonstrate its mechanism of action on tissue infiltrating, pro-tumoral, TrkA+ ILC2s,in turn impacting on Tregs. Pre-clinical targeting of the NGF-TrkA axis and the observation that increased NGF expression correlates with poor survival in BC patients attest of its therapeutic potential for this highly deadly disease. Neuronal-derived factors are emerging as key regulators of ILC functions, either by potentiating or by inhibiting their functions. Tumor derived mediators might be responsible to induce neurotrophic factor receptors’ expression on ILC2s. If other tumor types known to be heavily ILC2 infiltrated (e.g., prostate cancer9, hepatocellular carcinoma10, pancreas11, lung8, gastric cancer10, colorectal cancer12) also display enriched TrkA+innate lymphocytes remains to be established. Interestingly, TCGA mining of these ILC2-rich cancers for associations between survival and NGF concentrations showed strong survival reduction in gastric and colorectal cancer patients with high NGF transcript levels and ILC2 infiltration. TrkA+ILC2s respond to NGF by exacerbating their Type2 pro-tumoral phenotype. Besides its role in modulating neural plasticity, NGF has been described to act as an immunomodulator in different inflammatory processes, by activating immune cells. However, in the context of tumor immunity, the role of NGF has been mainly centered on its effect on tumor cells13, rather than on the immune system. In breast cancer, NGF alters tumor cell migration, proliferation andinvasiveness in vitro and in vivo. Similar observations were made using prostate cancer models,and high proNGF has been correlated with increased Gleason score in prostate cancer patients. In melanoma, it was recently reported on the NGF action on both malignant melanoma cells and TrkA+low-affinity CD8 T cells6. Knowing that NGF-TrkA inhibition was shown to directly impact cancer cell proliferation, survival5, and sensitization to IFN^^, synergistic effects can be expected by targeting tumors composed of both TrkA+cancer cells and TrkA+ILC2s, potentially resulting in the restoration of immune effector functions and impacting on survival.The in vivo TrkA blockade resulted in improved survival of tumor-bearing mice, when theinhibitor was delivered either intraperitoneally or intravesically. A number of TrkA inhibitors are currently tested in the clinics for treatment of chronic pain or other malignancies, with very good safety profiles. The conventional therapy for NMIBC being the intravesical delivery of BCG, the use of TrkA inhibitors for non-BCG-responsive patients or as alternative to BCG will increase responses rate and prevent relapse and disease progression, a major challenge in BC.Unitec Ref: PCT Application Final PAT8297PC00Furthermore, while immune checkpoint blockers were introduced for the treatment of MIBC and five of them have been approved by the Food and Drug Administration1, only a limited number of patients respond, despite the positive predictive score of PD1 / PD-L1 and the hightumor mutational burden of this cancer type. The present in vivo combination treatments’ resultssuggested that the use of TrkA inhibitors might pre-condition NGFhighBC patients, or patients with other NGFhightumors, for subsequent treatment with anti-PD-1 / PDL1 blocking agents, rendering non-responsive tumors amenable to immune checkpoint blockade. Table 1. Clinical characteristics of the BC patients. aCalculated at the surgery date.

[0003] Unitec Ref: PCT Application Final PAT8297PC00References1 Rouanne, M. et al. Development of immunotherapy in bladder cancer: present and future ontargeting PD(L)1 and CTLA-4 pathways. World J Urol 36, 1727-1740, doi:10.1007 / s00345-018- 2332-5 (2018).2 Lopez-Beltran, A. et al. Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer.Cancers (Basel) 13, doi:10.3390 / cancers13010131 (2021).3 Chevalier, M. F. et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancerrecurrence. J Clin Invest 127, 2916-2929, doi:10.1172 / JCI89717 (2017).4 Griffin, N., Faulkner, S., Jobling, P. & Hondermarck, H. Targeting neurotrophin signaling incancer: The renaissance. Pharmacol Res 135, 12-17, doi:10.1016 / j.phrs.2018.07.019 (2018).5 Meldolesi, J. Neurotrophin Trk Receptors: New Targets for Cancer Therapy. Rev PhysiolBiochem Pharmacol 174, 67-79, doi:10.1007 / 112_2017_6 (2018).6 Yin, T. et al. Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapyfor durable memory T cell protection. Nat Immunol, doi:10.1038 / s41590-023-01723-7 (2024).7 Taylor, S. et al. PD-1 regulates KLRG1(+) group 2 innate lymphoid cells. J Exp Med 214, 1663-1678, doi:10.1084 / jem.20161653 (2017).8 Schuijs, M. J. et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cellantimetastatic function in the lung. Nat Immunol 21, 998-1009, doi:10.1038 / s41590-020- 0745-y (2020).9 Trabanelli, S. et al. Tumour-derived PGD2 and NKp30-B7H6 engagement drives animmunosuppressive ILC2-MDSC axis. Nat Commun 8, 593, doi:10.1038 / s41467-017-00678-2 (2017).10 Xu, X. et al. Group-2 Innate Lymphoid Cells Promote HCC Progression Through CXCL2-Neutrophil-Induced Immunosuppression. Hepatology 74, 2526-2543, doi:10.1002 / hep.31855 (2021).11 Alam, A. et al. Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreaticcancer. Cancer Cell 40, 153-167 e111, doi:10.1016 / j.ccell.2022.01.003 (2022).12 Ercolano, G. et al. PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions. Nat Commun 12,2538, doi:10.1038 / s41467-021-22764-2 (2021).13 Aloe, L., Rocco, M. L., Balzamino, B. O. & Micera, A. Nerve growth factor: role in growth,differentiation and controlling cancer cell development. J Exp Clin Cancer Res 35, 116, doi:10.1186 / s13046-016-0395-y (2016).14 Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin CancerRes 38, 255 (2019)15. Twomey, J.D., Zhang, B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitorsand Companion Diagnostics. AAPS J 23, 39 (2021)16. Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonisticdrugs for cancer immunotherapy. MAbs.2023 Jan-Dec;15(1):216718917. Jian CZ, Lin L, Hsu CL, Chen YH, Hsu C, Tan CT, Ou DL. A potential novel cancer immunotherapy:Agonistic anti-CD40 antibodies. Drug Discov Today.2024 Mar;29(3)18. Hala B. El-Nassan, Mustafa A. Al-Qadhi, Recent advances in the discovery of tropomyosinreceptor kinases TRKs inhibitors: A mini review, European Journal of Medicinal Chemistry, Volume 258, 2023,11561819. Falquet M. et al, PhD thesis manuscript deposited at the University of Geneva Archives

