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Background: Hepatocellular carcinoma (HCC) is a highly lethal and invasive cancer. Targeted and immunotherapies are the primary treatment options for unresectable advanced HCC. There are no recognized and consistent systemic follow-up treatments for patients with HCC who experience disease progression after first-line targeted therapies and immune checkpoint inhibitors (ICIs). According to a few studies, lenalidomide is an immunomodulatory drug that has the potential to be an effective treatment for patients who have progressed after treatment with targeted drugs and ICIs. Case summary: This article focuses on a patient with HCC whose disease progressed after first-line targeted therapy and ICI therapy combined with lenalidomide as second-line therapy on the basis of the original targeted and ICI regimens, resulting in a favorable oncologic outcome with acceptable toxicity. The progression-free survival (PFS) of the patients in this study reached 3 years, which is much longer than that previously reported, and no progression has occurred thus far. Conclusions: This case implies that in patients with hepatocellular carcinoma who have failed first-line targeted therapy and ICIs, targeted therapy and ICIs can be restarted with the addition of lenalidomide, with surprising results. [ABSTRACT FROM AUTHOR]

BackgroundHepatocellular carcinoma (HCC) is a highly lethal and invasive cancer. Targeted and immunotherapies are the primary treatment options for unresectable advanced HCC. There are no recognized and consistent systemic follow-up treatments for patients with HCC who experience disease progression after first-line targeted therapies and immune checkpoint inhibitors (ICIs). According to a few studies, lenalidomide is an immunomodulatory drug that has the potential to be an effective treatment for patients who have progressed after treatment with targeted drugs and ICIs.Case summaryThis article focuses on a patient with HCC whose disease progressed after first-line targeted therapy and ICI therapy combined with lenalidomide as second-line therapy on the basis of the original targeted and ICI regimens, resulting in a favorable oncologic outcome with acceptable toxicity. The progression-free survival (PFS) of the patients in this study reached 3 years, which is much longer than that previously reported, and no progression has occurred thus far.ConclusionsThis case implies that in patients with hepatocellular carcinoma who have failed first-line targeted therapy and ICIs, targeted therapy and ICIs can be restarted with the addition of lenalidomide, with surprising results.

Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20–65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high‐dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent‐to‐treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1‐year maintenance, respectively. With a median follow‐up of 38 months, the 3‐year progression‐free survival (PFS) rate was 83.5% and the 3‐year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment‐related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high‐risk cytogenetics showed a trend toward lower 3‐year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra‐high‐risk cytogenetics (≥2 high‐risk cytogenetics) had an even worse prognosis, with 61.2% 3‐year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38‐antibody should be assessed in future studies. [ABSTRACT FROM AUTHOR]

Patients with hematologic malignancies are often complicated not only by severe bleeding due to thrombocytopenia and disseminated intravascular coagulation but also by thromboembolic events, just like in patients with solid cancers, and these events can negatively impact patient outcomes. Nevertheless, the prevention and treatment of cancer-associated thrombosis (CAT) in hematologic malignancies has not been adequately investigated due to the limited size, heterogeneity, and unique pathophysiology of the patient population. This article summarizes the current understanding, risk factors, prediction models, and optimal prevention and treatment strategies of CAT in hematologic malignancies on a disease-by-disease basis, including acute leukemia, lymphoma, myeloma, and myeloproliferative neoplasms. Specific considerations of novel molecular targeted therapeutics introduced in recent years, such as immunomodulatory drugs and tyrosine kinase inhibitors, are also discussed based on the latest clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Usual Interstitial Pneumonia (UIP) is characterized by progression of lung parenchyma that may be observed in various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and connective tissue diseases. From a diagnostic point of view, a UIP pattern related to ARDs may display imaging and pathological features able to distinguish it from that related to IPF, such as the “straight-edge” sign at HRCT and lymphoplasmacytic infiltrates at histologic specimens. Multidisciplinary approach (MDD), involving at least pulmonologist, rheumatologist and radiologist, is fundamental in the differential diagnosis process, but MDD is also required in the evaluation of severity, progression and response to treatment, that is based on the combination of changes in symptoms, pulmonary function trends, and, in selected patients, serial CT evaluation. Differently from IPF, in patients with ARDs both functional evaluation and patient-reported outcomes may be affected by systemic involvement and comorbidities, including musculoskeletal manifestations of disease. Finally, in regards to pharmacological treatment, immunosuppressants have been considered the cornerstone of therapy, despite the lack of solid evidence in most cases; recently, antifibrotic drugs were also proposed for the treatment of progressive fibrosing ILDs other than IPF. In ARD-ILD, the therapeutic choice should balance the need for the control of systemic and lung involvements with the risk of adverse events from multi-morbidities and -therapies. Purpose of this review is to summarize the definition, the radiological and morphological features of the UIP pattern in ARDs, together with risk factors, diagnostic criteria, prognostic evaluation, monitoring and management approaches of the UIP-ARDs.

Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression. [ABSTRACT FROM AUTHOR]

Usual Interstitial Pneumonia (UIP) is characterized by progression of lung parenchyma that may be observed in various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and connective tissue diseases. From a diagnostic point of view, a UIP pattern related to ARDs may display imaging and pathological features able to distinguish it from that related to IPF, such as the "straight-edge" sign at HRCT and lymphoplasmacytic infiltrates at histologic specimens. Multidisciplinary approach (MDD), involving at least pulmonologist, rheumatologist and radiologist, is fundamental in the differential diagnosis process, but MDD is also required in the evaluation of severity, progression and response to treatment, that is based on the combination of changes in symptoms, pulmonary function trends, and, in selected patients, serial CT evaluation. Differently from IPF, in patients with ARDs both functional evaluation and patient-reported outcomes may be affected by systemic involvement and comorbidities, including musculoskeletal manifestations of disease. Finally, in regards to pharmacological treatment, immunosuppressants have been considered the cornerstone of therapy, despite the lack of solid evidence in most cases; recently, antifibrotic drugs were also proposed for the treatment of progressive fibrosing ILDs other than IPF. In ARD-ILD, the therapeutic choice should balance the need for the control of systemic and lung involvements with the risk of adverse events from multi-morbidities and -therapies. Purpose of this review is to summarize the definition, the radiological and morphological features of the UIP pattern in ARDs, together with risk factors, diagnostic criteria, prognostic evaluation, monitoring and management approaches of the UIP-ARDs. [ABSTRACT FROM AUTHOR]

This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors (PIs) improve clinical outcomes in patients with myeloma; however, refractoriness to lenalidomide, a category of IMiD, predicts poor outcomes. Next-generation IMiDs, such as pomalidomide, are effective even for lenalidomide-refractory myeloma. Therefore, an IMiD-sequencing strategy from lenalidomide to pomalidomide would be desirable. PIs are an antimyeloma therapeutic agent with another mode of action that might restore cereblon, a target of IMiDs; therefore, an IMiD-free interval via class switching from lenalidomide to PIs may be a promising alternative for lenalidomide-refractory myeloma. Additionally, the anti-CD38 monoclonal antibody is a key drug for salvage therapy in anti-CD38 monoclonal antibody-naïve patients. In clinical practice, safety profiles and social convenience can play important roles in the choice of combination therapy. In the future, the selection of optimal treatments should be based on the status of the immunological environment and genetic alterations. This review aims to discuss IMiDs sequencing and IMiD-free interval strategies for lenalidomide- refractory myeloma. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. Methods We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. Results Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. Conclusion Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

IntroductionPatients with relapsed or refractory multiple myeloma (RRMM) are likely to be living with persistent symptoms, especially bone pain and fatigue, and experiencing restrictions in their physical and social functioning, which reduce health-related quality of life.MethodsThis qualitative interview study evaluated patients’ perspectives about living with RRMM and their treatment with belantamab mafodotin, using interviews embedded in the Phase II DREAMM-2 trial (NCT03525678) with belantamab mafodotin. Patients consented to participate in up to 2 recorded telephone interviews (at treatment cycle 4 [C4] and at end of treatment [EOT]) comprising open-ended questions.ResultsA total of 142 interviews were conducted with 111 unique patients. At C4, common symptoms included neuropathy, fatigue, and bone or joint pain. Improvements in symptom severity were reported by patients who responded to belantamab mafodotin. Symptoms associated with visual impairment, eye irritation, and eye pain reported during the trial were reported to be at- or near-resolution by the EOT interview. Regarding impacts of underlying MM, patients most commonly expressed concerns about changes in daily performance and lifestyle for both responders (67.5% of all impact expressions) and non-responders (63.2%). Overall, interview participants reported being satisfied with belantamab mafodotin treatment.DiscussionThis qualitative patient interview study provides valuable insight into patients’ symptomatic experience with belantamab mafodotin for their RRMM treatment and may help healthcare providers better anticipate their patients’ real-world experience and needs when prescribing this novel agent in the clinic.

