Secondary Immunodeficiency Diseases Research Articles

Treatment patterns and burden of infection in patients with chronic lymphocytic leukemia and secondary immunodeficiency: a retrospective database study.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and secondary immunodeficiency disease (SID) are susceptible to severe, recurrent, or persistent infections. This retrospective cohort study assessed the burden of infection in patients with CLL/SLL with and without SID, and in immunoglobulin replacement therapy (IgRT)-treated and -untreated patients with CLL/SLL and SID. Anonymized data from the US Optum-Humedica database (Oct-1-2015-Mar-10-2020) were used. Eligible patients aged ≥ 18 years with a confirmed CLL/SLL diagnosis were assigned to cohorts (SID or no-SID) using an algorithm based on serum IgG levels < 5.0g/L, hypogammaglobulinemia diagnosis codes, and ≥ 1 major infection. A further sub-categorization was made based on patients with SID who received IgRT and those who did not. During 12-month follow-up, patients with CLL/SLL and SID were significantly more likely to experience infections (70.1% vs. 30.4%), including severe bacterial infections (39.8% vs. 9.2%), and infections requiring hospitalization (27.7% vs. 5.8%) than patients without SID. The use of anti-infectives and healthcare resource utilization (HCRU) was also higher in the SID cohort versus the no-SID cohort. Overall survival was shorter in patients with SID than those without (12.3 vs. 16.9 months). In patients with CLL/SLL and SID, burden of infection and HCRU were greater in IgRT-treated patients than in no-IgRT patients, potentially highlighting the IgRT-treated cohort as a more vulnerable population. Increasing understanding of SID burden may help to improve outcomes in patients with CLL/SLL. Further research is needed to develop guidance for IgRT use and to assess the benefits of IgRT in this vulnerable population.

Burden of Infection in Patients With and Without Secondary Immunodeficiency Disease Following Diagnosis of a Mature B Cell Malignancy

BackgroundThis retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID). Patients and MethodsData were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin's lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded. ResultsOverall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort. ConclusionThis study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

Сучасні підходи до вакцинації в дітей з різними варіантами первинних та вторинних імунодефіцитів (огляд літератури)

Chronic disease and immunosuppression increase the risk of vaccine-preventable infections, complications, and mortality from infectious diseases. Safe vaccination and achieving an adequate serological response to vaccination are crucial aspects of the management of such patients. Purpose - to analyze data from domestic and foreign medical literature regarding modern approaches to vaccination of children with various primary and secondary immunodeficiency diseases. The majority of children with primary immunodeficiency who have preserved antibody production can demonstrate an immune response to vaccination, but this response can be rapidly lost over time. Limitations to vaccinating children with primary immunodeficiency are related to the use of live vaccines in conditions where the cellular immune system is compromised. Patients with primary antibody deficiency are treated with immunoglobulin preparations and depend on the presence of specific antibodies at a protective level against infectious pathogens, including vaccine-preventable infections. Several studies have shown the effectiveness of intravenous immunoglobulin treatment in reducing the number and severity of infections in patients with humoral deficiency. The majority of children with rheumatic diseases vaccinated according to the Schedule of Routine Immunisations before starting immunosuppressive therapy have protective antibody levels against vaccine-preventable infections. All non-live vaccines can be administered without restrictions, but should be administered two weeks before immunosuppressive therapy to increase immunogenicity. Children receiving high doses of immunosuppressive therapy should avoid receiving live attenuated vaccines. No conflict of interests was declared by the author.

