Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Chen HA ，Hsu RH ，Fang CY ，Desai AK ，Lee NC ，Hwu WL ，Tsai FJ ，Kishnani PS ，Chien YH ... -  《Frontiers in Immunology》

Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort.

Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.

Desai AK ，Baloh CH ，Sleasman JW ，Rosenberg AS ，Kishnani PS ... -  《Frontiers in Immunology》

High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient.

Alglucosidase alfa (rhGAA) has altered the course of an otherwise fatal outcome in classic infantile Pompe disease (IPD), which presents with cardiomyopathy and severe musculoskeletal involvement. However, the response to therapy is determined by several factors including the development of high and sustained antibody titers (HSAT) to rhGAA. Cross-reactive immunologic material (CRIM) negative patients are at the highest risk for development of HSAT. Immune tolerance induction (ITI) with methotrexate, rituximab, and intravenous immunoglobulin (IVIG) has been largely successful in preventing the immune response and in achieving tolerance when done in conjunction with enzyme replacement therapy (ERT) initiation. Reducing antibody titers in cases with an entrenched immune response remains a challenge in the field despite the use of multiple immunomodulatory agents. Success has been shown with addition of bortezomib to the ITI regimen, yet the prolonged course and potential risks with the use of such agents' demands caution. We present here a 7-year-old CRIM-negative IPD patient who was not successfully tolerized by an ITI regimen with rituximab, methotrexate, and IVIG due to intolerability to the regimen and recurrent infections. She went on to develop HSAT, with significant clinical decline, loss of all motor abilities, and a fragile medical state, which made it challenging to institute the bortezomib based regimen to reduce HSAT. She had severe developmental delay, respiratory failure with invasive ventilation and tracheostomy, persistent hypotonia, ptosis of eyelids, diffuse severe osteopenia, contractures, and was completely G-tube fed. As a rescue mechanism, we treated her with high dose and high frequency IVIG in an attempt to reduce rhGAA IgG antibody titers (antibody titers; titers). Her titers saw a steady decline on weekly IVIG doses at 1g/kg for 20weeks. Subsequently when the IVIG regimen was altered to 1g/kg every month, rising titers were detected and therefore the regimen was changed to a biweekly regimen. High dose IVIG resulted in an eightfold decrease in antibody titers. Clinically, she showed improvement with partial recovery of previously lost motor abilities, especially hand movements and better head and neck control than before. The regimen was safely tolerated with no hospitalizations. The effectiveness of IVIG as a single agent, in this case with multiple comorbidities and fragile clinical status, was lifesaving and may represent an effective, perhaps lifesaving rescue approach to reduce antibody titers.

Rairikar M ，Kazi ZB ，Desai A ，Walters C ，Rosenberg A ，Kishnani PS ... -  《-》

Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease.

Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals' native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual's native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient's relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.

De Groot AS ，Desai AK ，Lelias S ，Miah SMS ，Terry FE ，Khan S ，Li C ，Yi JS ，Ardito M ，Martin WD ，Kishnani PS ... -  《-》

HLA- and genotype-based risk assessment model to identify infantile onset pompe disease patients at high-risk of developing significant anti-drug antibodies (ADA).

In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measure (iTEM) scoring method predicts patient-specific risk of developing ADA against therapeutic recombinant human GAA (rhGAA) using individualized HLA-binding predictions and GAA genotype. CRIM-negative patients were six times more likely to develop high ADA titers than CRIM-positive patients in this retrospective study, whereas patients with high GAA-iTEM scores were 50 times more likely to develop high ADA titers than patients with low GAA-iTEM scores. This approach identifies high-risk IOPD patients requiring immune tolerance induction therapy to prevent significant ADA response to rhGAA leading to a poor clinical outcome and can assess ADA risk in patients receiving replacement therapy for other enzyme or blood factor deficiency disorders.

De Groot AS ，Kazi ZB ，Martin RF ，Terry FE ，Desai AK ，Martin WD ，Kishnani PS ... -  《-》