Objective The mechanism of immunomodulatory drugs (IMiDs) resistance to multiple myeloma (MM) cells has been gradually demonstrated by recently studies, and some potential novel strategies have been confirmed to have antimyeloma activity and be associated with IMiD activity in MM.Methods This article searched the Pubmed library, reviewed some recently studies related to IMiD resistance to MM cells and summarized some potent agents to improve IMiD resistance to MM cells.Results Studies have confirmed that cereblon is a primary direct protein target of IMiDs. IRF4 not only is affected by the IKZF protein but also can directly inhibit the expression of BMF and BIM, thereby promoting the survival of MM cells. Additionally, the expression of IRF4 and MYC also plays an important role in three important signaling pathways (Wnt, STAT3 and MAPK/ERK) related to IMiD resistance. Notably, MYC, a downstream factor of IRF4, may be upregulated by BRD4, and upregulation of MYC promotes cell proliferation in MM and disease progression. Recently, some novel therapeutic agents targeting BRD4, a histone modification-related ‘reader’ of epigenetic marks, or other important factors (e.g. TAK1) in relevant signaling pathways have been developed and they may provide new options for relapse/refractory MM therapy, such as BET inhibitors, CBP/EP300 inhibitors, dual-target BET-CBP/EP300 inhibitors, TAK1 inhibitors, and they may provide new options for relapsed/refractory MM therapy.Conclusions Accumulated studies have revealed that some key factors associated with the mechanism of IMiD resistance to MM cells. Some agents represent promising new therapeutics of MM to regulate the IRF4/MYC axis by inhibiting BRD4 expression or signaling pathway activation.

Introduction: Iatrogenic lung injury is a very rare, albeit serious complication with antineoplastic therapy, including immunomodulatory drugs. Pneumonitis typically presents clinically with symptoms such as cough, dyspnea, fever, and hypoxemia. Radiographic evaluation often demonstrates diffuse, patchy infiltrates and ground-glass opacities. Case report: We present a case in which therapy from an immunomodulatory drug, lenalidomide, elicited a pneumonitis in the form of a 9 cm lung mass. An exhaustive workup was completed to rule out viral, bacterial, and fungal infections as well as malignant causes. Lenalidomide-induced lung injury was suspected. Management and outcome: Lenalidomide was discontinued and corticosteroid therapy was initiated. This resulted in a complete clinical and radiographic resolution of symptoms. Discussion: Several case reports of pneumonitis have been associated with immunomodulatory drug therapy, and while most of these exhibit diffuse ground-glass opacities radiographically, our patient presented with a 9 cm lung mass. Our findings stress the importance of a thorough medication review while ruling out other potential causes of lung injury. [ABSTRACT FROM AUTHOR]

The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. [ABSTRACT FROM AUTHOR]

As an immunomodulatory drug, lenalidomide has been shown to have anti-lymphoma activity and is used in combination with several agents in the treatment of patients with relapsed/refractory disease. In this study, we aimed to evaluate the efficiency of lenalidomide in the treatment of B-cell NHL. This retrospective study included patients with relapsed/refractory B-cell NHL who received lenalidomide treatment between March 2018 and January 2021. Patients' demographic data, dose, and duration of the lenalidomide treatment, combined agents, response rates, side effects, and survival rates were evaluated. Twelve patients who diagnosed with relapsed/refractory NHL were included in the study. Lenalidomide treatment was initiated in combination with rituximab for nine of these patients and with temozolomide for the remaining three of them. At the initiation of the lenalidomide treatment, patients' median age was 72.5 (24-83) years. Number of females/males was 9/3. Nine of the patients were diagnosed with diffuse large b-cell lymphoma (DLBCL), 3 of whom had isolated central nervous system lymphoma (CNS) and 1 had Richter transformation of chronic lymphocytic leukemia. Two patients were diagnosed with mantle cell lymphoma (MCL) and 1 patient was diagnosed with marginal zone lymphoma. The median treatment duration was 4 (1-20) months. In the response assessment, 4 patients had complete response while progressed disease was observed in 5 patients. Three patients died before response assessment. In the median 33-month follow-up, progression-free survival and total survival were found as 4 (1-20) and 7 (1-22) months respectively. Due to its low toxicity profile and activity, lenalidomide could be a good option especially for elderly and fragile B-cell lymphoma patients. It is an agent to be considered particularly in lymphomas with CNS involvement with its good CNS penetration. Its synergistic effect may give better results when used in combination with several anti-lymphoma drugs. [Med-Science 2022; 11(2.000): 757-61]

