Targeting immunosuppressive tumor microenvironment by blocking nicotinamide phosphoribosyltransferase (NAMPT) in myeloid cells

Abstract

Provided are approaches to treating, inhibiting the progression of, or preventing disorders associated with the presence of immunosuppressive activity of myeloid-derived suppressor cells (MDSCs). The methods include administering an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) to an individual in need of prophylaxis or treatment of the disorder associated with the presence of the MDSCs. The NAMPT inhibitor can be combined with other agents or treatments to provide an enhanced effect.

Description

[0001] TARGETING IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT BY BLOCKING NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) IN MYELOID CELLS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. provisional application no. 63 / 659,397, filed June 13, 2024, the entire disclosure of which is incorporated herein by reference.

[0004] BACKGROUND

[0005] Many patients with cancer unfortunately experience inadequate responses to treatment, and immune suppression in the tumor microenvironment (TME) continues to be a significant driver of poor outcomes. A major process contributing to this phenomenon is the expansion of myeloid-derived suppressor cells (MDSCs)1,2, as these cells potently suppress antitumor immune responses4'6. MDSC populations are comprised of a diverse collection of cells derived from the bone marrow of mice and humans, and they are commonly described as either monocytic MDSCs (M-MDSCs), which resemble immature monocytes, or polymorphonuclear MDSCs (PMN-MDSCs), which resemble immature neutrophils.7Several cancers, such as triple negative breast cancer (TNBC), often promote the expansion of MDSCs8, and their accumulation in patients is associated with poor clinical outcomes9,10, increased rates of metastasis11, and decreased efficacy of immunotherapy -based 17 13 treatments ’ .

[0006] Multiple Myeloma (MM) is the second most common hematologic malignancy and is considered incurable in most patients. Even though, there has been significant improvement in MM patient survival mainly facilitated by the development of novel treatment options including immunomodulatory drugs (IMiDs), proteasome inhibitors (Pls), monoclonal antibodies (mabs), bispecific antibodies and cellular therapies. However, many of these treatment options heavily rely on a healthy, intact, patient immune system to fully leverage their efficacy14,15. Prior studies have shown that the phenotype and function of immune cells in the BM microenvironment in MM is dysregulated. Several indications of this dysregulation include changes in cytokines released, the activation of various signaling pathways, and numerous alterations in T cell, natural killer (NK) cell, and myeloid cell populations. It has also been shown that MM cells can induce immunosuppression through accumulation of regulatory T cells, tumor associated neutrophils (TANs), dysfunctional NK cells and tumor associated macrophages16. The accumulation of immunosuppressive cells in the MM patient BM is linked to impaired anti-tumor responses and increased angiogenesis17. Rigorous research efforts to reprogram myeloid cells in the tumor microenvironment (TME) to unleash antitumor immunity and improve outcomes may prove to be a fruitful approach18. There has been significant increase in our understanding about the biology of myeloid cells especially immature and mature neutrophils in TME19but there is still a need to discover new targetable pathways that are specifically increased in tumor associated- but not normal neutrophils. The present disclosure is pertinent to this need.

[0007] BRIEF SUMMARY

[0008] The present disclosure provides approaches to treating, inhibiting the progression of, or preventing disorders associated with the presence of immunosuppressive activity of myeloid-derived suppressor cells (MDSCs). In an example, the disclosure provides a method comprising administering an effective amount of a composition comprising an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) to an individual in need of prophylaxis or treatment of a disorder associated with the presence of the MDSCs. In examples, the disclosure includes also administering at least one additional agent or treatment to the individual. In examples, the additional agent or treatment provides an improved effect on the disorder relative to administration of the additional agent or the NAMPT inhibitor alone. In examples, the additional agent comprises an immunotherapy, a chemotherapy, or a vaccine, or the treatment comprises therapeutic radiation. Combinations of additional agent(s) and a described treatment are included. In examples, a combination of the NAMPT inhibitor and the additional agent is administered to an individual who is resistant to the additional agent when used as a monotherapy. In examples, the MDSCs are in a tumor microenvironment of the individual. In examples, the disclosure includes administering a described NAMPT inhibitor with a vaccine or other immunogenic agent. In examples, administering the NAMPT inhibitor provides an improved effect on the disorder relative to administration of the vaccine or other immunogenic agent compared to using the or the NAMPT inhibitor alone. In examples, the disorder comprises cancer, obesity, or a chronic infection, or a combination thereof. In examples, the individual treated according to a described approach is at least 65 years old. In examples, administration of the NAMPT inhibitor is a systemic administration. In a non-limiting example the NAMPT inhibitor is OT-82. BRIEF DESCRIPTION OF FIGURES

