Pathological landscape of tumor flare reaction to epcoritamab treatment.

Tumor flare reaction (TFR) is characterized by an increase in lesion size during immune-based therapy, often resembling disease progression. It signifies inflammation at the tumor site and is frequently seen in immunotherapy, where it is termed "tumor pseudoprogression." The exact mechanisms behind TFR remain unclear. We report the case of a 62-year-old Japanese man with relapsed and refractory diffuse large B cell lymphoma treated with epcoritamab. On day 10 of the first epcoritamab cycle, after two subcutaneous injections of epcoritamab, the cutaneous lymphoma lesions became swollen. This was identified as TFR, and was managed with a three-day course of intravenous dexamethasone at 12 mg/day. The third injection, scheduled for day 15, was delayed by 1 week. Four doses of epcoritamab were completed over the initial 35-day period. A skin biopsy was performed on day 30. Histopathological examination showed CD20+ large atypical lymphocytes forming residual nodules, encircled by CD4+ and CD8+ lymphocytes, with a predominance of CD8+ T cells over CD4+ T cells. Although infrequent, TFR may be a significant indicator of tumor response to epcoritamab therapy. The diagnosis of TFR could be underestimated, and proper identification and understanding of its clinicopathological features are crucial for its effective management.

Comprehensive procedure for injecting Evusheld® for hematological diseases in a single institute.

Tixagevimab and cilgavimab (EVA, Evusheld®), monoclonal antibody combination treatments, consisted of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EVA showed prophylactic and therapeutic effects against coronavirus disease 2019. The Japanese Society of Hematology recommended EVA for such patients with active treatment, but each institution decided on comprehensive administration. We develop a systematic procedure for comprehensive EVA injection prophylactically in patients with hematological malignancies without any over/under-indication. We listed all patients with the required indications from November 2022 to March 2023. We included 178 cases, 84 females and 94 males, with a median age of 70 (range: 19-90) years. Underlying diseases are myeloid neoplasms in 36 (20%), lymphoid neoplasms in 75 (73%), and others. Indications were intensively hematological malignancy treatment, rituximab treatment within 12 months, burton kinase inhibitor treatment, after chimeric antigen receptor T cell immunotherapy, and after stem cell transplantation in 74 (41%), 73 (41%), 3 (2%), 5 (3%), and 23 (13%) cases, respectively. Of the 178 cases, 22 (12.4%) refused EVA injection. Further, 42 and 136 cases were administered outpatient and inpatient, respectively. Over 95% of the listed cases received EVA injection within 3 months. No severe toxicities were observed among them (N = 156), and 8 (5.2%) cases had breakthrough SARS-CoV-2 infection, which was significantly lower (P = 0.02) than those without EVA (4 [18.2%] of 22 cases). Both groups showed no moderate or severe infection cases. This single-center experience showed that comprehensive EVA injection management effectively generated safer completion with preferable clinical impact.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study).

Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.

Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.

Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

Potential factors for and the prognostic impact of ascites after allogeneic hematopoietic stem cell transplantation.

Ascites is sometimes detected after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, since limited information is currently available, its clinical meaning remains unclear. Therefore, we herein examined potential factors for and the impact of ascites on the prognosis of patients after allo-HSCT at our institutes. Fifty-eight patients developed ascites within 90 days of allo-HSCT (small in 34 (16%), moderate-large in 24 (11%)). A multivariate analysis identified veno-occlusive disease/sinusoidal obstruction syndrome (p = 0.01) and myeloablative conditioning (p = 0.01) as significant potential factors for the development of small ascites. Thrombotic microangiopathy (TMA) (p < 0.01) was a significant potential factor for moderate-large ascites. The incidence of both small and moderate-large ascites correlated with lower overall survival (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites) and higher non-relapse mortality rates (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites). Lower OS and higher NRM rates correlated with the incidence of both small and moderate-large ascites. Further investigation is warranted to establish whether the clinical sign of ascites improves the diagnostic quality of TMA in a large-scale study.

Colchicine-responsive chronic recurrent multifocal osteomyelitis associated with familial Mediterranean fever in the presence of MEFV mutation: A case report.