Real-World Usage of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% in Patients with Multiple Myeloma Diagnosed with Secondary Immunodeficiency Disease

Introduction: In patients with mature B-cell malignancies such as multiple myeloma (MM), both the underlying disease and immunosuppressive therapy can result in patients developing secondary immunodeficiency disease (SID). SID often manifests in severe, recurrent, or persistent infections that can impair a patient's quality of life and are a major cause of morbidity and mortality in patients with MM, thereby resulting in significant clinical and socioeconomic burden. The use of immunoglobulin (Ig) replacement therapy is well established for the treatment of hypogammaglobulinemia in patients with primary immunodeficiency disease (PIDD). Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% is a dual-vial unit of IgG 10% and recombinant human hyaluronidase (rHuPH20). fSCIG 10% is approved in the USA for the treatment of adults and children aged 2 years or older with PIDD, and in the EU for adults and children of any age with PIDD or SID. fSCIG 10% is not fully integrated into standard of care for patients with SID in many countries, in part owing to comparatively less familiarity of hematologists and oncologists with the evidence supporting the use of fSCIG 10% than for intravenous IgG therapy in patients with SID. Therefore, the HyMMy study (NCT05879757) aims to generate real-world evidence to gain a better understanding of patterns of fSCIG 10% use and outcomes in patients with MM and SID. Methods: HyMMy is a prospective, noninterventional, observational study that will be conducted at 30 centers in Europe and South America. It is planned for 100 patients to be enrolled and observed over a 12-month follow-up period. The overall duration of the study will be 38 months. Patients will be eligible for inclusion if they are aged 18 years or older, have a diagnosis of MM, and fulfill the diagnosis criteria for SID: patient suffers from severe, recurrent, or persistent infection despite appropriate anti-infective treatment, and has proven specific antibody failure or a serum IgG trough level of less than 4 g/L (excluding paraprotein). Patients may enter the study after being diagnosed with SID and no more than 30 days after fSCIG 10% treatment initiation, or with no more than 2 doses of fSCIG 10% already infused ( Figure). Patients newly starting fSCIG 10% have a 30-day window from enrollment to inclusion. Patients will be excluded if they have PIDD, have received Ig treatment or prophylaxis within 3 months of enrollment, have an ongoing serious infection requiring intravenous antimicrobial therapy, have a history of malignancy other than MM within 3 years of enrollment, or have had major surgery within 2 weeks of enrollment. The primary endpoint is to characterize the real-world infusion parameters of fSCIG 10% administration (dosing and administration characteristics; treatment interval; infusion volume, sites, rate, and duration; training visits; and fSCIG 10% discontinuation, interruption, or switch to other treatment). Secondary endpoints will examine the disease course and clinical management of MM (including overall survival and healthcare resource utilization) in patients treated with fSCIG 10%. The exploratory endpoints include: burden of infection; infection rate, type, duration, and severity; patient-reported outcomes pertaining to health-related quality of life, collected via questionnaire at the patients' visit; and overall physician assessment of fSCIG 10% utilization, tolerability, and effectiveness, as measured by a 5-point Likert scale questionnaire. Results: Patient recruitment started in June 2023. Interim analysis is planned after enrollment of the first 50 patients, and the estimated end of the study is 2026. Conclusions: HyMMy is the first prospective, observational study that focuses on the assessment of fSCIG 10% utilization patterns in adults with MM diagnosed with SID. The study will help to improve understanding of the treatment patterns and options available for patients with SID and hematologic malignancies, in particular MM. Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

Insights into Facilitated Subcutaneous Immunoglobulin Use in Patients with Secondary Immunodeficiency Diseases: A FIGARO Subgroup Analysis.

