IL-2 + Abatacept for Frontotemporal Dementia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: The Methodist Hospital Research Institute
Disqualifiers: Infections, Cardiac dysfunction, Cancer, others
No Placebo Group
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Neuroinflammation is a significant component of Frontotemporal Disorder (FTD). Our preliminary unpublished data demonstrated that regulatory T cells (Tregs) have a compromised phenotype and reduced suppressive function in FTD patients, skewing the immune system toward a proinflammatory status and potentially contributing to disease progression. Low dose interleukin-2 (IL-2) is now viewed as a very promising immunoregulatory drug with the capacity to selectively expand and restore functional Tregs. Our preclinical data also demonstrated synergistic effect of interleukin-2 and abatacept (CTLA4-IgG) in remodeling immunologic pathways. Abatacept is an FDA approved medication that has been indicated as a monotherapy or concomitantly with other anti-inflammatory drugs to modulate inflammation in autoimmune disorders. This study is a phase I, open-label study to assess safety and tolerability of low dose IL-2 plus abatacept immunotherapy in FTD individuals. In the first part of this study, 5 FTD patients will be recruited. These five individuals will receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks for a total of 21 weeks (part-1 of the study). If the treatment strategy is safe and well-tolerated, up to 5 additional FTD subjects will be recruited to receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks for a total of 21 weeks (part 2 of the study).
Will I have to stop taking my current medications?
The trial does not require you to stop taking your current medications, but you must be on a stable dosage for at least 4 weeks before starting the study and remain on a stable dosage during the study.
What data supports the effectiveness of the drug IL-2 Plus Abatacept for Frontotemporal Dementia?
Abatacept has been shown to be effective in treating rheumatoid arthritis by improving disease activity and quality of life, and it has also helped in cases of immune system disorders like CTLA4-haploinsufficiency. This suggests that abatacept can modulate immune responses, which might be beneficial in treating conditions like Frontotemporal Dementia that involve immune system components.
12345Is the combination of IL-2 and Abatacept safe for humans?
Abatacept, also known as Orencia or CTLA4-Ig, has been used safely in humans for conditions like rheumatoid arthritis and immune-related disorders, with a safety profile comparable to other similar treatments. While severe infections are more common than with placebo, opportunistic infections and malignancies are not increased. In pediatric cases of immune disorders, abatacept showed no side effects over 7-15 months of use.
16789How is the drug IL-2 Plus Abatacept different from other treatments for frontotemporal dementia?
IL-2 Plus Abatacept is unique because it combines IL-2, which can help regulate immune responses, with Abatacept, a drug that blocks specific signals needed for T-cell activation, potentially reducing inflammation. This combination targets immune pathways differently than other treatments, which may not focus on immune modulation for frontotemporal dementia.
14101112Eligibility Criteria
This trial is for individuals with Frontotemporal Dementia (FTD). Participants should have a compromised immune system, specifically with regulatory T cells that are not functioning properly. The study aims to recruit FTD patients who can undergo treatment with immunotherapy drugs.Inclusion Criteria
English language speaking
I have been diagnosed with frontotemporal dementia.
Formal education of eight or more years
+5 more
Exclusion Criteria
I have had issues with my bowels like blockages, tears, or serious bleeding needing surgery.
I have been diagnosed with a form of dementia such as Alzheimer's or Parkinson's.
I have a seizure disorder.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment Part 1
5 FTD patients receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks for a total of 21 weeks
21 weeks
Treatment Part 2
Up to 5 additional FTD subjects receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks for a total of 21 weeks
21 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4-8 weeks
Participant Groups
The trial is testing the combination of two drugs: Abatacept and Aldesleukin (IL-2), which may help regulate the immune system in FTD. It's an open-label phase I study, starting with five patients receiving these drugs over 21 weeks to check safety and tolerability before possibly expanding to more participants.
2Treatment groups
Active Control
Group I: Abatacept plus Aldesleukin every 4 weeksActive Control1 Intervention
Subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks will be administered for a total of 21 weeks
Group II: Abatacept plus Aldesleukin every 2 weeksActive Control1 Intervention
Subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks will be administered for a total of 21 weeks
IL-2 Plus Abatacept is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Orencia for:
- Moderate to severe adult rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Active psoriatic arthritis
🇪🇺 Approved in European Union as Orencia for:
- Moderate to severe adult rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Active psoriatic arthritis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Houston Methodist Research InstituteHouston, TX
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Who Is Running the Clinical Trial?
The Methodist Hospital Research InstituteLead Sponsor
References
Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency. [2021]CTLA4-haploinsufficiency is a complex disease of immune dysregulation presenting with a broad spectrum of clinical manifestations. CTLA4-Fc fusion proteins such as abatacept have been described to alleviate immune dysregulation in several adult cases of CTLA4-haploinsufficiency. However, until now only few cases of pediatric CTLA4-haploinsufficiency treated with abatacept have been described. Here we present two pediatric cases of severe CTLA4-haploinsufficiency refractory to conventional immunosuppressive therapies that responded rapidly to treatment with abatacept. No side effects were observed during a follow-up period of 7-15 months. While one patient has successfully undergone HSCT the second patient continues to receive abatacept. Our cases demonstrate safe medium-term use of abatacept in the pediatric population.
