Ibrutinib

Chronic Lymphocytic Leukemia (CLL) Models

Preclinical studies in CLL models have shown that this compound can induce apoptosis in CLL cells, even in the presence of stromal support and pro-survival factors like CD40L and B-cell activating factor nih.gov. This suggests that this compound can overcome the protective effects of the tumor microenvironment. This compound effectively blocks signaling through BTK, a key kinase in the BCR pathway, inhibiting the phosphorylation of downstream substrates such as PLC-γ in a dose-dependent manner nih.gov.

Beyond directly impacting CLL cell survival and proliferation, this compound also impairs CLL cell migration in response to homing chemokines like CXCL12 and CXCL13 nih.gov. Furthermore, it downregulates the secretion of BCR-dependent chemokines CCL3 and CCL4, contributing to tumor regression in xenograft mouse models, such as the TCL1 model nih.gov.

In vitro studies have shown dose- and time-dependent cytotoxicity in CLL cells via a caspase-3 dependent apoptotic pathway researchgate.net. This compound has an IC50 of 0.5 nM for inhibiting BTK phosphorylation on Tyr 223 for over 24 hours researchgate.net.

Mantle Cell Lymphoma (MCL) Models

In preclinical MCL cell lines, this compound has demonstrated inhibition of downstream BCR signaling and induction of cell apoptosis nih.gov. Studies in canine models of spontaneous B-cell lymphoma, which share similarities with human MCL, showed objective clinical responses in a subset of dogs with rapidly progressive disease nih.govnih.gov. A single administration of 2.5–20 mg/kg per day was sufficient to fully occupy BTK in peripheral blood and tumor tissue for 24 hours nih.gov. Three out of eight treated dogs achieved a partial response, and three maintained stable disease nih.gov.

More recent preclinical studies in MCL models have explored combination therapies involving this compound. For instance, combining this compound with the Aurora A kinase inhibitor alisertib and rituximab displayed significantly stronger tumor growth inhibition compared to doublet therapies in an MCL mouse model onclive.com. The triplet therapy resulted in approximately 82% tumor growth inhibition, compared to approximately 76% for this compound plus rituximab and approximately 62% for alisertib plus this compound onclive.com. This compound monotherapy showed approximately 50% tumor growth inhibition in this model, while alisertib monotherapy showed approximately 13% onclive.com. Alisertib and this compound demonstrated synergistic effects, enhancing apoptosis and reducing phosphorylated proteins in MCL cell lines onclive.com.

Preclinical models also suggest synergistic activity when venetoclax, a BCL-2 inhibitor, is combined with BTK inhibitors in MCL, providing a rationale for combination therapy hematologyandoncology.net.

Burkitt Lymphoma (BL) Models

Preclinical investigations of this compound in Burkitt lymphoma models have shown promising results. This compound significantly inhibited the levels of phospho-BTK protein in BL cells in vitro (p < 0.001) nih.govtandfonline.com. A significant decrease in cell proliferation was observed, along with a significant decrease in the IC50 of this compound when combined with agents such as dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001) nih.govtandfonline.com.

In vivo studies using human BL xenografted immune-deficient mice demonstrated that this compound treatment significantly reduced tumor burden and prolonged survival nih.govtandfonline.com. The median survival of mice treated with this compound was significantly extended compared to control groups nih.govtandfonline.com.

Other B-Cell Lymphoma Models

This compound has shown preclinical activity in other B-cell lymphoma subtypes, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) nih.gov. It has demonstrated encouraging efficacy in the activated B cell-like (ABC) subtype of DLBCL, which is characterized by constitutively activated NF-κB signaling, but not typically in the germinal center B cell-like (GCB) subtype tandfonline.comaacrjournals.org.

Studies using patient-derived xenograft (PDX) models of de novo DLBCL have investigated this compound responses in different genotypes aacrjournals.org. Moderate to robust efficacy was observed in models with MYD88L265P/CD79BY197N double mutations, suggesting that CD79B mutation may be a predictive biomarker for good responses to BTK inhibitors aacrjournals.org. Interestingly, a MYD88 single mutant model also showed a response to this compound aacrjournals.org. Some wild-type DLBCL PDXs also showed partial or full sensitivity, indicating that BCR pathway addiction can occur through mechanisms other than CD79B mutation aacrjournals.org.

Preclinical studies have also explored combinations in other B-cell lymphomas. For instance, the combination of this compound and lenalidomide showed synergistic effects on cell growth inhibition and cell death induction in a preclinical model of primary central nervous system lymphoma (PCNSL) oup.com.

Glioblastoma Research

Preclinical research has explored the potential of this compound in glioblastoma, the most common and lethal type of brain tumor europeanpharmaceuticalreview.comccf.orgclevelandclinic.org. Studies have shown that this compound can slow brain tumor growth in preclinical models and extend survival europeanpharmaceuticalreview.comccf.orgclevelandclinic.org. In one study, this compound extended survival more than 10 times the rate observed with the standard-of-care chemotherapy drug, temozolomide europeanpharmaceuticalreview.comccf.orgclevelandclinic.org.