A 38-year-old female was referred with a history of fever, polyarthralgia, and bone pain. She was diagnosed with chronic recurrent multifocal osteomyelitis based on imaging and biopsy findings. Non-steroidal anti-inflammatory drugs and bisphosphonate caused no improvement. Then, she developed recurrent diarrhoea and abdominal pain. Genetic testing revealed MEFV mutation. Based on the symptoms and genetic mutation results that emerged during the course of these events, she was diagnosed with familial Mediterranean fever. All symptoms, including bone pain, improved with daily colchicine administration. This case was considered familial Mediterranean fever complicated with a clinical diagnosis of chronic recurrent multifocal osteomyelitis, which is included in the spectrum of pyrine autoinflammatory diseases. Considering this case, patients with chronic recurrent multifocal osteomyelitis with MEFV gene variants may respond to colchicine.

Repeated spontaneous remission of acute myeloid leukemia in response to various infections: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. CASE PRESENTATION: We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens-nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient's peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. CONCLUSIONS: We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Cost-Effectiveness Analysis of Transplantation-Ineligible Elderly Patients With Acute Leukemia Harboring a Molecular Target: Ph-Positive Acute Leukemia and FLT3-Mutated Acute Myeloid Leukemia.

Background: Tyrosine kinase inhibitors (TKIs) and FMS-like tyrosine kinase 3 (FLT3) inhibitors are promising agents for Ph-positive acute leukemia (Ph+ AL) and FLT3 mutated acute myeloid leukemia (FLT3-AML), respectively. Methods: We examined the cost-effectiveness ratio (CER) of dasatinib and ponatinib for Ph+ AL and the cost-effectiveness of gilteritinib and quizartinib for FLT3-AML in elderly patients. Molecular therapy can fit the elderly population better than chemotherapy (CT). Results: The daily drug cost of dasatinib, ponatinib, gilteritinib, and quizartinib was $240, $170, $524, and $479 in terms of treatment maintenance dose, respectively. Treatment of Ph+ AL with stem cell transplantation (SCT), CT, dasatinib, and ponatinib yielded CERs of $322,375, $34,928, $61,104, and $46,234, respectively. The CERs for FLT3-AML treated with SCT, CT, gilteritinib, and quizartinib were $355,270, $42,717, $94,987, and $90,080, respectively. Treatment of elderly patients with TKIs and FLT3 inhibitors remained expensive and inferior to conventional CT. Conclusion: Although TKIs and FLT3 inhibitors have an inferior CER than does conventional CT, their promising survival benefit with better QOL can offer a profound advantage. TKI or FLT3 inhibitor monotherapy is recommended as an alternative treatment option for unfit (vulnerable) elderly patients with Ph+ AL or FLT3-AML.

Humoral immune response against BNT162b2 mRNA COVID-19 vaccine in patients with rheumatic disease undergoing immunosuppressive therapy: A Japanese monocentric study.

We investigated serum total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain after BNT162b2 mRNA vaccination against coronavirus disease 2019 (COVID-19) in Japanese patients taking various immunosuppressive medications for rheumatic disease. In 212 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers (controls), all of whom had received 2 doses of BNT162b2 vaccine, serum antibody titers of SARS-CoV-2 spike protein were analyzed at least 14 days after the second dose. Many of the patients were taking immunosuppressive agents to manage their rheumatic disease. The antibody titers against SARS-CoV-2 spike protein in these patients were significantly lower than those in controls. The analysis of therapeutic agents revealed that the antibody titers in patients treated with rituximab were much lower than those in controls. In patients treated with tacrolimus, baricitinib, azathioprine, mycophenolate mofetil, abatacept, tumor necrosis factor inhibitors, cyclosporine, interleukin-6 inhibitors, methotrexate, or glucocorticoids, antibody titers were moderately lower than those of controls. Interleukin-17 and interleukin-23 inhibitors did not impair the humoral response. In addition, the combination of methotrexate with various immunosuppressive agents reduced titers, although not significantly. In Japanese patients with rheumatic disease, many immunosuppressants impaired the immune response to the BNT162b2 vaccine. The degree of decline in antibody titers differed according to immunosuppressant. When used concomitantly with other immunosuppressants, methotrexate may impair the immune response to the BNT162b2 vaccine. However, immunomodulatory treatments such as interleukin-17 and -23 inhibitors may not attenuate this response in patients with rheumatic disease.

FDG-PET/CT imaging parameters for predicting spontaneous regression of methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis.