Abatacept in the treatment of rheumatoid arthritis. [2015]Over the past decade, biological immunotherapy has revolutionised the treatment of rheumatoid arthritis (RA). The most widely used of these therapies targets tumour necrosis factor-alpha (TNF-alpha). Approximately 20% of patients fail to respond to TNF-alpha antagonism, however, and a significant number of additional patients become refractory to anti-TNF-alpha therapy over time. Thus investigators have sought to target other pathogenic elements of RA using novel biological therapies. Abatacept is the first immunotherapy directed against the process of T-cell costimulation. Abatacept has shown clinical effectiveness in RA by improving disease activity, quality of life measures and radiographic progression of disease. In this article, we review the immunology of T-cell activation and costimulation, define the role of abatacept in this process, and discuss the clinical trials that led to the approval of abatacept as the latest biological therapy in RA in the USA and Canada. We also address the role of abatacept in the greater context of biological therapy for RA.
Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry. [2018]We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients.
[Abatacept in the treatment of active rheumatoid arthritis]. [2015]Abatacept (CTLA4Ig) is a human fusion protein which consists of a cytotoxic lymphocytic-associated type 4 antigen which is bound to the Fc part of the IgG1. Abatacept binds to CD80/CD86 on antigen-presenting cells thus blocking the co-stimulatory signal to the naïve T cells and interfering with a central inflammatory rheumatoid arthritis signal pathway.
Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. [2022]To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy.
Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4- and PD-1-targeted immunotherapy. [2023]Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.
[Selective co-stimulation blockade. CTLA4-Ig (Abatacept)]. [2021]Abatacept is a soluble fusion protein comprising the extracellular domain of human CTLA4 linked to the modified Fc portion of human IgG(1). It is approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate and juvenile chronic arthritis by blocking the co-stimulatory signal required for full T-cell activation. Abatacept has added to the growing armamentarium of targeted therapies for RA, including the challenging group of RA patients who are refractory to TNF-alpha blockade. To date, abatacept has its main application in cases failing to respond to TNF-alpha blockade. In several studies, the efficacy and safety of abatacept was not only shown for TNF-IR patients, but also for DMARD-IR patients. Recently, the EU has approved abatacept in combination with methotrexate in DMARD-IR patients. The significant and similar response rates in TNF-alpha blockade failure to those observed in only DMARD failure implies that the pathways targeted with the two treatments remain distinct. In terms of safety profile, incidence rates of malignancy in the abatacept trials were consistent with those in a comparable RA population. The rate of opportunistic infections does not seem to be increased in patients treated with abatacept.
[A novel treatment option in rheumatoid arthritis: abatacept, a selective modulator of T-cell co-stimulation]. [2021]Abatacept is the first drug in a new class of disease-modifying anti-rheumatic drugs known as selective modulators of T-cell costimulation. The efficacy of abatacept in the treatment of rheumatoid arthritis (RA) has been shown in several clinical phase II and phase III trials, wherein abatacept was used in monotherapy, either in combination with methotrexate (MTX) after MTX-failure, in combination with MTX after failure of anti-TNF-alpha therapy or in combination with TNF-alpha blockers. In addition, the combination of abatacept/MTX was directly compared with infliximab/MTX. Current data on abatacept demonstrate an encouraging safety profile of this drug. The number of adverse events in patients on abatacept is comparable to that in patients treated with other biologics. Severe infections, however, are more common in abatacept-treated patients than in placebo-treated patients. Opportunistic infections are rare in patients with abatacept and the frequency of malignancies is not higher than expected in RA-patients. Additional studies are now warranted to get more information on rare adverse events and long-term unwanted effects.
Abatacept in the treatment of rheumatoid arthritis. [2021]Abatacept (CTLA4-Ig) is a new agent which targets T-cell activation, an event which is thought to be critical to the onset and maintenance of rheumatoid arthritis (RA). Abatacept now has substantial evidence from phase III trials for efficacy in patients with RA who have failed to respond to disease-modifying antirheumatic drugs (DMARDs) and antitumor necrosis factor-alpha (TNF-alpha) biologic agents. Safety profile is favorable in combination with DMARDs. The mechanism of action and available evidence of its efficacy and safety are reviewed in this article.
[Effect of CTLA4-Ig on radiographic outcome of patients with rheumatoid arthritis]. [2016]CTLA4-Ig (abatacept) is a recombinant fusion protein containing components of immunoglobulin G (IgG) and cytotoxic T-lymphocyte-associated protein-4 that inhibit costimulatory signal from antigen presenting cells and prevent activation of T cells. Abatacept significantly ameliorated signs and symptoms and improved physical function of patients with rheumatoid arthritis (RA) who had shown inadequate response to methotrexate (MTX) or TNF antagonists. Abatacept also retarded the radiological progression of structural damage of affected joints in MTX-resistant patients. This article briefly discussed the mechanism of action and the results of clinical trials of abatacept.
The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. [2018]Abatacept (CTLA4-Ig) is a novel fusion protein designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. Clinical trials have provided preliminary evidence of the efficacy of this compound in the treatment of rheumatoid arthritis. This review describes the molecular and biologic bases for the use of abatacept in rheumatoid arthritis and summarizes the current clinical data on its safety and effectiveness in this disease.
Abatacept (Cytotoxic T Lymphocyte Antigen 4-Fragment Crystallizable) Reduces Allergic Inflammation of Ovalbumin-Sensitized Mice. [2023]Label="BACKGROUND" NlmCategory="BACKGROUND">Abatacept (Aba) is a cytotoxic T-lymphocyte antigen-4 and fragment crystallizable fusion protein. Aba blocks B7/Cluster of differentiation 28 - cytotoxic T-lymphocyte antigen-4 costimulatory pathway, inhibits cluster of differentiation 4+ T-cell activation, and is used as an anti-inflammatory drug.