Engineered FVIII-expressing cytotoxic T cells target and kill FVIII-specific B cells in vitro and in vivo

Parvathaneni, Kalpana; Scott, David W.

doi:10.1182/bloodadvances.2018018556

Cited by 47 publications

(38 citation statements)

References 25 publications

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“…In vivo administration of A2/C2 BAR T cells in HA mice followed by immunization with FVIII resulted in prevention of anti-FVIII antibody formation even after a rechallenge with FVIII 10 weeks later. Moreover, analysis of splenocytes from mice 12 weeks after injection of A2/C2 BAR T cells showed the absence of FVIII-specific memory B cells, confirming that A2/C2 BAR T cells were able to prevent anti-FVIII antibody formation probably by eliminating FVIII-specific memory B cell precursors (53).…”

Section: T Cell Therapymentioning

confidence: 74%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

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Section: T Cell Therapymentioning

confidence: 74%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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“…These engineered cells are referred to as B-cell Antigen Receptor, or "BAR" T cells, since the expressed domains would be recognized by FVIIIspecific B-cell receptors (BCR). The Treg and CD8 + BARs suppressed and killed, respectively, FVIII-specific B cells, thereby blocking anti-FVIII antibody production (172,173). Thus, these various engineered FVIII-specific Tregs (Figure 5) are demonstrably functional, with different targets and advantages.…”

Section: T-cell Engineering For Tolerancementioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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“…Our labs have approached this issue by expressing specific receptors (or antigen) in expanded polyclonal Tregs or CD8 T cells, based on the seminal work by Eshhar (76,77) and on clinical success of chimeric antigen receptor (CAR) T cells as reported by June and colleagues (78,79). Since these studies have recently been published (80)(81)(82)(83) and reviewed (52, 84), we will provide only a brief outline of these approaches to induce immune tolerance.…”

Section: Modulation Of Fviii Immunogenicitymentioning

confidence: 99%