The Facilitated Immunoglobulin Administration Registry And Outcomes (FIGARO) Study was a European, multicenter, prospective, observational study conducted across Europe designed to provide insights on the clinical use and tolerability of facilitated subcutaneous immunoglobulin (fSCIG). Data herein are reported for the cohort of patients with secondary immunodeficiency (SID), with a subgroup analysis by age. The SID cohort included 31 patients: 1 pediatric, 15 adult, and 15 older adult patients. Over the 36-month observation period, the median monthly dose of fSCIG (30 g) and median monthly infusion volume per patient (300 mL) remained constant in both adult-age cohorts. Serum trough levels tended to increase over time. Most patients required only one infusion site and could receive the full dose every 3-4 weeks. There was a trend toward self-administration at home. In the adult group, infusion site inflammation and headache were reported at the inclusion visit (n = 1 each), with no adverse drug reactions reported at any of the follow-up visits. No acute severe bacterial infections were reported during the study follow-up. These results demonstrate the feasibility and tolerability of fSCIG use in patients with SID and the flexibility of administration settings including self-administration at home in patients aged ≥65 years.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients with lymphoid malignancies such as chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) are at risk of developing secondary immunodeficiency disease (SID), which can lead to increased susceptibility to severe, recurrent or persistent infections. This study evaluated burden of infection in patients with and without SID following diagnosis of CLL/SLL. Methods: This observational, retrospective cohort study was conducted using anonymized data from the Optum-Humedica database in the USA (1-Oct-15–10-Mar-20). Patients with SID (SID cohort) and without SID (no-SID cohort) were identified 1-Apr-16–10-Mar-19 (selection window). The definition of SID included International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) hypogammaglobulinaemia (HGG) codes, low immunoglobulin G (IgG) levels (<5.0 g/L) and signs/symptoms of SID. The SID index date was the earliest occurrence of an ICD-10-CM HGG code or record of low IgG levels. In patients without SID, the index date was randomly assigned to replicate the distribution of index dates in the SID cohort. CLL/SLL diagnosis and baseline characteristics were identified during a 6-month pre-index period. Included patients were aged ≥18 years with a confirmed diagnosis of CLL/SLL. Infection-related outcomes and overall survival were assessed in patients with ≥12-month and ≥3 months follow-up post-index date, respectively. Results: Of patients with CLL/SLL, 502 and 3928 with and without SID, respectively, were included (SID vs no-SID: mean [standard deviation; SD] age 70.6 [9.7] vs. 71.6 [10.5] years; 59.2% vs 57.7% male). At 12-month follow-up, a larger proportion of patients with SID had ≥1 infection than those without SID (SID: 70.1%; no-SID: 30.4%; p < 0.001). Compared with the no-SID cohort, in the SID cohort there was also a higher number of infections (SID vs no-SID: mean [SD]: 8.4 [12.7] vs. 4.1 [5.4]; p < 0.001), proportion of patients with ≥1 SBI (SID: 39.8%; no-SID: 9.2%; p < 0.001) and proportion of patients with ≥1 infection-associated hospitalization (SID: 27.7%; no-SID: 5.8%; p < 0.001). The most common type of infection was bacterial (SID: 63.7%; no-SID: 24.9%); in those patients who experienced an SBI, the most frequently reported infection was bacterial pneumonia. To assess overall survival, 646 and 4719 patients with and without SID, respectively, were included. Overall survival at 24 months was lower in the SID cohort (77.3%) than the no-SID cohort (87.2%). Conclusions: Patients with CLL/SLL who subsequently developed SID had a greater burden of infection than patients who did not develop SID. Increasing understanding of this burden of infection may help to improve outcomes in this population Encore Abstract—previously submitted to EHA 2023 The research was funded by: Takeda Development Center Americas, Inc. Writing support was funded by: Takeda Pharmaceuticals International AG. Keywords: cancer health disparities, chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract M. S. Davids Consultant or advisory role AbbVie, Adaptive Biotechnologies, Aptitude Health, BeiGene, Bioascend, Celgene, Curio Science, Eli Lilly, Janssen, Merck, Research to Practice and Takeda Other remuneration: Grant support (paid to his institution): Bristol Myers Squibb, Secura Bio and Surface Oncology; grant support (paid to his institution) and consulting fees: Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, Genentech, MEI Pharma, Pharmacyclics and TG Therapeutics. J. Richter Consultant or advisory role Adaptive Biotechnologies, AstraZeneca, Bristol Myers Squibb, Celgene, Janssen, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda and X4 Pharmaceuticals. Honoraria: Bristol Myers Squibb and Janssen C. Anderson-Smits Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda M. Kamieniak Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda K. Ren Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda D. Shah Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda C. Siffel Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda

Cost-minimization analysis of HYQVIA® in the treatment of primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID) in Italy