This compound appears to exert its effects in glioblastoma by inhibiting glioma stem cells (GSCs), which are aggressive cancer cells known for their resistance to treatment and ability to spread europeanpharmaceuticalreview.comccf.orgclevelandclinic.org. In both preclinical models and cultured human glioblastoma cells, this compound effectively suppressed GSC-driven tumor growth and potently induced GSC death ccf.orgclevelandclinic.org. Researchers found that this compound works by inhibiting proteins like BMX (bone marrow and X-linked non-receptor tyrosine kinase) and STAT3 (signal transducer and activator of transcription 3), which are involved in the aggressive characteristics of GSCs europeanpharmaceuticalreview.com.

Combining this compound with radiation therapy in a preclinical model prevented glioblastoma cells from developing resistance and extended lifespan more effectively than either treatment alone europeanpharmaceuticalreview.comccf.org. In vitro studies using glioblastoma cell lines (U87MG and DBTRG-05MG) have also shown that this compound can suppress tumorigenesis mdpi.com. This compound decreased cellular proliferation and migration and increased apoptosis and autophagy in LN229 and U87 cell lines mdpi.com. Inhibition of Akt protein by a PI3K inhibitor increased apoptosis and autophagy in these cell lines, suggesting potential for combination approaches mdpi.com. While moderately effective on its own, combinations of this compound with other agents, such as the PI3K inhibitor LY294002 and temozolomide, have shown more promise in preclinical glioblastoma research mdpi.com.

Synergistic Effects with Radiation Therapy

Preclinical studies have also explored the potential for combining this compound with radiation therapy in glioblastoma. Glioblastoma tumor cells are known for their ability to evade treatment, with highly resistant GSCs enabling rapid tumor recurrence after initial therapy clevelandclinic.orgccf.org. Researchers discovered in a preclinical model that combining radiation therapy with GSC-targeting this compound helped overcome this resistance clevelandclinic.orgccf.org. Combination therapy demonstrated enhanced efficacy in overcoming therapeutic resistance and extending lifespan more effectively than either radiation or this compound treatment alone clevelandclinic.orgccf.org.

Further investigation into the mechanism of this synergism revealed that this compound decreased the phosphorylation of EGFR and reversed the upregulation of p-AKT and downstream genes induced by radiation nih.gov. This compound combined with radiotherapy induced G2/M arrest and cell apoptosis in cancer cells nih.gov.

Non-Small Cell Lung Cancer (NSCLC) Research

Preclinical investigations have also evaluated the antitumor activity of this compound in non-small cell lung cancer (NSCLC) cell lines nih.govnih.gov. This compound was found to selectively inhibit the growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells nih.gov.

This compound induced dose-dependent inhibition of phospho-EGFR at both Y1068 and Y1173 sites, suggesting it functions as an EGFR inhibitor nih.gov. In vivo studies demonstrated that this compound statistically significantly suppressed H1975 tumor growth and prolonged the survival of tumor-bearing mice nih.gov.

These results indicate that this compound could be a candidate drug for the treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors nih.gov.

Furthermore, this compound has been identified as a potent inhibitor of IL-6 and the Laminin α5/FAK pathway in lung cancer cell lines researchgate.net. A combination treatment of osimertinib and this compound efficiently reversed drug resistance in osimertinib-resistant NSCLC cell lines through inhibition of IL-6 and lamininα5/FAK signaling researchgate.net. The exact mechanism for the synergism between this compound and trametinib in NSCLC is not fully understood, but it may relate to this compound's potential to inhibit EGFR mdpi.com.

Neuroendocrine Neoplasms (NENs) Research

Preclinical data suggested a potential role for this compound in the treatment of neuroendocrine neoplasms (NENs). These studies indicated that mast cells are recruited within NENs, where they stimulate angiogenesis and tumor growth nih.govascopubs.orgscite.ainih.govresearchgate.net. This compound was shown to inhibit mast cell degranulation and was associated with tumor regression in a mouse insulinoma model nih.govascopubs.orgscite.ainih.gov. Additionally, the drug was found to directly inhibit the proliferation of NEN cells, although the specific mechanisms were not fully elucidated in these preclinical investigations nih.gov.

Based on this preclinical evidence, a phase II study was conducted to investigate this compound in patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs). However, this study did not demonstrate significant clinical activity, with no objective radiographic responses observed in the enrolled patients nih.govascopubs.orgscite.ainih.gov.

Autoimmune Disorders

This compound has shown significant activity in preclinical models of various autoimmune diseases frontiersin.orgd-nb.infobohrium.com. Preclinical evidence suggests that this compound effectively ameliorates disease symptoms in patient samples or animal models of conditions such as Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and systemic sclerosis (SSc) frontiersin.org.