[0009] FIG. 1 : Myeloid cell subpopulation alterations in the Bone Marrow (BM) and Osteolytic Lesions (OL) of patients with newly diagnosed multiple myeloma (NDMM) compared to BM from healthy donors (HDBM). Myeloid cell sub-population distribution in HDBM and NDMM patient BM and OL. CD1 lb+ CD3- CD56- CD138- cells were freshly sorted from BM and OL aspirates. After QC and normalization, all samples are pooled together for a total of 120,237 CD1 lb+ cells. UMAP dimensionality reduction and unsupervised clustering was performed. UMAP plots from left to right: Samples from HDBM (total 11,490 cells sequenced from 3 HD controls), NDMM patient BM (total 26,828 cells sequenced from 7 patients), NDMM patient OL (total 27,502 cells sequenced from 6 patients). Populations 1, 4, 8, and 11 are highly enriched in MM patients compared to HDBM.

[0010] FIG. 2: Nicotinamide phosphoribosyltransferase (NAMPT) is highly expressed in OL neutrophils. UMAP plot with the normalized expression of the selected neutrophil population marker.

[0011] FIG. 3: Preclinical MM treatment with OT-82 with monitoring by serum protein electrophoresis (SPE). C57BL / 6 mice were intravenously injected with VK*MYC12653 MM cells (1 x 106). When the M-band ratio (IgG to albumin) reached 0.28 (almost 4 weeks after tumor injection), the NAMPT inhibitor, OT-82, was administered at dose of 40 mg / kg orally for 6 days of the week based on previous studiesl3. Tumor burden and overall survival were monitored. Results are representative of two independent experiments with n=5 mice per group. Two-way ANOVA was used to analyze statistical significance among tumor growth in different groups. For comparison of survival curves, a log-rank (Mantel-Cox) test was used. Data are shown as Mean ± SD. *p < 0.05.

[0012] FIG. 4: NAMPT inhibition decreased the immunosuppressive function of neutrophils. CD1 lb+ Ly6G+ cells were generated in vitro using IL-6 (40 ng / ml) and GM-CSF (40 ng / ml) for 4 days in the presence of OT-82 (1 nM) or vehicle (DMSO). CD1 lb+Ly6C-Ly6G+ were sorted by flow cytometry. Sorted CD1 lb+Ly6C-Ly6G+ were co-cultured with anti-CD3 / anti- CD28 stimulated T cells (Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE)-labeled). After 72 hrs., proliferation of CD8+ T cells were assessed by flowcytometry. Unsimulated T cells served as a negative control and T cells alone stimulated with anti-CD3 and anti-CD28 served as a positive control (data not shown). The Student’s t test was used to analyze statistical significance between 2 groups in each dilutions.

[0013] FIG. 5. Graphs summarizing data showing blocking NAMPT using OT-82 decreases MM tumor progression in Vk*MYC (Vkl263) model. C57BL / 6 mice were injected with Vk*MYC tumor cells. Four weeks after tumor injection, mice were treated with either vehicle or OT-82 (40 mg / kg, six days per week) for the duration of the study. M-spike in the left panel of FIG. 5 is the ratio of gamma globulin (monoclonal antibody secreted by tumor cells) to albumin. M-spike is a measurement of tumor burden wherein a higher number means a greater tumor burden. The asterisk means the significance of the differences between groups. * means P value is less than 0.05. The data were obtained from 5 mice. The right panel of FIG. 5 shows the probability of survival.

[0014] FIG. 6. Graph summarizing data showing blocking NAMPT with OT-82 enhances the efficacy of bortezomib and dexamethasone against multiple myeloma tumor progression in the Vk*MYC (Vkl263) model. To obtain the data shown in FIG. 6, C57BL / 6 mice were injected with Vk*MYC tumor cells. Four weeks after tumor injection, mice were treated for the duration of the study with one of the following regimens: vehicle; OT-82 (40 mg / kg, intraperitoneally, six days per week); bortezomib (0.5 mg / kg, subcutaneously, once weekly); dexamethasone (0.6 mg / kg, intraperitoneally, once weekly); or a combination of OT-82, bortezomib (BTZ), and dexamethasone (DEX).