In this study, we investigated the usefulness of FDG-PET/CT for predicting spontaneous regression in methotrexate-associated lymphoproliferative disorder (MTX-LPD). Twenty patients with rheumatoid arthritis who were diagnosed with MTX-LPD were enrolled in the study. These patients were divided into those who showed spontaneous regression (SR group: ten patients) and those who received chemotherapy after discontinuation of MTX (CTx group: ten patients). Between-group differences in potential biomarkers were compared, including clinical markers at the onset of LPD [serum LDH and interleukin 2 receptor (sIL-2R)], change in absolute number of peripheral lymphocytes (ΔALC) over follow-up, and the FDG-PET/CT-derived parameters of maximum standardized uptake value (SUVmax), mean SUV (SUVmean), peak SUV (SUVpeak), sum of the metabolic tumor volume (MTVsum), and sum of total lesion glycolysis (TLGsum). The levels of sIL-2R, MTVsum, and TLGsum were significantly lower in the SR group than in the CTx group. In addition, ΔALC was higher in the SR group. In conclusion, MTV and TLG values measured by FDG-PET/CT may be suitable for use as predictors of SR in patients with MTX-LPD.

Application of PD-L1 blockade in refractory histiocytic sarcoma: A case report.

Histiocytic sarcoma (HS) is a rare hematological malignancy, which exhibits morphological and immunophenotypic features of histiocytes. A standard therapy for HS has not yet been established due to its rareness; therefore, disease control is not always possible. A multimodal treatment strategy has been suggested for HS. The present study reported on a case of a 43-year-old female patient who complained of left femoral pain, which was caused by left femoral bone mass. A biopsy of their left femoral bone tumor revealed that the patient had HS. Their sarcoma was localized in the femoral bone and was not considered to be curable, due to local infiltration of the bone tumor beyond the periosteum. The patient then underwent two types of HS-specific chemotherapy; however, both regimens were ineffective. As a result, they underwent radiation therapy at the sites of progressive disease. Because the HS cells of the patient expressed PD-L1, they were treated with nivolumab (240 mg/body, biweekly) for residual diseases in the right occipital bone, multiple lung nodules, intrapelvic right lymph node and primary site. Nivolumab treatment resulted in a complete response at all sites, with the exception of the primary site, which was confirmed by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography. The patient received additional nivolumab treatment as consolidation therapy for 1 year. In addition, residual disease of the femoral head was completely resected. The surgically resected refractory tumor revealed the tumor cells no longer pathologically expressed PD-L1 . In conclusion, for refractory and recurrent HS in which surgical resection is not appropriate, treatment with immune-checkpoint inhibitors, such as nivolumab, may be considered an optional but promising immunotherapy if the tumor histologically expresses PD-L1. The present study detected one of the refractory mechanisms of ICI treatment.

Supplemental hydroxychloroquine therapy regulates adipokines in patients with systemic lupus erythematosus with stable disease.

BACKGROUND: In patients with systemic lupus erythematosus (SLE), a higher frequency of atherosclerotic lesions is associated with poor prognosis. Hydroxychloroquine (HCQ) has been reported to improve the lifespan and the prognosis of dyslipidaemia in patients with SLE, but the mechanism is unclear. We investigated the effect of supplemental HCQ treatment on the levels of serum cytokines associated with atherosclerosis in patients with stable SLE. METHODS: Patients with SLE who received supplemental HCQ and maintained low disease activity between January 2016 and September 2020 were included in this study. Disease activity was assessed using Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index, Cutaneous Lupus Erythematous Disease Area and Severity Index, and Lupus Low Disease Activity State. Serum complement titres, anti-dsDNA antibodies, and serum cytokines (adiponectin, resistin, and leptin) were analyzed before and after HCQ treatment. RESULTS: Forty-one patients (4 males and 37 females, mean age 41.3 ± 13.2 years) were included. Serum adiponectin levels were significantly increased after 3 months of HCQ treatment compared to baseline, and serum resistin levels were significantly reduced. The change in serum resistin level after HCQ administration was correlated with a significant reduction in serum TNF-α, interleukin (IL)-6, IL-8, and IL-1RA levels. CONCLUSIONS: Supplemental HCQ treatment in patients with SLE improved adipokine levels. HCQ may improve prognosis by controlling disease activity in SLE and reducing risk factors for atherosclerosis. Key Points • Hydroxychloroquine has been reported to improve the prognosis of dyslipidaemia in patients with SLE, but the underlying mechanism is unclear. • In this study, hydroxychloroquine improved adipokine levels in patients with SLE, implicating adipokines as a potential mechanism underlying the benefit of hydroxychloroquine on dyslipidaemia. • Supplemental hydroxychloroquine should be considered in patients with SLE harboring lipid abnormalities and risk factors for atherosclerosis.