This compound's potential in autoimmune disorders is linked to its immunosuppressive effects, which extend beyond its primary target, BTK frontiersin.orgbohrium.com. This compound binds covalently to IL-2 inducible tyrosine kinase (ITK) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells researchgate.net. This action can shift the balance of Th1/Th2 cells towards the Th1 subset researchgate.net. Preclinical studies have demonstrated that this compound alleviates T cell dysfunction by reversing T cell exhaustion and promoting antitumor immunity nih.gov. Genetic or this compound-mediated inhibition of ITK has been shown to regulate Th17 and Treg cell differentiation in vitro nih.gov. The reduction in the Treg:CD4 T cell ratio observed with this compound treatment further supports an ITK-dependent mechanism of T cell modulation nih.gov.

In vivo studies have demonstrated the potential of this compound in reducing autoantibody production and suppressing kidney disease development in lupus mouse models bohrium.com. This compound has also demonstrated efficacy in preventing disease development in a mouse model of rheumatoid arthritis (RA) researchgate.net.

Infectious Diseases (e.g., Mycobacterium tuberculosis)

Preclinical evidence suggests a potential application for this compound in certain infectious diseases, including Mycobacterium tuberculosis (Mtb) infection frontiersin.orgnih.gov. Studies have investigated the effects of this compound on host-directed responses to Mtb.

One mechanism by which this compound may impact Mtb infection is through the induction of macrophage autophagy frontiersin.orgnih.gov. Autophagy is a cellular process that can help clear intracellular pathogens. Research has shown that this compound treatment can suppress the growth of intracellular Mtb in human macrophages nih.gov. This effect appears to be mediated by the inhibition of the BTK-AKT-mTOR pathway, leading to increased levels of LC3b protein and decreased levels of p62, markers associated with increased autophagy nih.gov. Furthermore, this compound increased the colocalization of LC3b with intracellular Mtb and promoted auto-lysosome fusion, a crucial step in the autophagic degradation of pathogens nih.gov. Inhibition of autophagy using siRNA targeting ATG7 abolished the suppressive effect of this compound on intracellular Mtb growth nih.gov.

In vivo studies using Mtb-infected mice have also provided supportive evidence. Administration of this compound significantly reduced the Mtb load in the mediastinal lymph nodes and spleens of these mice frontiersin.orgnih.gov. These findings suggest that this compound could potentially serve as a host-directed therapy candidate against tuberculosis nih.govmdpi.com.

Inflammatory Responses

This compound has demonstrated effects on inflammatory responses in various preclinical models frontiersin.orgmdpi.com. BTK is involved in signaling pathways beyond the BCR, including those activated by Toll-like receptors (TLRs) and Fc receptors, which play roles in innate immunity and inflammation mdpi.com.

Preclinical evidence indicates that BTK inhibitors, including this compound, can suppress the activation of TLR-NF-κB and NLRP3 inflammasomes in myeloid cells frontiersin.orgnih.gov. This suppression leads to a decrease in the release of inflammatory cytokines and chemokines frontiersin.orgnih.gov. Studies have shown that this compound can inhibit the production of inflammatory cytokines such as IL-6, TNFα, IL-1, IFNγ, and MCP-1 frontiersin.org.

In animal models of sepsis, a condition characterized by uncontrolled systemic inflammatory response, preclinical studies have demonstrated the efficacy of this compound in preventing and inhibiting cytokine storm and protecting against organ damage frontiersin.orgnih.gov. Evidence from Xid mice with an inactivating mutation of Btk further supports that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by BTK inhibition frontiersin.orgnih.gov.

This compound has also shown therapeutic effects in animal models of rheumatoid arthritis (RA), such as the collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models, in a dose-dependent manner mdpi.com. It demonstrated an inhibitory effect on FcγR- and FcεR-mediated cytokine release by monocytes, macrophages, and mast cells mdpi.com.

Furthermore, this compound has been shown to attenuate both TH2/TH17 and neutrophilic/eosinophilic airway inflammation in a mouse model of mixed granulocytic asthma by inhibiting BTK phosphorylation in neutrophils and ITK activation in CD4 T cells frontiersin.org.

Preclinical studies also indicate that this compound can modulate the immune environment and impact various immune cell subsets beyond B cells, including monocytes and macrophages frontiersin.orgtargetedonc.com. In CLL patients, this compound treatment significantly and progressively increased circulating monocyte counts frontiersin.org. Treatment with this compound has been shown to reduce the refractory state of monocytes and restore LPS-induced inflammatory responses in CLL patients frontiersin.org.