Background: Primary (PID) or secondary (SID) immunodeficiencies are diseases caused by quantitative and/or functional alterations of the different mechanisms involved in the innate and adaptive immune response. This economic evaluation was conducted to compare the cost of treatment of HYQVIA® (hyaluronidase-facilitated subcutaneous infusion of immunoglobulin, fSCIG) compared to intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), currently reimbursed in Italy, in the treatment of PIDs or SIDs. Methods: A cost-minimisation analysis was carried out, considering the hospital’s perspective. The direct medical costs (cost of immunoglobulins and cost of administration) were assessed. The analysis was conducted considering one year (52 weeks) time horizon. The reference population included adult patients with PID with impaired antibody production or adult patients with SID with severe or recurrent infections, ineffective antimicrobial treatment and documented specific antibody defect (PSAF) or serum IgG level &lt; 4 g/L. Results: In the maintenance treatment of PID, HYQVIA® (€ 20,020.00) was the therapeutic alternative with the lowest mean annual cost compared to HIZENTRA® (€ 22,165.19) and VENITAL® (€ 24,967.68). Moreover, in the maintenance treatment of SIDs, HYQVIA® (€ 17,160.00) was the cost-saving therapeutic alternative compared to VENITAL® (€ 22,107.68). A sensitivity analysis confirmed the base case results. Conclusion: Due to lower costs of administration and different scheme of administration, HYQVIA® was a cost-saving alternative to SCIG e IVIG in the treatment of PID and to IVIG in the treatment of SID

Facilitated Subcutaneous Immunoglobulin Treatment in Patients with Immunodeficiencies: the FIGARO Study

PurposeThe FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID).MethodsThis prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [< 18 years], adult [18–64 years], older adult [≥ 65 years]). Patients were followed up to 36 months.ResultsThe study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged < 65 years and for SID among older adults. At inclusion, 75.6% received their fSCIG infusion at home, and 78.7% self-administered. Adults were more likely to receive their initial infusion at home and self-administer (81.7% and 86.6%, respectively) than pediatric patients (53.3% each) and older adults (57.1% and 52.4%, respectively). At 12 months, the proportion of patients infusing at home and self-administering increased to 85.8% and 88.2%. Regardless of age, most patients self-administered the full fSCIG dose at home every 3–4 weeks and required a single infusion site. The tolerability profile was consistent with previous pivotal trials. Acute severe bacterial infections occurred in 0%–9.1% of patients during follow-up visits (full cohort).ConclusionsFIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility.Trial registration numberClinicalTrials.gov NCT03054181

Celebrating the 15th Anniversary ofImmunotherapy: A Reflection on 2022

Celebrating the 15th Anniversary of<i>Immunotherapy</i>: A Reflection on 2022

Immunoglobulin replacement therapy in patients with immunodeficiencies: impact of infusion method on patient-reported outcomes

BackgroundUnderstanding the impact of different immunoglobulin (Ig) infusion methods (intravenous [IVIg] and subcutaneous [SCIg]) upon treatment experience can potentially facilitate optimization of patient outcomes. Here, the perspective of patients with primary and secondary immunodeficiency diseases (PID and SID, respectively) receiving IVIg and SCIg was evaluated, in terms of treatment satisfaction, accounting for treatment history, using Association des Patients Immunodéficients du Québec (APIQ) survey data.MethodsThe online APIQ survey (shared October 2020–March 2021) of patients with immunodeficiencies in Canada contained 101 questions on: Ig use, history, and detailed infusion characteristics; as well as structured patient-reported outcomes such as treatment satisfaction (via TSQM-9), symptom state (via PASS), general health perception (via GHP), and physical and mental function (via PROMIS). Adult respondents (≥ 18 years old) currently using Ig were compared by their current Ig infusion method (IVIg or SCIg cohort) overall, and in a sub-analysis, the IVIg cohort was compared with the SCIg cohort after stratification by respondents who started SCIg when naïve to Ig (‘SCIg naïve’) or with previous IVIg experience (‘SCIg switch’).ResultsIn total, 54 respondents currently used IVIg and 242 used SCIg. The average duration per infusion of a weekly SCIg infusion was significantly shorter compared with the average duration of a 3–4 weekly IVIg infusion (p < 0.001). The SCIg cohort was associated with significantly higher scores for the TSQM-9 effectiveness domain compared with the IVIg cohort. The scores for TSQM-9 convenience and global satisfaction domains were similar in the two cohorts. The SCIg cohort was also associated with a significantly higher proportion of respondents who were in an acceptable symptom state and a lower proportion who reported very poor or poor perception of health compared with the IVIg cohort. Further, the SCIg naïve subgroup was associated with significantly higher TSQM-9 effectiveness and convenience domain scores compared with the IVIg cohort, while there was no significant difference between the SCIg switch subgroup and the IVIg cohort in terms of convenience.ConclusionsA better understanding of how different IgRT administration methods impact treatment experience and satisfaction may assist with informed treatment decision making and ultimately further improvements in patient outcomes.