Background: Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. Methods: We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. Results: Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. Conclusion: Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is the second most common hematological malignancy. Initially, prognosis for MM patients was poor. However, due to the development of novel treatment regimens, their clinical outcomes have significantly improved. One of the milestones in the treatment of MM was the implementation of immunomodulatory drugs (IMiDs). Lenalidomide (LEN) is probably the most commonly used IMiD worldwide. However, despite its potent anti-MM activity, the vast majority of patients become LEN-resistant. In this review, we focus on LEN-resistance mechanisms as well as on strategies for the treatment of LEN-refractory disease. Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions. [ABSTRACT FROM AUTHOR]

The mechanism of immunomodulatory drugs (IMiDs) resistance to multiple myeloma (MM) cells has been gradually demonstrated by recently studies, and some potential novel strategies have been confirmed to have antimyeloma activity and be associated with IMiD activity in MM. This article searched the Pubmed library, reviewed some recently studies related to IMiD resistance to MM cells and summarized some potent agents to improve IMiD resistance to MM cells. Studies have confirmed that cereblon is a primary direct protein target of IMiDs. IRF4 not only is affected by the IKZF protein but also can directly inhibit the expression of BMF and BIM, thereby promoting the survival of MM cells. Additionally, the expression of IRF4 and MYC also plays an important role in three important signaling pathways (Wnt, STAT3 and MAPK/ERK) related to IMiD resistance. Notably, MYC, a downstream factor of IRF4, may be upregulated by BRD4, and upregulation of MYC promotes cell proliferation in MM and disease progression. Recently, some novel therapeutic agents targeting BRD4, a histone modification-related 'reader' of epigenetic marks, or other important factors (e.g. TAK1) in relevant signaling pathways have been developed and they may provide new options for relapse/refractory MM therapy, such as BET inhibitors, CBP/EP300 inhibitors, dual-target BET-CBP/EP300 inhibitors, TAK1 inhibitors, and they may provide new options for relapsed/refractory MM therapy. Accumulated studies have revealed that some key factors associated with the mechanism of IMiD resistance to MM cells. Some agents represent promising new therapeutics of MM to regulate the IRF4/MYC axis by inhibiting BRD4 expression or signaling pathway activation. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide are antitumor compounds that have direct tumoricidal activity and indirect effects mediated by multiple types of immune cells in the tumor microenvironment (TME). IMiDs have shown remarkable therapeutic efficacy in a set of B-cell neoplasms including multiple myeloma, B-cell lymphomas and chronic lymphocytic leukemia. More recently, the advent of immunotherapy has revolutionized the treatment of these B-cell neoplasms. However, the success of immunotherapy is restrained by immunosuppressive signals and dysfunctional immune cells in the TME. Due to the pleiotropic immunobiological properties, IMiDs have shown to generate synergetic effects in preclinical models when combined with monoclonal antibodies, immune checkpoint inhibitors or CAR-T cell therapy, some of which were successfully translated to the clinic and lead to improved responses for both first-line and relapsed/refractory settings. Mechanistically, despite cereblon (CRBN), an E3 ubiquitin ligase, is considered as considered as the major molecular target responsible for the antineoplastic activities of IMiDs, the exact mechanisms of action for IMiDs-based TME re-education remain largely unknown. This review presents an overview of IMiDs in regulation of immune cell function and their utilization in potentiating efficacy of immunotherapies across multiple types of B-cell neoplasms. [ABSTRACT FROM AUTHOR]