CD4+ and CD8+ T-Cell Dynamics and Reconstitution

Studies have shown that this compound treatment can lead to changes in the absolute counts and percentages of CD4+ and CD8+ T cells in patients. Some studies initially observed a decrease in CD4+ and CD8+ T-cell counts, which then normalized over time with continued treatment. frontiersin.orgaai.org Other research indicates that this compound can markedly increase CD4+ and CD8+ T cell numbers, particularly within effector and effector memory subsets. mdpi.comjci.org This increase in T-cell numbers, observed in some patient cohorts, may be related to diminished activation-induced cell death through ITK inhibition. jci.org Long-term this compound therapy has been suggested to contribute to the reconstitution of immune function, including the normalization of adaptive immune cell populations. nih.govresearchgate.net

Data on CD4+ and CD8+ T-cell counts under this compound treatment show variability across studies and time points:

T-Helper Cell Polarization (TH1, TH2, TH17, TH22)

This compound has been shown to influence the differentiation and balance of T-helper cell subsets, which are crucial for orchestrating immune responses. jci.orgresearchgate.netguidetopharmacology.orgfrontiersin.org Inhibition of ITK by this compound is hypothesized to play a role in shifting CD4+ T cells towards a T helper 1 (Th1) phenotype. ashpublications.orgashpublications.org Th1 cells are generally associated with cell-mediated immunity and anti-tumor responses, producing cytokines like IFN-γ. jidc.orgbdbiosciences.com Conversely, Th2 cells are involved in humoral immunity and are often associated with a more immunosuppressive environment in certain cancers like CLL. jidc.orgnih.gov

Studies have provided evidence for this compound-induced shifts in Th polarization:

A progressive decrease in Th2 (CD3+CD4+IL-4+) cells and a relative increase in Th1 (CD3+CD4+IFNγ+) cells have been documented with this compound treatment. nih.govnih.gov

The Th2/Th1 ratio significantly decreased early in treatment and remained lower, suggesting a shift towards a Th1-mediated immune response. nih.govnih.gov

This modulation of the Th2/Th1 ratio has been associated with the achievement of complete response in some patients, suggesting a potential link between this shift and anti-tumor immune activation. nih.govnih.gov

this compound has also been reported to decrease Th17 (CD3+CD4+IL-17+) cells. nih.govnih.gov Th17 cells are involved in immunity against extracellular pathogens but can also contribute to inflammation and autoimmunity. jidc.orgbdbiosciences.com

Some research suggests that this compound may have positive effects on Th22 (IL-22+) cell numbers in the presence of myeloid-derived suppressor cells (MDSCs) and monocytes. mdpi.com

Data on T-Helper Cell Polarization changes under this compound:

Regulatory T-Cells (Tregs) and Their Balance

Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance and suppressing immune responses. frontiersin.org Elevated levels of Tregs are often observed in cancer, contributing to an immunosuppressive microenvironment that hinders anti-tumor immunity. nih.govfrontiersin.org

This compound treatment has been shown to impact Treg populations:

The absolute count and percentage of Tregs have been reported to be significantly reduced in patients treated with this compound. nih.govfrontiersin.org

This reduction in Tregs can occur relatively early after the initiation of therapy. nih.gov

While some studies indicate a decrease in Treg numbers, others suggest that the number of Treg cells may remain unchanged, but the ratio of Tregs to conventional CD4+ T cells is reduced with this compound, which is attributed to the expansion of non-Treg CD4+ subsets. jci.orgfrontiersin.org

The decrease in Tregs or the reduction in the Treg/CD4+ ratio is considered beneficial as it may facilitate effector T cell responses against cancer and infections. frontiersin.orgfrontiersin.org

Immunosuppressive regulatory T cells were reported to be normalized within the first 1-2 years of this compound treatment and then plateaued. nih.gov

Vγ9Vδ2 T Cells

Vγ9Vδ2 T cells are a subset of unconventional T cells that can recognize and kill tumor cells in a major histocompatibility complex (MHC)-independent manner. frontiersin.orgashpublications.orgresearchgate.net In diseases like CLL, Vγ9Vδ2 T cells may exhibit functional impairments. nih.govfrontiersin.orgashpublications.org

Research indicates that this compound can influence Vγ9Vδ2 T cells:

this compound treatment has been shown to restore the function and cytotoxicity of Vγ9Vδ2 T cells that were impaired in CLL patients. nih.govresearchgate.net

This restoration may be associated with this compound promoting a Th1 phenotype in Vγ9Vδ2 T cells, potentially through ITK inhibition. nih.govfrontiersin.orgashpublications.orgresearchgate.net

While some studies observed no significant impact of this compound treatment on the absolute numbers of Vγ9Vδ2 T cells over time, functional improvements were noted. researchgate.net

Ex vivo studies have shown that this compound treatment can promote an anti-tumor Th1 phenotype in Vγ9Vδ2 T cells activated with monocyte-derived dendritic cells. ashpublications.orgresearchgate.net

Modulation of T-Cell Activation, Proliferation, and Cytotoxicity

This compound influences key aspects of T-cell function, including activation, proliferation, and cytotoxic capacity. nih.govresearchgate.netguidetopharmacology.orgfrontiersin.org

Activation and Exhaustion: this compound can reverse the pseudo-exhaustion of T cells, particularly in the context of chronic antigen exposure in malignancies like CLL. nih.govfrontiersin.orgresearchgate.netfrontiersin.org This is supported by observations of decreased expression of inhibitory receptors like PD-1 and CTLA-4 on T cells during this compound therapy. mdpi.comjci.orgresearchgate.netresearchgate.net Long-term treatment may reduce PD-1 expression on chronically activated CD8+ T cells. researchgate.net