P1611: INSIGHTS INTO FACILITATED IMMUNOGLOBULIN (FSCIG) USE IN PATIENTS WITH SECONDARY IMMUNODEFICIENCY DISEASES: FINAL RESULTS FROM THE FIGARO STUDY

Background: Secondary immunodeficiency diseases (SID) are common among patients with hematological malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma, putting patients at increased risk of severe, recurrent/persistent infections and contributing to morbidity and mortality. Pharmacotherapeutic options available to patients with SID include antimicrobial treatment and immunoglobulin replacement therapy (IGRT). Facilitated subcutaneous immunoglobulin (fSCIG) is a dual-vial unit of immunoglobulin G 10% and recombinant human hyaluronidase (rHuPH20) approved in the European Union for patients with SID. rHuPH20 depolymerizes hyaluronan in the extracellular matrix to transiently increase local subcutaneous tissue permeability, allowing for fSCIG infusion at rates, volumes, and frequencies comparable to intravenous immunoglobulin with better systemic tolerability. Aims: To provide insights on the real-world utilization and tolerability of fSCIG for up to 3 years in a broad population of patients with SID and assess any impact of older age on use. Methods: FIGARO (NCT03054181) was a European prospective, observational study in 14 sites. Patients (n=156) who received ≥1 fSCIG infusion for primary immunodeficiency diseases or SID and provided informed consent were included and followed for up to 3 years. Study initiation was December 2016; database closure was May 2021. Here we report final data for the overall cohort of patients with SID, together with further subgroup analysis for patients aged 18–64 years [adult] and ≥65 years [older adult]. Results: The SID cohort included 31 patients; 1 pediatric (not reported as age subgroup), 15 adult, and 15 older adult patients. At study close, 1-, 2-, and 3-year follow-up data were available for 25, 13, and 11 patients, respectively. The most common indications for IGRT were CLL (n=20) and non-Hodgkin lymphoma (n=6); the most common supportive therapies included Pneumocystis jirovecii pneumonia prophylaxis, virostatics, and antibiotics. In the year prior to inclusion, 10 (32%) patients had experienced ≥1 acute severe bacterial infection. At the inclusion visit, fSCIG was most recently infused at home (61%) or a medical facility (39%) by the patient (58%) or a nurse (42%), with a tendency of adult patients to more self-application than older adults. Most patients received fSCIG every 4 weeks (71%), infused into a single site (most commonly upper abdomen in adults, and lower abdomen in older adults). Over the 3-year observation period, the median monthly dose of fSCIG, and median monthly infusion volume per patient remained consistent at 30 g and 300 mL, respectively, in both the adult and older adult groups. All patients received the full dose as planned, except for 1 patient at the 36-month follow-up visit who experienced infusion/technical problems. Two patients (in the adult group) each reported 1 adverse drug reaction (ADR; infusion site inflammation and headache) at the inclusion visit, with no ADRs reported at any of the follow-up visits. No acute severe bacterial infections were reported during the study. Summary/Conclusion: These data provide insights into the long-term feasibility and tolerability of fSCIG administration at home or in a medical facility in patients with SID primarily due to hematologic malignancies, including in older patients aged ≥65 years.