The ovarian tumor microenvironment (TME) is characterized by the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and granulocytic cells. Very small size particles (VSSP), comprised of the ganglioside NAcGM3 and Neisseria meningitidis derived outer membrane vesicles, is being developed as a nanoparticulated modulator of innate immunity. Prior studies have shown that VSSP enhanced antigen-specific cytotoxic T cell responses and reduced the suppressive phenotype of splenic granulocytic cells in tumor-bearing mice. Here, we hypothesized that intraperitoneal VSSP would modify myeloid cell accumulation and phenotypes in the ovarian TME and abrogate suppressor function of TAMs and tumor-associated granulocytic cells. In the ID8 syngeneic model of epithelial ovarian cancer, VSSP reduced peritoneal TAMs and induced M1-like polarization in TAMs. In addition, VSSP stimulated peritoneal inflammation characterized by increased granulocytes and monocytes, including inflammatory monocytic cells. VSSP treatment resulted in peritoneal TAMs and granulocytic cells being less suppressive of ex vivo stimulated CD8+ T cell responses. VSSP alone and combined with anti-PD-1 modestly but significantly prolonged survival in tumor-bearing mice. In addition, ex vivo treatment with VSSP induced M1-like polarization in TAMs from patients with metastatic ovarian cancer and variably abrogated their suppressor phenotype. VSSP treatment also partially abrogated the induction of suppressor function in healthy donor neutrophils exposed to ascites supernatants from patients with ovarian cancer. Together, these results point to VSSP reprogramming myeloid responses resulting in abrogation of suppressive pathways and raise the potential for administration of VSSP into the TME to enhance anti-tumor immunity. [ABSTRACT FROM AUTHOR]

As an immunomodulatory drug, lenalidomide has been shown to have anti-lymphoma activity and is used in combination with several agents in the treatment of patients with relapsed/refractory disease. In this study, we aimed to evaluate the efficiency of lenalidomide in the treatment of B-cell NHL. This retrospective study included patients with relapsed/refractory B-cell NHL who received lenalidomide treatment between March 2018 and January 2021. Patients' demographic data, dose, and duration of the lenalidomide treatment, combined agents, response rates, side effects, and survival rates were evaluated. Twelve patients who diagnosed with relapsed/refractory NHL were included in the study. Lenalidomide treatment was initiated in combination with rituximab for nine of these patients and with temozolomide for the remaining three of them. At the initiation of the lenalidomide treatment, patients' median age was 72.5 (24-83) years. Number of females/males was 9/3. Nine of the patients were diagnosed with diffuse large b-cell lymphoma (DLBCL), 3 of whom had isolated central nervous system lymphoma (CNS) and 1 had Richter transformation of chronic lymphocytic leukemia. Two patients were diagnosed with mantle cell lymphoma (MCL) and 1 patient was diagnosed with marginal zone lymphoma. The median treatment duration was 4 (1-20) months. In the response assessment, 4 patients had complete response while progressed disease was observed in 5 patients. Three patients died before response assessment. In the median 33-month follow-up, progression-free survival and total survival were found as 4 (1-20) and 7 (1-22) months respectively. Due to its low toxicity profile and activity, lenalidomide could be a good option especially for elderly and fragile B-cell lymphoma patients. It is an agent to be considered particularly in lymphomas with CNS involvement with its good CNS penetration. Its synergistic effect may give better results when used in combination with several anti-lymphoma drugs. [ABSTRACT FROM AUTHOR]

Traditional herbal medicines, which emphasize a holistic, patient-centric view of disease treatment, provide an exciting starting point for discovery of new immunomodulatory drugs. Progress on identification of herbal molecules with proven single agent activity has been slow, in part because of insufficient consideration of pharmacology fundamentals. Many molecules derived from medicinal plants exhibit low oral bioavailability and rapid clearance, leading to low systemic exposure. Recent research suggests that such molecules can act locally in the gut or liver to activate xenobiotic defense pathways that trigger beneficial systemic effects on the immune system. We discuss this hypothesis in the context of four plant-derived molecules with immunomodulatory activity: indigo, polysaccharides, colchicine, and ginsenosides. We end by proposing research strategies for identification of novel immunomodulatory drugs from herbal medicine sources that are informed by the possibility of local action in the gut or liver, leading to generation of systemic immune mediators.

In multiple myeloma (MM), the impaired function of several types of immune cells favors the tumor’s escape from immune surveillance and, therefore, its growth and survival. Tremendous improvements have been made in the treatment of MM over the past decade but cellular immunotherapy using dendritic cells, natural killer cells, and genetically engineered T-cells represent a new therapeutic era. The application of these treatments is growing rapidly, based on their capacity to eradicate MM. In this review, we summarize recent progress in cellular immunotherapy for MM and its future prospects.