Proliferation: The effect of this compound on T-cell proliferation appears complex. While some in vitro studies suggest that this compound can inhibit TCR-mediated proliferation of T cells from both healthy donors and CLL patients, it may reduce the abnormally high proliferation rates seen in CLL T cells to levels closer to those of healthy donors. haematologica.orgresearchgate.netnih.gov Other studies have reported a decrease in T-cell proliferation after treatment initiation. haematologica.org However, the long-term impact may involve restoring T-cell fitness and the ability to respond to subsequent activation. nih.gov

Cytotoxicity: this compound treatment has been shown to enhance the cytotoxic function of effector T cells, including CD8+ T cells. nih.govmdpi.comhaematologica.org This can involve increased secretion of cytotoxic molecules like granzyme B and perforin. nih.gov Single-cell analysis has indicated that this compound can significantly increase the expression of cytotoxic genes in CD8+ T cells and enhance the function of cytotoxic T lymphocytes (CTLs). nih.gov this compound can also promote immune synapse formation between T and tumor cells, which is crucial for effective killing. mdpi.comfrontiersin.org The combination of this compound with checkpoint blockade has shown potential to further improve CD8+ T-cell function. mdpi.comhaematologica.org

Data on this compound's effects on T-Cell Function:

Monocytes and Macrophages (including Tumor-Associated Macrophages)

This compound treatment influences the function and phenotype of monocytes and macrophages. In patients with chronic lymphocytic leukemia (CLL), this compound treatment significantly and progressively increases circulating monocyte counts towards the range observed in healthy donors frontiersin.org. This compound can reduce the refractory state of monocytes in CLL patients and restore lipopolysaccharide (LPS)-induced inflammatory responses by enhancing ERK1/2 phosphorylation and antigen presentation frontiersin.org.

This compound affects macrophages, particularly monocytic nurse-like cells (NLCs) in CLL, which share properties with M2-skewed tumor-associated macrophages (TAMs) frontiersin.orgmdpi.com. This compound treatment sustains the M2 phenotypes and immunosuppressive profile of NLCs in lymphoid organs of CLL patients by hindering TLR4 signaling frontiersin.org. It also alters M-CSF-induced differentiation of monocytes to fibrocyte-like cells with impaired phagocytosis and adhesion frontiersin.org.

Studies have shown that BTK is highly expressed in TAMs and MDSCs, which play roles in tumor progression and immunosuppression frontiersin.org. This compound treatment or BTK deficiency can shift macrophage polarization from tumor-promoting M2-like macrophages towards inflammatory M1-like macrophages frontiersin.org. This compound also diminishes the expression of PD-1 and SIRPα on macrophages frontiersin.org.

Both this compound and acalabrutinib can inhibit TLR-BTK, TREM-1-BTK, and Dectin-1-BTK signaling pathways in monocytes and macrophages, leading to reduced production of inflammatory cytokines and chemokines and impaired phagocytosis of tumor cells and infectious pathogens frontiersin.org. This compound inhibits α4β1 integrin-mediated adhesion of macrophages to VCAM1 and disaggregates interactions between macrophages and CLL cells in the bone marrow frontiersin.org.

In macrophages derived from CLL patients, this compound decreases the secretion of TNF-α and affects polarization, impairing the macrophage-mediated response against Mycobacterium tuberculosis mdpi.com.

Dendritic Cells (DCs) Maturation and Migration

This compound has been shown to enhance the maturation and activation of dendritic cells (DCs) aai.orgresearchgate.net. Studies have reported that this compound enhances the expression of co-stimulatory molecules on DCs and promotes DC-mediated T cell activation aai.orgresearchgate.net.

In a mouse inflammation model, this compound significantly improved DC maturation and migration from the injection site to draining lymph nodes, inducing T cell activation and proliferation in vivo aai.orgresearchgate.net. Additionally, this compound enhanced monocyte maturation to DCs in the skin aai.orgresearchgate.net.

In patients with metastatic pancreatic ductal adenocarcinoma (PDAC), this compound treatment was found to change the myeloid compartment, specifically circulating monocytes and DCs, with an increase in mature DCs within the tumor microenvironment targetedonc.com. These DCs showed a more mature phenotype, marked by positive expression of DC-LAMP targetedonc.com.

Data on this compound's effects on DC maturation and migration:

Natural Killer (NK) Cells

This compound has significant effects on NK cell function, partly due to its off-target inhibition of ITK, a kinase involved in NK cell activation frontiersin.orgmdpi.comnih.gov.

One clinically significant effect is that this compound, but not more selective BTK inhibitors, significantly affects antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells frontiersin.orgmdpi.comnih.govd-nb.info. This compound strongly inhibits NK cell-mediated killing of target cells coated by anti-CD20 antibodies in vitro frontiersin.orgmdpi.comnih.gov. This inhibition of ADCC can be attributed to this compound's off-target inhibition of ITK in NK cells frontiersin.org.