Long-term monitoring of antibody titers against microorganisms in human intravenous immunoglobulin lots derived from healthy donors in Japan manufactured during 1998-2018.

Studies evaluating long-term trends of intravenous immunoglobulin (IVIG) titers against microorganisms such as bacteria and fungi have not been conducted. We herein evaluated long-term trends of titers of IVIG lots manufactured from 1998 to 2018, derived from donors in Japan, against microorganisms affecting patients with primary or secondary immunodeficiency diseases. Titers against four strains of Pseudomonas aeruginosa, three strains of Staphylococcus aureus, four strains of Haemophilus influenzae, two strains of Klebsiella pneumoniae, one strain of Streptococcus pneumoniae, Enterococcus faecium, Bordetella pertussis, Serratia marcescens, and Candida albicans, were tested immediately after lot release in a commercial clinical testing facility in 1998. The long-term (whole period) and short-term (first and second half of the period) trends of titers were evaluated using regression analysis. The IVIG lots indicated meaningful titers against all microorganisms that were stable in the short term. The long-term trends could be categorized into stable, slightly decreasing, or decreasing trends, except for the metallo-β-lactamase-producing K. pneumoniae, which indicated a slight increase. Notably, three strains of P. aeruginosa showed remarkable decreasing long-term trends in the titer. Some titers indicate decreasing trends against microorganisms over the long-term, however, is not clear whether the phenomenon diminishes the performance of IVIG. The titers of the IVIG lots could provide helpful information to optimize replacement therapy, such as considering trough values based on the titers in the patient plasma. Therefore, continuous monitoring of IVIG titers against microorganisms is important to understand titer fluctuation and epidemiological background.

A phase I trial of T-cell receptor gene therapy targeting KK-LC-1 for gastric, breast, cervical, lung and other KK-LC-1 positive epithelial cancers.

TPS2678 Background: T cell receptor (TCR)-T cell therapy is an emerging cancer treatment strategy. Thus far, demonstration of clinical activity has been limited to a subset of solid tumors including melanoma, synovial cell sarcoma and HPV-associated cancer. It is estimated that metastatic epithelial cancers are responsible for approximately 90% of cancer deaths in the United States. The estimated 600,000 cancer deaths each year is driven largely by lung adeno- and squamous cell carcinoma and invasive breast cancer, which account for approximately 30% of all cancer-related deaths. Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1) is a cancer germline antigen with expression restricted to germ cells in adults and certain epithelial cancers including lung, breast, gastric and cervical. We identified a KK-LC-1 TCR from the tumor-infiltrating lymphocytes (TIL) of a patient with cervical cancer who had a complete tumor response to TIL therapy. The KK-LC-1 TCR was the most dominate clonotype in the infused TIL product and persisted in the peripheral blood following infusion, suggesting that it may have contributed to cancer regression in this patient. Methods: We are conducting a phase I cell dose escalation trial to test the safety and efficacy of KK-LC-1 TCR-T cell therapy in patients with metastatic KK-LC-1 positive epithelial cancer. Patients receive a lymphocyte depleting conditioning regimen followed by a one-time infusion of genetically engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-T cells) and high-dose systemic aldesleukin. KK-LC-1 positivity is determined by RNAscope assay measuring the percentage of cancer cells expressing CT83 (gene encoding KK-LC-1) with a percentage of 25 or greater considered positive. Main inclusion criteria include HLA-A*01:01 allele, prior first-line therapy, ECOG of 0 or 1 and adequate organ and hematologic function. Main exclusion criteria include active major medical illness of the cardiovascular, respiratory or immune system, primary or secondary immunodeficiency and autoimmune disease. Participants will be entered in sequential dose levels and receive escalating doses of cells beginning at 1x108 and ending with 6x1010. Dose-limiting toxicities will be assessed during the first 30 days of cell infusion. The primary objective is to determine the maximally tolerated dose of KK-LC-1 TCR-T cells. Exploratory objectives include assessing the safety and efficacy of KK-LC-1 TCR-T cells and to conduct immunologic studies to understand and improve the administered treatment. Clinical trial information: NCT05035407.