The transition to oral therapies in patients with multiple myeloma (MM) offers potential benefits to patients; however, they must self-manage their medication and adherence plays an important role in patient care. It has been shown that patient satisfaction with their medication has a strong positive correlation with adherence in chronic diseases. The aim of this study was to estimate adherence rate of oral antimyeloma therapies and to identify risk factors for medication non-adherence. This observational, prospective, and multicentre survey based on a self-report questionnaire enrolled MM patients with at least 3 months of oral therapy. The 6-item Girerd scale and the medication possession ratio (MPR) were used for measuring medication adherence and the SATMED-Q® questionnaire was used for measuring satisfaction. An analysis of risk factors for non-adherence to oral therapy was performed using univariate analysis. A total of 101 patients participated in the survey, yielding a response rate of 87%. The prevalence of adherence to oral antimyeloma therapy was estimated at 51.5% using the Girerd questionnaire. According to the MPR, adherence was evaluated at 96% (i.e. MPR ≥ 0.80). Both methods combined, adherence was estimated at 50.5%. One risk factor for medication non-adherence was identified: Eastern Cooperative Oncology Group Performance Status > 2 (p = 0.007). One predictive factor for high medication adherence was identified: high satisfaction with treatment (p = 0.01). Identifying patients at higher risk for non-adherence allows clinical pharmacists to personalise therapeutic information and education and to improve the quality of healthcare overall. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma B-cell malignancy characterized by immune dysfunction, with infection representing a major complication. Bacteria, including Streptococcus pneumoniae, are common pathogens in patients with MM, but reports on infections with nontuberculous mycobacteria (NTM) have been limited. We herein report a case of disseminated NTM infection in a patient with MM undergoing treatment with immunomodulatory drugs. At the diagnosis, the patient showed lymphocytopenia and was treated with clarithromycin, rifampicin, and ethambutol; however, culture positivity persisted, and the patient died. The possibility of NTM infection should be considered in cases of unexplained deterioration of the MM patient's general condition.

Thalidomide and its analogues are known as immunomodulatory drugs (IMiDs) that possess direct antimyeloma effects, in addition to other secondary effects, including antiangiogenic, antiinflammatory, and immunomodulatory effects. Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both γ‐interferon (IFN‐γ) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide‐treated mice, there was a significant increase in the terminally differentiated mature CD27lo NK cells in the peripheral tissues and NK cells in thalidomide‐treated mice showed significantly higher cytotoxicity and IFN‐γ production. The NK cell expression of T‐bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase‐3β expression was observed in thalidomide‐treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T‐bet expression to inhibit lung metastasis of cancer cells. [ABSTRACT FROM AUTHOR]

Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m2 of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse. [ABSTRACT FROM AUTHOR]

Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin. [ABSTRACT FROM AUTHOR]

• Treatment regimens based on proteasome inhibitors and immunomodulatory drugs are effective and safe after allogeneic hematopoietic stem cell transplantation (HSCT). • Similar responses to these regimens are achieved in the pre-HSCT and post-HSCT settings. • Chronic graft-versus-host disease is associated with improved overall survival after relapse. • Time to relapse after allogeneic HSCT discriminates patients with very different outcomes. Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P <.001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P <.001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) is a plasma cell cancer with high mortality and morbidity rates. Its incidence rate has increased by 143% since 1975. Adipokines, cytokines, chemokines, and genetic variations influence the development and progression of MM. Chromosomal translocations cause mutations associated with MM. The pathogenesis of MM is complicated by novel issues like miRNAs, RANKL, Wnt/DKK1, Wnt, and OPG. Conventional diagnosis methods include bone marrow biopsy, sPEP or uPEP, sIFE and uIFE, and sFLC assay, along with advanced techniques such as FISH, SNPA, and gene expression technologies. A novel therapeutic strategy has been developed recently. Chemotherapy, hematopoietic stem cell transplantation, and a variety of drug classes in combination are used to treat patients with high-risk diseases. Alkylating agents, PIs, and IMiDs have all been developed as effective treatment options for MM in recent years. This review overviews the current recommendations for managing MGUS, SMM, MM, SP and NSMM and discusses practices in diagnosing and treating MM. [ABSTRACT FROM AUTHOR]