This compound inhibits NK cell activation-induced death and slightly decreases proliferation after IL-2 + IL-15 stimulation in vitro mdpi.com. Long-term this compound treatment has been shown to decrease levels of CD16-negative NK cells without altering CD16-positive NK counts in CLL patients mdpi.com.

A recent study identified a novel CLL_NK cell subset in patients exhibiting favorable responses to this compound treatment, suggesting its potential role in therapeutic efficacy pharmacytimes.com.

Data on this compound's effects on NK Cells:

Myeloid-Derived Suppressor Cells (MDSCs)

This compound has demonstrated effects on myeloid-derived suppressor cells (MDSCs), which are known to contribute to tumor progression and immunosuppression nih.govnih.govresearchgate.netnih.gov. BTK is expressed by both murine and human MDSCs nih.govresearchgate.net.

This compound can inhibit BTK phosphorylation in MDSCs nih.gov. Treatment of MDSCs with this compound significantly impaired nitric oxide production and migration in vitro nih.govaacrjournals.org. This compound also inhibited the in vitro generation of human MDSCs nih.gov.

In multiple murine tumor models, this compound treatment resulted in a significant reduction of MDSCs in both the spleen and tumor nih.govresearchgate.net. This reduction was dependent on BTK inhibition, as it was not observed in mice harboring a BTK mutation nih.govresearchgate.net.

In CLL patients, this compound treatment generally decreases the abnormally high counts of MDSCs frontiersin.orgresearchgate.net. A reduction of MDSCs and a concomitant increase in classical monocytes were demonstrated in CLL patients after 12 months of this compound treatment, likely due to both direct effects of BTK inhibition in MDSCs and indirect effects induced through reduced tumor burden haematologica.org.

This compound can inhibit the migration of MDSCs induced by GM-CSF or CXCL12 in vitro and restrict the in vivo migration of MDSCs into the tumor microenvironment in melanoma-bearing mice frontiersin.org.

Data on this compound's effects on MDSCs:

Granulocytes, Osteoclasts, and Mast Cells

This compound has been shown to have immunomodulatory effects on granulocytes, osteoclasts, and mast cells frontiersin.orgfrontiersin.orgresearchgate.netresearchgate.net.

BTK is expressed in granulocytes, and inhibition of BTK with this compound can lead to changes in their function researchgate.netd-nb.info. BTK inhibition has been associated with impaired neutrophil effector activity against certain fungal pathogens in vitro mdpi.com.

Regarding osteoclasts, this compound has been suggested as a potential treatment option for bone diseases characterized by increased osteoclast activity and enhanced bone resorption, such as osteoporosis and rheumatoid arthritis nih.gov. While studies on bone density in this compound-treated patients are limited, its therapeutic effect in an RA mouse model is attributed to its effects on B lymphocytes and inflammatory cells, which include BTK-expressing effector cells involved in arthritis pathology nih.gov.

This compound can also affect mast cells. Preclinical evidence shows that this compound can attenuate inflammation in a mouse model of mixed granulocytic asthma by inhibiting BTK phosphorylation in neutrophils and ITK activation in CD4 T cells frontiersin.org.

Treatment-Naïve CLL

Diffuse Large B-Cell Lymphoma (DLBCL)

A retrospective study evaluating this compound in 40 patients with R/R DLBCL showed an ORR of 22.5%. nih.gov The median progression-free survival (PFS) was 13.0 months, and the median OS was 15.0 months. nih.gov Combined treatment of this compound with other drugs was found to be more effective than this compound monotherapy in this study. nih.gov

A phase II trial combining this compound with rituximab, lenalidomide, and chemotherapy (RLI-chemotherapy) in newly diagnosed non-GCB DLBCL patients demonstrated a high ORR of 86.2% after two cycles of RLI alone and a complete response rate of 94.5% after completion of RLI-chemotherapy. ascopubs.org At a median follow-up of 31 months, the 2-year PFS and OS rates were 91.3% and 96.6%, respectively. ascopubs.org

Data Table: Efficacy of this compound in DLBCL

Lymphoplasmacytic Lymphoma (LPL)

This compound has shown significant activity in lymphoplasmacytic lymphoma (LPL), also known as Waldenström's macroglobulinemia (WM). wikijournalclub.orgdovepress.com It is approved for the treatment of WM. wikipedia.org

In a study of 23 patients with LPL, most of whom had IgM secretion, this compound treatment resulted in a median maximum IgM decrease of 67%. researchgate.netspandidos-publications.com For the one patient with IgG secretion, the decrease was 37%. researchgate.netspandidos-publications.com The response to this compound often requires long-term continuation of treatment. researchgate.netspandidos-publications.com