Claims

Unitec Ref: PCT Application Final PAT8297PC00CLAIMS1. A pharmaceutical composition comprising a therapeutically effective amount of at leastone Tropomyosin receptor kinase A (TrkA) inhibitor for use in the treatment and / or preventionof an ILC2 rich cancer and at least one pharmaceutically acceptable carrier, diluent, excipient,and / or salt , wherein the TrkA inhibitor is administered concomitantly, separately or staggeredin time with a therapeutically effective amount of at least one immune therapy.

2. The pharmaceutical composition of claim 1, wherein the ILC2 rich cancer is not a TrkAfusion cancer.

3. The pharmaceutical composition of claim 1 or 2, wherein the immune therapy is animmune checkpoint blockade (ICB) therapy.

4. The pharmaceutical composition of claim 3, wherein the ICB therapy is selected fromthe group comprising a PD-1 inhibitor, a PD-L1 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor,a TIGIT inhibitor, and a CTLA-4 inhibitor, or combination of one or more thereof.

5. The pharmaceutical composition of anyone of claims 1 to 2, wherein the immunetherapy is selected from the group comprising a 4-1BB agonist, a CD73 inhibitor, a CD40agonist, Bacillus Calmette-Guerin (BCG), and Ty21a, or combination of one or more thereof.

6. The pharmaceutical composition of any one of the preceding claims, wherein the ILC2rich cancer is selected from the group comprising prostate cancer, bladder cancer,hepatocellular carcinoma, pancreatic ductal adenocarcinoma, cholangiocarcinoma, lungadenocarcinoma, gastric cancer, breast cancer, colorectal cancer, and chronic myelogenousleukemia, or a combination of one or more thereof.

7. The pharmaceutical composition of any one of the preceding claims, wherein the ILC2rich cancer is a solid tumor, preferably a tumor that is non-responsive or resistant to immunecheckpoint blockade.

8. The pharmaceutical composition of any one of the preceding claims, wherein the TrkAinhibitor is selected from the group comprising GW441756, Larotrectinib, Danusertib,Unitec Ref: PCT Application Final PAT8297PC00Entrectinib, Selitrectinib, Repotrectinib, Taletrectinib, Belizatinib, and VMD-928, or acombination of one or more thereof.

9. The pharmaceutical composition of any one of the preceding claims , wherein the ILC2rich cancer displays high levels of Nerve Growth Factor (NGF).

10. The pharmaceutical composition of any one of the preceding claims, wherein thepharmaceutical composition is administered by a route of administration selected from the group comprising inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal,intravenous, nasal, oral, parenteral, pulmonary, instillation (e.g. intravesical instillation) andsubcutaneous routes, or a combination of one or more thereof.

11. A kit comprising the pharmaceutical composition of any one of claims 1 to 10.

12. A method of treatment and / or prevention of an ILC2 rich cancer, comprisingadministering a pharmaceutical composition of any one of claims 1 to 10 to a subject in needthereof.

13. A method of treatment and / or prevention of an ILC2 rich cancer, comprisingi) detecting whether the cancer is an ILC2 rich cancer and, if the cancer is determinedas an ILC2 rich cancer, ii) administering a pharmaceutical composition of any one of claims 1 to 10 to asubject in need thereof.

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