Relapsed and refractory multiple myeloma (MM) is defined as progression during anticancer therapy, or within 60 days of therapy completion. Patients with double resistance to bortezomib and lenalidomide that is two key anti-myeloma drugs are considered to have a very poor prognosis, and new regimens are needed to improve this setting. Pomalidomide is an immunomodulatory drug third generation, studied in combination with low-dose dexamethasone (LDD) as salvage therapy for patients with double refractory. This article reviews the clinical pharmacology, therapeutic efficacy and safety, dosage and administration, peculiar properties of the practical application of pomalidomide. The article is illustrated by the description of a 59-year-old woman with relapsed and refractory MM, who received pomalidomide in combination with LDD. Medical history prior to treatment with pomalidomide was included 8 lines of therapy conducted over 6.5 years, with the formation of the double refractory to lenalidomide and bortezomib. In March 2012, treatment with pomalidomide (4 mg days 1–21 of a 28-day cycle) and LDD (160 mg / cycle) has been started as the ninth line. In total, up to March 2014 the patient received 30 cycles of therapy with pomalidomide. After the first 2 cycles documented partial response (52 % reduction of IgGk), the deepest response is received after 10 cycles (82 % reduction). The patient is alive at the time of this article. The duration of response to pomalidomide is 25 months and overall survival from the time of his appointment is more than 37 months. In addition, this review presents the results of base clinical trials testing pomalidomide and LDD. Problems of development of new treatment regimens based on pomalidomide for relapsed and refractory MM are also discussed.

Results of the development of an immunomodulating drug timofer based on coordination compounds isoleucyl-tryptophan dipeptide with iron (II), including the study of coordinate isoleucyl-tryptophan dipeptide with iron (II), the study of the immunostimulatory activity of the coordination compounds, the results of the preclinical and clinical studies of timotsin are presented. Method of pH titration showed that the interaction of zinc and dipeptide isoleucyltryptophan formed in solution following complex forms: [Fe (HL±)]2+ (β = 1,00×1034), [Fe(HL±)2]2+ (β = 6,25×1011), [Fe (HL±)OH]+ (β = 4,01×1026), [Fe (L)]+ (β = 8,10×1018), [Fe (L)2]+ (β = 7,50×1028), [Fe (L)OH]+ (β = 1,03×1029). It was shown that the immunostimulatory activity of the coordination compounds is 2 times higher than that starting dipeptide. The substance sample and standard formulation of timofer were developed and standardized. The developed immunomodulatory drug timofer showed a high therapeutic efficacy in the treatment of iron deficiency anemia patients with inflammatory processes and traumatic injuries of the maxillofacial region, with chronic inflammatory diseases of the the genitals (CMV, HSV, chlamydia, chronic endometritis, chronic salpingoopharitis, ureaplasmosis) with chronic bronchitis, chronic obstructive bronchitis, bronchial asthma, pneumonia, chronic glomerulonephritis, and chronic renal failure complicated by anemia Bright, withrheumatic diseases, gynecological patients with anemia of moderate and severe degrees of severity, at surgical treatment of patients with suppurative lung disease, heart disease and chronic pericarditis operated with cardiopulmonary bypass. Timofer is registered in Tajikistan (registration number of medical drug №002866).

Abstract: Background: Patients with relapsed/refractory multiple myeloma (RRMM) have poor prognosis. Pomalidomide is an immunomodulatory compound that has demonstrated activity in MM patients with disease refractory to lenalidomide and bortezomib. Objectives: Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. Patients and Methods: We analyzed retrospectively 50 patients treated with pomalidomide in 12 Polish sites between 2014 and 2017. Median age was 63 years, median time since diagnosis 4.5 years and median number of prior regimens 4. Results: The overall response rate was 39.1%. Median progression‐free survival (PFS) and overall survival (OS) were 10.0 and 14.0 months, respectively. Previous treatment with immunomodulatory drugs, bortezomib or stem cell transplant had no impact on PFS and OS. Most frequent grade 3/4 treatment‐emergent adverse events were hematologic (neutropenia 24.0%, thrombocytopenia 10.0%, anemia 8.0%). Most common grade 3/4 non‐hematologic toxicities were respiratory tract infection (14.0%) and neuropathy (4.0%). Conclusions: This real‐world data have confirmed that pomalidomide is an active drug in RRMM and support results of published clinical trials and other real‐world studies. [ABSTRACT FROM AUTHOR]