In treatment-naïve WM patients, a prospective study of this compound monotherapy in 30 patients, all with MYD88 mutated disease, showed an ORR of 100% and a major response rate of 83%. dovepress.com CXCR4 wild-type patients demonstrated a higher major response rate (94%) compared to CXCR4 mutated patients (71%). dovepress.com The 18-month PFS rate was 92%. dovepress.com

The combination of this compound with rituximab has also been evaluated in WM. The Phase III iNNOVATE trial showed that the combination resulted in significantly prolonged PFS compared with rituximab monotherapy, particularly for rituximab-refractory patients. dovepress.com

Data Table: Efficacy of this compound in LPL/WM

BTK Mutations (e.g., C481S)

The most common acquired resistance mechanism involves mutations in the BTK gene itself. aacrjournals.org A prominent example is the C481S mutation, where a cysteine residue at position 481 is replaced by serine. aacrjournals.org This cysteine residue is the specific site where this compound forms its irreversible covalent bond. wikipedia.org The C481S mutation prevents the formation of this covalent bond, leading to reversible binding of this compound with significantly reduced affinity. aacrjournals.org This altered binding allows BTK activity to be restored, thereby conferring resistance to this compound. aacrjournals.org BTK mutations, particularly C481S, have been demonstrated as a mechanism of this compound resistance in relapsed MCL tumors. nih.gov

PLCG2 Mutations (e.g., R665W)

Mutations in the PLCG2 gene, which encodes phospholipase C-γ2, an immediate downstream effector of BTK in the BCR pathway, also contribute to this compound resistance. aacrjournals.org These mutations are typically gain-of-function mutations. aacrjournals.org Hotspot mutations in PLCG2 result in the proximal activation of PLCG2 independent of BTK activity. aacrjournals.org This leads to continuous downstream signaling through the BCR pathway, effectively bypassing the BTK block imposed by this compound. aacrjournals.org While the specific R665W mutation was mentioned in the prompt, search results confirm that hotspot mutations in PLCG2 are generally gain-of-function and lead to BTK-independent activation of the pathway. aacrjournals.org Mutations in PLCG2 play a role in acquired resistance to covalent BTK inhibitors in MCL. mdpi.com

PI3K-AKT-mTOR Pathway Activation

The PI3K-AKT-mTOR signaling pathway is frequently dysregulated in cancers and plays a significant role in cell growth, survival, and resistance to therapy. vulcanchem.comguidetopharmacology.org Dysregulated PI3K/Akt signaling is often concomitant with BTK activation and fosters cell proliferation and drives metabolic reprogramming in NHL cells. mdpi.com Upregulation of the PI3K/AKT/mTOR signaling pathway has been observed in this compound-resistant cases, leading to increased tumor cell survival. mdpi.com The PI3K-mediated signaling pathway is important in tumor development, and its dysregulation is associated with tumor growth and resistance to antineoplastic agents. wikipedia.org Targeting the PI3K pathway using isoform-specific inhibitors has shown promise in inducing tumor regression in this compound-resistant models. nih.gov

MAP3K14-NF-κB Pathway Activation

Chronic activation of the MAP3K14-NF-κB pathway is a mechanism of primary resistance to this compound, particularly in MCL. nih.govmdpi.comresearchgate.net This pathway can lead to constitutive NF-κB activation, independent of BTK signaling. nih.govmdpi.commdpi.comresearchgate.net Mutations in negative regulators of NF-κB, such as TRAF2, TRAF3, and BIRC3, can contribute to this primary resistance by leading to loss-of-function and promoting the stabilization of the MAP3K14 enzyme, thereby activating the non-canonical NF-κB signaling pathway. nih.govmdpi.commdpi.comresearchgate.net The activation of non-canonical NF-κB signaling, which is distinct from the classical NF-κB activation mediated through BCR signaling, has been shown to instruct resistance to this compound. nih.gov The activation of non-canonical NF-κB and MAPK pathways through CD40L-CD40 signaling can also bypass BTK signaling, diminishing this compound efficacy. nih.govmdpi.com

SYK and LYN Kinase Over-Activation

Other kinases, such as SYK and LYN, can also contribute to this compound resistance through their interplay with the BTK pathway and their ability to modulate BCR signaling. mdpi.com While direct over-activation as a primary mechanism of resistance was not extensively detailed in the provided search results, the crosstalk between BTK and kinases like LYN and SYK is integral to the regulation of B-cell signaling and function. mdpi.com Dysregulation or over-activation of these kinases could potentially provide alternative signaling routes that circumvent this compound-mediated BTK inhibition.