Overview of subcutaneous immunoglobulin 16.5% in primary and secondary immunodeficiency diseases.

Most primary immunodeficiency diseases, and select secondary immunodeficiency diseases, are treated with immunoglobulin (IG) therapy, administered intravenously or subcutaneously (SCIG). The first instance of IG replacement for primary immunodeficiency disease was a 16.5% formulation administered subcutaneously in 1952. While most SCIG products are now a 10or 20% concentration, this review will focus on SCIG 16.5% products with a historical overview of development, including the early pioneers who initiated and refined IG replacement therapy, as well as key characteristics, manufacturing and clinical studies. In determining an appropriate IG regimen, one must consider specific patient needs, characteristics and preferences. There are advantages to SCIG, such as stable serum immunoglobulin G levels, high tolerability and the flexibility of self-administered home treatment.

Facilitated subcutaneous immunoglobulin use in pediatric patients with primary or secondary immunodeficiency diseases.

Aim: While facilitated subcutaneous immunoglobulin (fSCIG) has been evaluated in pediatric patients with primary immunodeficiency diseases in clinical trials, real-world data are lacking. Materials & methods: This multicenter, retrospective, chart review study assessed fSCIG utilization in 30 patients less than 18years old, with primary or secondary immunodeficiency diseases. Medical records were reviewed at fSCIG initiation and at6months. Results: Most (90%) patients received their first fSCIG infusion at a medical facility; by 6months, all fSCIG infusions were administered at home by the patient/caregiver, the majority infusing every 3-4weeks into a single site. No serious adverse drug reactions occurred. Conclusion: This study supports the feasibility and tolerability of administering fSCIG at home to pediatric patients with immunodeficiencies. Clinical Trial Registration: DRKS00015436 (German Clinical Trials Register).

Variable clinical characteristics and laboratory results in five patients with Chinese Good's syndrome (thymoma and hypogammaglobulinemia): an 8-year retrospective analysis in a university hospital in China

BackgroundGood's syndrome (GS) is a rare secondary immunodeficiency disease presenting as thymoma and hypogammaglobulinemia. Due to its rarity, the diagnosis of GS is often missed.MethodsWe used the hospital information system to retrospectively screen thymoma and hypogammaglobulinemia patients at the First Affiliated Hospital of Wenzhou Medical University from Apr 2012 to Apr 2020. The clinical, laboratory, treatment, and outcome data for these patients were collected and analyzed.ResultsAmong the 181 screened thymoma patients, 5 thymoma patients with hypogammaglobulinemia were identified; 3 patients had confirmed diagnoses of GS, and the other 2 did not have a diagnosis of GS recorded in the hospital information system. A retrospective review of the clinical characteristics, laboratory results, and follow-up data for these 2 undiagnosed patients confirmed the diagnosis of GS. All 5 GS patients presented with pneumonia, 2 patients presented with recurrent skin abscesses, 2 patients presented with recurrent cough and expectoration, 1 patient presented with recurrent oral lichen planus and diarrhea, and 1 patient presented with tuberculosis and granulomatous epididymitis. In the years after the diagnosis of hypogammaglobulinemia with mild symptoms, all 5 patients had received irregular intravenous immunoglobulin (IVIG) treatment. As the course of the disease progressed, the clinical symptoms of all patients worsened, but the symptoms were partly resolved with IVIG in these patients. However, 4 patients died due to comorbidities.ConclusionGS should be investigated as a possible diagnosis in thymoma patients who present with hypogammaglobulinemia, especially those with recurrent opportunistic infections, recurrent skin abscesses, chronic diarrhea, or recurrent lichen planus.