The effect of immunomodulatory drugs (IMiDs) on serious infection remains uncertain. We therefore conducted a systematic review and meta-analysis to assess the possible impact of IMiDs on serious infection in patients with multiple myeloma (MM). We searched randomized controlled trials (RCTs) and observational studies from databases that addressed the effect of IMiDs on serious infection in patients with MM. We pooled data from RCTs and observational studies separately and used the GRADE approach to rate the quality of evidence. Rates in patients with individual IMiDs at different treatment status ranged from 7.00 to 23.00%. The use of thalidomide- or lenalidomide-based regimen induction therapy for autologous stem cell transplantation (ASCT)-ineligible patients suggests increase in serious infection (RR = 1.59, 95% CI 1.31-1.93, p < 0.01). Compared to conventional therapy, IMiDs' induction in ASCT-eligible patients significantly decreases the risk of serious infection (RR = 0.82, 95% CI 0.72-0.94, p < 0.01). Lenalidomide-based therapy was associated with a significant increase in risk of serious infection in patients treated compared with conventional therapy (RR = 2.45, 95% CI 1.57-3.83, p < 0.01). The current evidence suggests that patients with MM treated with IMiDs are at a high risk of serious infection. [ABSTRACT FROM AUTHOR]

Despite the advent of novel therapies and improvements in survival, multiple myeloma (MM) remains an incurable disease. Thus, new treatment strategies including immunotherapies are needed for MM patients with stable disease after induction chemotherapy as well as for disease control in patients with advanced disease. However, profound immune dysregulation not only of B cells, but also of other immune cells such as natural killer cells, T cells, and dendritic cells and increase in the number of immunosuppressive cells, i.e., regulatory T and B cells and myeloid-derived suppressor cells, have been demonstrated in advanced MM patients, which may be involved in disease progression. Because of immune dysfunction, immunotherapies have not shown clinical efficacy in MM patients. It is therefore crucial to resolve immunosuppressive mechanisms and improve immune responses, especially in advanced MM patients. Recently, excellent clinical efficacy of new immunotherapeutic strategies such as immunomodulatory drug-intensified monoclonal antibody treatment, immune checkpoint inhibitors, and chimeric antigen receptor T-cell therapy targeting B cell maturation antigen has been reported in advanced-stage MM patients. Those new treatments or their combination will improve prognosis and possibly point toward a cure for myeloma. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the efficacy of tocilizumab in uveitic macular edema (ME) resistant to various immunomodulatory drugs.Methods: Patients received tocilizumab every 4 weeks intravenously. Central foveal thickness (CFT) was assessed by optical coherence tomography (OCT).Results: Five patients (8 eyes) who were ineffectively pretreated with systemic prednisolone, at least one immunosuppressive drug, and at least one biologic drug for uveitic macular edema were included in the study. At 3 months, a response of ME (≥25% reduction in CFT) was observed in 6 eyes (75.0%) of 5 patients. During follow-up, complete resolution of ME was achieved in 5 eyes (62.5%) of 4 patients. Improvement of BCVA was observed in 3 eyes of 3 patients, and stabilization in 3 eyes of 3 patients. Tocilizumab was well tolerated, and no severe side effects occurred.Conclusions: Treatment with tocilizumab can be considered in chronic uveitic macular edema even if previous immunomodulatory therapy has failed. [ABSTRACT FROM AUTHOR]

Leflunomide is an immunomodulatory drug exhibiting anti-inflammatory, anti-proliferative and immunosuppressive effects. It has been widely used for treatment of active rheumatoid arthritis. Despite its good safety profile cutaneous side effects like alopecia, eczema, pruritis and dry skin have been reported with Leflunomide use. Skin ucleration, vasculitis, lichenoid drug rash and Subacute Cutaneous Lupus Erythematosus (SCLE) have been rarely reported with its use. A rare case of Leflunomide induced SCLE is being reported in a female patient with rheumatoid arthritis. The clinical features, histopathological and immunological characteristics were consistent with drug induced SCLE. Withdrawal of Leflunomide along with short course of topical steroids resulted in resolution of symptoms suggesting the drug to be the culprit. As this drug comes into widespread use, it remains to be seen whether more cases of DI-SCLE will occur/ be reported. Fortunately, such a condition till times appears rare and is reversible once the drug is discontinued thus avoiding over evaluation and over treatment if the triggering drug is recognized.

Background Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. Methods Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans . Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4 + cells, CD8 + cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. Results Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4 + , NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4 + , 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P < 0.05. Conclusions Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease. [ABSTRACT FROM AUTHOR]