Second-Generation Irreversible BTK Inhibitors

Second-generation irreversible BTK inhibitors, such as Acalabrutinib and Zanubrutinib, were developed with improved selectivity for BTK compared to this compound. nih.goviwmf.com While they also bind covalently to the C481 residue of BTK, their enhanced selectivity may lead to reduced off-target effects. nih.goviwmf.com Studies have shown that these inhibitors demonstrate similar or improved efficacy and potentially superior toxicity profiles compared to this compound in the relapsed/refractory setting. nih.gov However, resistance to these second-generation inhibitors can also occur, often through the development of the same BTK C481 mutation seen with this compound, although to a lesser extent, mutations in the downstream enzyme PLCG2 can also contribute. nih.gov

Here is a table summarizing key second-generation irreversible BTK inhibitors:

Combination with BCL2 Inhibitors (e.g., Venetoclax)

BCL2 is an anti-apoptotic protein that plays a critical role in the survival of many B-cell malignancies. ashpublications.org Venetoclax is a selective BCL2 inhibitor that induces apoptosis in cancer cells by mimicking BH3 proteins. ashpublications.orgguidetopharmacology.org Combining this compound with Venetoclax targets two distinct survival pathways: BCR signaling (inhibited by this compound) and the intrinsic apoptotic pathway (regulated by BCL2 and inhibited by Venetoclax). hematologyandoncology.nettandfonline.com This combination has shown promise in overcoming this compound resistance and achieving deeper responses, including undetectable minimal residual disease (MRD). hematologyandoncology.nettandfonline.comlls.org Clinical trials are investigating the efficacy of this compound and Venetoclax combination in patients with this compound resistance mutations or those at high risk of relapse. hematologyandoncology.netlls.org While this combination can be effective, further investigation is needed to address the possibility of de novo resistance to the combination itself. nih.gov

Combination with PI3K/mTOR Inhibitors

The PI3K-AKT-mTOR pathway is another crucial survival pathway in B-cell malignancies, and its activation can contribute to this compound resistance, particularly in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ashpublications.orgnih.govfrontiersin.org Activation of this pathway can occur through feedback mechanisms or acquired genetic alterations, bypassing the need for active BTK signaling. ashpublications.orgfrontiersin.org Combining this compound with inhibitors of the PI3K/mTOR pathway aims to block this alternative survival route. ashpublications.orgfrontiersin.org Preclinical studies and early clinical trials have explored combinations of this compound with PI3K inhibitors (e.g., Idelalisib, Umbralisib) or dual PI3K/mTOR inhibitors. ashpublications.orgdovepress.comfrontiersin.orgoncotarget.combiorxiv.org These combinations have shown potential in reducing tumor growth and overcoming resistance in models where the PI3K/mTOR pathway is upregulated. nih.govfrontiersin.orgbiorxiv.org Targeting PI3K signaling in combination with this compound has been shown to reduce the growth of this compound-resistant tumors in xenograft models. nih.gov

Combination with Immune Checkpoint Inhibitors (e.g., Anti-PD-L1)

Combining this compound with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, has shown promise in preclinical models. aacrjournals.orgcancernetwork.compnas.org This combination has demonstrated the ability to suppress tumor growth and improve survival in mouse models of lymphoma that were inherently insensitive to this compound as a single therapy. aacrjournals.orgcancernetwork.com The synergistic therapeutic activity is thought to result from their effects on the immune system rather than a direct effect on tumor cells. aacrjournals.orgpnas.orgnih.gov this compound can influence the tumor microenvironment and enhance anti-tumor T-cell immune responses. researchgate.netaacrjournals.orgpnas.org Preclinical results suggest that combining PD-1/PD-L1 blockade with this compound could be explored in hematologic malignancies and potentially solid tumors. aacrjournals.orgpnas.org

Combinations with Other Immunotherapeutic Agents (e.g., T-cell engaging bispecific antibodies)

Beyond immune checkpoint inhibitors, combinations with other immunotherapeutic agents, such as T-cell engaging bispecific antibodies, are being explored as a means to overcome resistance to BTK inhibitors like this compound. ashpublications.org Next-generation inhibitors and bispecific antibodies have the potential to overcome this resistance. ashpublications.org

Multi-agent Regimens (e.g., with Rituximab, Bendamustine, Lenalidomide, Obinutuzumab)

Multi-agent regimens incorporating this compound with other established therapies are being investigated to improve outcomes and potentially overcome or prevent resistance. Combinations with agents like Rituximab, Bendamustine, Lenalidomide, and Obinutuzumab are part of these strategies. researchgate.netcancernetwork.comresearchgate.netaacrjournals.orgnih.govnih.govnih.gov

For instance, Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, has shown efficacy in combination with chemotherapy in previously untreated CLL patients and in combination with bendamustine followed by monotherapy in follicular lymphoma patients who relapsed after or were refractory to a rituximab-containing regimen. nih.govnih.govdovepress.com While these combinations are not always specifically designed to overcome this compound resistance, they represent approaches that could be utilized in patients who have developed resistance or as initial strategies to achieve deeper responses and potentially prevent resistance development.

A phase 2 trial is assessing acalabrutinib (a second-generation BTK inhibitor), lenalidomide, and rituximab in treatment-naive MCL, exploring the feasibility of an MRD response-adapted strategy. cancernetwork.com This highlights the interest in combining BTK inhibitors with immunomodulatory drugs and monoclonal antibodies.