[0015] DETAILED DESCRIPTION

[0016] Unless defined otherwise herein, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0017] Every numerical range given throughout this specification includes its upper and lower values, as well as every narrower numerical range that falls within it, as if such narrower numerical ranges were all expressly written herein.

[0018] The disclosure provides for administering one or more NAMPT inhibitors to an individual in need thereof. Examples of this disclosure are based at least in part on the discovery that the gene NAMPT, encoding Nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme of NAD biosynthesis is highly overexpressed in tumor-associated neutrophil populations in MM patients.

[0019] For modeling human therapeutic approaches, the disclosure in some examples uses murine models, which permits use of CD1 lb+, Ly6Cmid, and Ly6G+markers to identify TANs that encompass all populations including polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs)20). We previously demonstrated strong NAMPT dependence of cells representing a variety of hematologic malignancies making them especially vulnerable to NAMPT inhibitors3.

[0020] In examples of this disclosure, the individual is in need of treatment with an NAMPT inhibitor is in need of treatment for a pathological condition or disease associated with the immunosuppressive activity of MDSCs. In an example, the individual is treated using systemic administration of a NAMPT inhibitor. NAMPT inhibitor treatment can be combined with other approaches, non-limiting examples of which include immunotherapy, radiation therapy, targeted therapies, chemotherapy, or other agents that will be apparent to those skilled in the art when given the benefit of the present disclosure.

[0021] In an example the individual to whom an NAMPT inhibitor is administered (alone or in combination with one or more other agents) has cancer, obesity, a chronic infection, or has aging-associated immunosenescence. In an example, the individual is above 65 years old.

[0022] In an example, a NAMPT inhibitor is used to potentiate an immune response. As such, a NAMPT inhibitor may be combined with vaccination. The vaccination may be prophylactic or therapeutic.

[0023] In examples, use of a NAMPT inhibitor produces a greater than additive effect when combined with another agent that is intended to treat a disease or condition as described herein, and thus a synergistic effect may be elicited. In an example, administration of a NAMPT inhibitor sensitizes an individual to an agent to which the individual has been determined to be resistant.

[0024] In an example, a NAMPT inhibitor named OT-82 may be used3,21. Examples providing a proof-of-principle using OT-82 are provided herein, but other NAMPT inhibitors could be substituted for, or combined with OT-82, representative and non-limiting examples of which include FK866, GEN617, LSN3154567, CHS828, A1293201, GMX1777, KPT- 9274, APO866, ATG-019, which are described in PMID: 36160449, the disclosure of which is incorporated herein by reference.

[0025] In examples, a described NAMPT inhibitor is combined with a chemotherapeutic agent, or an immunomodulatory agent such as an agent that may induce tolerance to one or more antigens, or with therapeutic radiation, or with an immune effective amount of a vaccine, adjuvant, or combination thereof. In examples, a described NAMPT inhibitor is combined with one or more immune checkpoint inhibitors, such as anti-PD-1, anti-PD-Ll, anti-CTLA-4, anti LAG-3, or related antibody -based agents. In an example, use of an NAMPT inhibitor may overcome resistance to immune checkpoint inhibition exhibited by so- called “cold tumors.” In examples, a described NAMPT inhibitor is used in combination with an anticancer agent, such as an anti-MM agent, a non-limiting example of which comprises bortezomib. In examples, a described NAMPT inhibitor is used in combination with another agent, such as a corticosteroid, a non-limiting example of which comprises dexamethasone. In an example, a described NAMPT inhibitor is used in combination with another anti-cancer agent and another agent, such as a corticosteroid. In an example, the only active agent(s) administered may comprise a described NAMPT inhibitor. In examples, the NAMPT inhibitor is used in combination with only one, or only two, additional agents, the provide a described anti-cancer therapeutic effect.

