# Engineering cellular immunotherapy to modulate immune responses in hemophilia

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $416,250

## Abstract

Abstract
Inhibitors, alloantibodies against factor VIII, are the most significant complication of factor VIII replacement
therapy for hemophilia A. The development of inhibitors substantially increases the mortality and morbidity of
the disease. Unfortunately, current therapeutic options are limited. New therapies are urgently needed to
address these unmet clinical needs of hemophilia A patients with inhibitors. To this end, we propose to several
new strategies with translational potential to address this clinical problem, but will also delineate the
pathological immune response responsible for inhibitor development and persistence. Together, our
laboratories have extensive expertise in hemophilia and cellular therapy. Using hemophilia models, we seek to
develop novel therapeutic approaches based on recent success of chimeric antigen receptor (CAR) technology
for B cell neoplasia. We are harnessing the effect of CAR T cell on B cells to specifically eliminate those
involved in generation of immune response to FVIII protein. In aim 1, our goal is to eradicate inhibitors in
murine models by leveraging the proven the ability of CAR T-cells to eliminate specific compartments in the B-
cell lineage. Specifically, we will target memory B-cells and plasma cells through their CD19 and B-cell
maturation antigen (BCMA) respectively. This strategy will provide an ideal experimental system to define the
contribution of specific populations of B-cells or plasma cells responsible for alloantibody production and
persistence. Because inhibitor eradication does not necessarily induce immune tolerance, in aim 2, our goal is
to test the ability of these CAR T-cells to induce immune tolerance. In this aim, we will determine if the
reconstitution immunological environment created after B- or plasma-cell depletion is biased towards inducing
tolerance. We will test this hypothesis in both naïve and inhibitor mice. This study will also clarify the immune
cells responsible for amnestic or new alloantibody responses. Because of the potential safety concern related
to broad B- and plasma-cell deletion leading to immunosuppression, we have also developed technology that
specifically targets anti-FVIII immune cells while sparing non-pathological cells. We have accomplished this by
reversing the traditional CAR design and developing a novel construct, which we have called a chimeric allo-
antigen receptor (or CALLAR), were domains of FVIII are coupled to modified T-cell receptors. In aim 3, we
test the safety, efficacy, and specificity of CALLAR T-cells to eradicate inhibitors in murine models while
avoiding non-pathological cells. Together, we propose a comprehensive plan to characterize and identify B
cells in pathological responses that are highly applicable to other disease treatments which are also
complicated by the formation of antibodies to enzyme replacement therapy. Specifically, the CALLAR strategy
may be applicable for diseases in which specific immune epitopes ar...

## Key facts

- **NIH application ID:** 9966022
- **Project number:** 5R01HL137335-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael C. Milone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,250
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966022

## Citation

> US National Institutes of Health, RePORTER application 9966022, Engineering cellular immunotherapy to modulate immune responses in hemophilia (5R01HL137335-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966022. Licensed CC0.

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