Clinical features of children with immunodeficiency and Mycobacterium tuberculosis infection

OBJECTIVE To study the clinical features of Mycobacterium tuberculosis infection in children with secondary immunodeficiency disease (SID) versus primary immunodeficiency disease (PID). METHODS A retrospective analysis was performed on the medical data of children with immunodeficiency and Mycobacterium tuberculosis infection (36 children with SID and 52 with PID) and 108 children with Mycobacterium tuberculosis infection but without immunodeficiency (control group). RESULTS The onset age in the PID group was significantly lower than those in the control and SID groups (P < 0.05), and the proportation of males in the PID group was significantly higher than those in the control and SID groups (P < 0.05). Compared with the control group, the SID and PID groups had significantly lower incidence rates of tuberculosis poisoning symptoms (night sweeting, weight loss, fatigue and loss of appetite) and positive rate of PPD test (P < 0.05), as well as a significantly higher incidence rate of the involvement of ≥ 3 pulmonary lobes (P < 0.05). The children with PID tended to have the involvement of multiple organs (P < 0.05). The SID group had a significantly higher incidence rate of miliary shadow on chest CT than the control and PID groups (P < 0.05). The PID group had a significantly lower positive rate of IFN-gamma release assay (IGRA) than the control and SID groups (P < 0.05). Mycobacterium tuberculosis infection manifested as latent tuberculosis infection (36.1%) and active tuberculosis (63.9%) in the SID group. The infection mainly manifested as bacille Calmette-Guerin disease in the PID group (90.4%), among whom 2 children (3.8%) also had tuberculosis. CONCLUSIONS Children with immunodeficiency and Mycobacterium tuberculosis infection have atypical clinical symptoms, with a high incidence rate of disseminated infection and low positive rates of PPD and IGRA tests, which may lead to misdiagnosis and missed diagnosis. Children with immunodeficiency should undergo regular tuberculosis screening for early identification and intervention.

Monoclonal Gammopathy of Undetermined Significance (MGUS)-Not So Asymptomatic after All.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.

Long-term efficacy, safety, and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HyQvia(®)) in immunodeficiency diseases: real-life data from a monocentric experience.

Humoral immunodeficiency diseases represent a heterogeneous group of disorders that require long-term therapies. Thus, the treatment provided must not only be effective but also safe and well tolerated. In this paper, we report our data on the efficacy, safety, and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HyQvia(®)) in immunodeficiency patients. We collected retrospective data from 30 patients with primary and secondary immunodeficiency diseases in therapy with fSCIG from September 2014 to December 2019. We evaluated the efficacy of the therapy, taking into account serum IgG values during follow-up and the number of annual infectious events and serious bacterial infections reported by patients. Safety was assessed on the basis of the number and intensity of adverse events (AEs) and local reactions reported. Our real-life data suggest that long-term repeated self-administration of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulins results in a reduced rate of infectious events if compared to the pre-treatment rate. Both AEs and local reactions are mild to moderate and were never reasons for treatment discontinuation. Therapy with HyQvia shows prolonged efficacy and good tolerability; these aspects, together with the possibility of self-administration at home, minimize the impact the illness has on patients.

Bioengineered Immunotherapy Techniques for the Treatment of Select Secondary Immunodeficiency Disorders

The inner workings of the immune system are quite complex. Each component works diligently in order to protect us from invaders such as pathogens: viruses, microbes, and fungi. Unfortunately, the immune system may become dysfunctional, which can result in secondary immunodeficiency diseases. The treatments available for these disorders and diseases of the immune system do not typically serve to cure, and much too often the side effects associated can exacerbate the conditions. As an alternative, the area of immunotherapy seeks to remedy the limitations of today’s medicine. Through this review, insight into the current conventional treatments available for select secondary immunodeficiency diseases will be provided, particularly in Human Immunodeficiency Virus disease and Systemic Lupus Erythematosus. The modern immunotherapy approaches that are underway will then be analyzed in their capacity and potential to treat these defects of the immune system.