# Applying precision MEdicine to optimize desensitization with noveL bIOlogics or cellular theRApies in highly sensiTized kidney transplant patiEnts (AMELIORATE)

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $819,899

## Abstract

PROJECT ABSTRACT
HLA sensitization is a significant barrier in organ transplantation. Kidney transplant candidates
who are very highly sensitized (cPRA ≥99.9%) continue to have very poor access to a compatible
donor and are more likely to be removed from the list or die than undergo transplantation.
Desensitization has a clear survival benefit; however previous approaches have met with limited
success especially in patients with the highest levels of HLA antibodies, and are hamstrung by
the problem of antibody rebound. We hypothesize that durable reduction in HLA antibodies can
be achieved by a two pronged approach: elimination of plasma cells plus prevention of the
compensatory expansion of the germinal center. Both anti-CD38 antibodies and chimeric antigen
receptor (CAR) T cells directed against plasma cells have emerged as novel therapeutic options
in multiple myeloma. Germinal center activation can be inhibited by blockade of the IL-6 or
CD40/CD40L pathway. Furthermore, we have identified a novel biomarker (specific HLA/KIR
genotype combinations) which predicts poor plasma cell killing by NK cells in response to anti-
CD38 antibodies. We propose to conduct a multicenter, prospective, open-label, interventional
study in 68 patients with cPRA ≥99.9% who will be assigned to receive dual biologic therapy
(n=60) or cellular therapy (n=8) for desensitization. Allocation into the dual biologic therapy or
cellular therapy will be based on our novel biomarker using a precision medicine approach. Those
assigned to dual biologic therapy will be further randomized to receive the anti-CD38 antibody,
isatuximab, in combination with either VIB4920, a CD40L antagonist (n=30) or sarilumab, an IL-
6R antagonist (n=30). Those assigned to the cell therapy arm will receive a single infusion of ide-
cel, a CAR T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the
surface of plasma cells. The primary efficacy endpoint is a ≥0.4% reduction in cPRA or receipt of
transplant from a previously incompatible donor and is assessed at 16 weeks after completion of
therapy. The primary safety endpoint is freedom from ≥grade 3 infusion reactions, ≥grade 3 or
higher infections, and malignancy assessed at 16 weeks after completion of therapy or until
receiving a transplant, whichever occurs earlier. Mechanistic analyses will focus on changes in
the bone marrow and circulating T and B cell compartments after treatment, as well as in the
lymph nodes of those who receive a transplant during the study. Transplanted subjects will
receive additional study-directed therapy after transplant and be evaluated for post-transplant
outcomes including freedom from rejection, graft loss and death.

## Key facts

- **NIH application ID:** 10461851
- **Project number:** 5U01AI113362-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Flavio Vincenti
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $819,899
- **Award type:** 5
- **Project period:** 2014-08-05 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461851

## Citation

> US National Institutes of Health, RePORTER application 10461851, Applying precision MEdicine to optimize desensitization with noveL bIOlogics or cellular theRApies in highly sensiTized kidney transplant patiEnts (AMELIORATE) (5U01AI113362-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461851. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*