Efficacy and safety of apremilast and its impact on serum cytokine levels in patients with Behçet's disease.

To evaluate the long-term clinical efficacy of apremilast in Behçet's disease (BD) and its effect on serum cytokine levels. This study included 15 BD patients who were treated with apremilast. The rates of change in oral and genital ulcers, skin lesions, arthritis, and arthralgia were evaluated every 3 months for 12 months. The efficacy of apremilast was compared between patients with and without oral ulcer remission. Changes in the serum levels of interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-10, IL-17A, IL-6, IL-8, and IL-23 between baseline and 3 months after apremilast initiation were compared. After 3 months, oral and genital ulcers disappeared in most cases. The skin and joint lesions tended to improve for up to 6 months; however, recurrence was observed after 9 months. The improvement of genital ulcers was earlier in the oral ulcer remission group than the oral ulcer non-remission group, with the genital ulcers disappearing within the first 3 months. The baseline levels of serum cytokines, analyzed in seven patients, did not exhibit significant associations with specific organ lesions. After administration of apremilast, the TNF-α and IL-23 levels significantly decreased; however, the IFN-γ, IL-6, IL-8, and IL-10 levels did not show significant changes. The rates of decrease in the serum IL-6, IFN-γ, and IL-10 levels were greater in patients with improved oral ulcers. Modulation of serum cytokine levels with apremilast might underlie the efficacy of apremilast in oral ulcers in BD patients.

Effect of add-on hydroxychloroquine therapy on serum proinflammatory cytokine levels in patients with systemic lupus erythematosus.

We investigated the effect of hydroxychloroquine (HCQ) as an add-on treatment to immunosuppressants on the expression of proinflammatory cytokines in patients with systemic lupus erythematosus. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and interleukin 1 receptor antagonist (IL-1ra) were measured immediately before and 3 months after treatment with oral HCQ. Among the 51 patients enrolled in the study, HCQ treatment led to significantly reduced serum levels of TNF-α, IL-6, IL-8, VEGF-A, IL-1ra, and IL-2 (p < 0.0001; p = 0.0006; p = 0.0460, p = 0.0177; p < 0.0001; p = 0.0282, respectively) and to decreased (but not significantly) levels of MIP-1α (p = 0.0746). No significant changes were observed in the serum MCP-1 levels before and after HCQ administration (p = 0.1402). Our results suggest that an add-on HCQ treatment modulates the expression of proinflammatory cytokines even in systemic lupus erythematosus patients with low disease activity.

Intratumoral cancer immunotherapy exploiting anti-viral immunity.

After a long period of endeavor, immunotherapy has become the mainstream of cancer therapies. This success is mostly ascribed to immune checkpoint blockade, chimeric antigen receptor-transduced T cell therapies, and bispecific antibodies. However, these methods have been effective or applicable to only a limited proportion of patients so far. Thus, further development of broadly applicable and effective immunotherapies is eagerly anticipated. Given that innate immunity is key to the induction of robust adaptive immunity and that the immunosuppressive tumor microenvironment is a major hurdle to overcome, intratumoral immunotherapy in which delivery of immunostimulatory microbial agents to the tumor site triggers innate immunity in situ is a rational strategy. There has been a plethora of preclinical and clinical trials conducted involving the delivery of either mimetics of viral nucleic acids or oncolytic viruses intratumorally to trigger innate immunity via various nucleic acid sensors in the tumor site. Many of these have shown significant antitumor effects in mice, particularly in combination with immune checkpoint blockade. Oncolytic herpes simplex virus type 1 has been approved for the treatment of advanced melanoma in the United States and Europe and of glioblastoma in Japan. Whereas direct intratumoral administration has mainly been chosen as a delivery route, several promising compounds amenable to systemic administration have been developed. Intratumoral delivery of immunostimulatory agents will become an important option for cancer immunotherapy as an off-the-shelf, broadly applicable, and rational strategy that exploits the physiology of immunity, namely anti-microbial immunity.