[0026] The disclosure includes a proviso that any described use of a NAMPT inhibitor, and specifically OT-82, may exclude any use that is expressly described in PCT publication WO2017189553. In non-limiting examples, the disclosure may exclude, for example, administration of an NAMPT inhibitor solely for the purpose of selectively killing senescent cells, including but not necessarily limited to senescence associated macrophages (SAMs).

[0027] In examples, a described NAMPT inhibitor is administered in a formulation such that it is targeted to neutrophils. In examples, human neutrophil markers that may be used for targeting neutrophils to provide a therapeutic benefit to the individual include but are not necessarily limited to CD66 and CD16b. In examples, N2 neutrophils may be targeted.

[0028] In examples, a therapeutically effective amount of one or NAMPT inhibitors, alone or in combination with another agent, is delivered to an individual. The term “therapeutically effective amount” as used herein refers to an amount of a described agent, in a single dose or multiple doses, to achieve the intended purpose of treatment. The amount desired or required may vary depending its mode of administration, patient specifics and the like. Appropriate effective amounts can be determined by one of ordinary skill in the art informed by the instant disclosure using routine experimentation. In examples, a combination of described agents is administered to an individual. In examples, a described agent alone or in combination with at least one other described agent is administered to an individual and is sufficient to achieve a therapeutic effect. The described agent(s) may also be used prophylactically.

[0029] In non-limiting embodiments a described agent of this disclosure is combined with one or more pharmaceutically acceptable agents. In examples, a described agent is combined with unilamellar and / or multilamellar vesicular structures such as liposomes or lipid nanoparticles, cationic polymers, lipoplexes, polyplexes, or inorganic nanoparticles. Any delivery agent described herein may comprise polyethylene glycol (PEG) and thus may be PEGylated.

[0030] In an example, the disclosure provides for testing a biological sample from an individual to determine differential expression of the NAMPT gene, relative to a value for expression of the NAMPT gene obtained from one or more individuals who do not have a condition of interest to be treated. Upon determining differential expression of the NAMPT gene for any particular individual, the disclosure includes administration of one or more NAMPT inhibitors as described herein, alone or with other therapeutic or prophylactic agents.

[0031] The following examples are intended to illustrate but not limit the disclosure.

[0032] To characterize the phenotype and transcriptional changes in myeloid cells in MM patients, we used single-cell RNA sequencing (scRNA seq) transcriptomics to dissect the differences between the myeloid cell populations in the BM and osteolytic lesions (OL) TME of MM patients (n=13) and compared them with myeloid cells of BM from healthy donors (HDBM) (n=3 controls). We sorted myeloid cells from fresh samples (to avoid freezingthawing to maintain PMN cell viability) to gain insight into the spectrum of myeloid cell heterogeneity. We observed that the myeloid cell composition in the MM patient BM and OL is substantially different compared to HDBM (FIG. 1). We discovered four subpopulations of neutrophils (1, 4, 8, and 11; FIG. 1) emerging in the TME of MM patients that do not exist or are at extremely low levels in HDBM. Based on previous scRNA seq literature, it seems that populations 2, 1, and 0 are the precursors of neutrophils22. Three main neutrophil populations (1, 4, and 11) were identified in all MM patients, but population 8 was seen primarily in one patient. We also observed populations of CD 16" HLA-DR+and CD16+HLA-DR+tumor associated macrophages in the BM and OL of MM patients (FIG.l and FIG. 2). We compared the differential gene expression in myeloid cells between OL and BM in individual patients to determine if there was a unique gene profile of myeloid cells in OL. The top gene expressed by BM and especially OL neutrophils in MM patients was NAMPT (FIG. 2).

[0033] NAMPT mediates the rate-limiting step of the nicotinamide adenine dinucleotide (NAD) salvage pathway, maintaining cellular bioenergetics and provides a necessary substrate for essential functions for proliferating cells and particularly cancer cells. Indeed, NAMPT has been long considered a potential cancer treatment target23. Preclinically, pharmacologic NAMPT inhibitors (NAMPTis) have been shown to deplete NAD, resulting in loss of cell viability in a variety of different cancers24. Because the cellular functions of NAD are broad, NAMPT may have multiple anti-cancer effects including inhibition of energy metabolism, increased susceptibility to oxidative stress, and impairment of DNA damage repair via indirect PARP inhibition25'27. Since NAMPT deletion is embryonically lethal, most studies on NAMPT function have been conducted with NAMPTis. First-generation NAMPTis were tested in early phase clinical trials in adult patients with advanced cancer28,29. BM suppression, especially thrombocytopenia and gastrointestinal toxicities were doselimiting, but due to the low objective responses and NAMPTi-associated toxicities30, further development was halted31.

[0034] OT-82 possesses a favorable toxicity profile than earlier-generation NAMPTs, especially with regard to retinal and cardiac toxicities seen in animal studies with earlier- generation molecules but not observed with OT-823and higher efficacy in in vitro testing against leukemia stem cells.

[0035] Despite previous knowledge about the role of NAMPT in tumor growth32, little is known about how NAMPT regulates the TME, including neutrophil accumulation and function or whether targeting NAMPT will limit MM-associated neutrophil accumulation. Accordingly, in examples, the disclosure includes testing a biological sample from an individual to assess neutrophil accumulation. Such testing may be performed prior to a first described treatment, or to monitor effects on neutrophils during a course of treatment.

[0036] NAMPT is a negative regulator of the CXCR4 retention axis of BM immature myeloid cells leading to mobilization of immature myeloid suppressor cells out of the BM33. The presently provided in vivo MM patient data suggest that NAMPT is an important factor in neutrophil accumulation and function.

[0037] We analyzed if the NAMPT inhibitor, OT-82 can decrease tumor growth in a preclinical model of MM. VK*MYC MM cells (1 x lO6) were given intravenously. Tumor growth was monitored by plasma clonal IgG accumulation by serum protein electrophoresis (SPE). When the IgG monoclonal protein (M-spike) to albumin ratio surpasses 0.28 (corresponding to ~10 g / L clinically), treatment with OT-82 started (FIG. 3). OT-82 significantly decreased tumor burden and improved overall survival (FIG. 3).

[0038] FIG. 4 shows that NAMPT inhibition decreased the immunosuppressive function of neutrophils.

[0039] FIG. 5 shows that blocking NAMPT using OT-82 decreases MM tumor progression in Vk*MYC (Vkl263) model.

[0040] FIG. 6 shows that blocking NAMPT with OT-82 enhances the efficacy of bortezomib and dexamethasone against multiple myeloma tumor progression in the Vk*MYC (Vkl263) model.

[0041] REFERENCES - This reference listing is not an indication that any particular reference is material to patentability:

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Claims

What is claimed is:

1. A method comprising administering an effective amount of a composition comprising an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) to an individual in need of prophylaxis or treatment of a disorder associated with the presence of immunosuppressive activity of myeloid-derived suppressor cells (MDSCs).

2. The method of claim 1, further comprising administering at least one additional agent or treatment to the individual, wherein the at least one additional agent or treatment provides an improved effect on the disorder relative to administration of the additional agent or the NAMPT inhibitor alone.

3. The method of claim 2, wherein the additional agent comprises an immunotherapy, a chemotherapy, or a vaccine, or wherein the treatment comprises therapeutic radiation.

4. The method of claim 3, wherein a combination of the NAMPT inhibitor and the additional agent is administered to the individual, and wherein the individual is resistant to the additional agent when used as a monotherapy or when the additional agent is used in a combination of agents that does not include the NAMPT inhibitor.

5. The method of claim 4, wherein the MDSCs are in a tumor microenvironment of the individual.

6. The method of claim 5, comprising administering the NAMPT inhibitor with a vaccine or other immunogenic agent.

7. The method of claim 6, wherein administering the NAMPT inhibitor provides an improved effect on the disorder relative to administration of the vaccine or the NAMPT inhibitor alone.

8. The method of any one of claims 1-7, wherein the disorder comprises cancer, obesity, or a chronic infection.

9. The method any one of claims 1-7, wherein the individual is at least 65 years old.

10. The method of any one of clams 1-7, wherein the administration of the NAMPT inhibitor is a systemic administration.

11. The method of any one of claims 1-7, wherein the NAMPT inhibitor is OT-82.

12. The method claim 8, wherein the NAMPT inhibitor is OT-82.

13. The method of claim 9, wherein the NAMPT inhibitor is OT-82.

14. The method of claim 10, wherein the NAMPT inhibitor is OT-82.

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