Lung Transplant Plasmapheresis/Belatacept/Carfilzomib for Antibody Mediated Rejection and Desensitization

Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes
after lung transplantation. Additionally, high antibodies detected pre transplant in
candidates limit donor availability for lung transplant. Multimodal therapies with rituximab,
intravenous immunoglobulin, plasmapheresis and proteasome inhibitors have not significantly
altered the antibodies in these patients. Belatacept targets the T and B cell interaction
such that it represents a novel therapeutic strategy. This proposal would include belatacept
in a multi-therapy regimen.

This is an open label study with two patient cohorts for safety and efficacy of belatacept in
a multi-modal protocol. The two patient cohorts are an AMR post-transplant cohort and
pre-transplant desensitization cohort. A total of 10 patients will be enrolled.The primary
objection is drug tolerability and secondary objectives are antibody measurements and
allograft function.

Inclusion Criteria:

Inclusion criteria for the AMR post-transplant cohort

- Positive DSAs and allograft dysfunction defined by changes in pulmonary physiology,
gas exchange, radiological features or deteriorating functional performance that is
highly suspicious for AMR

- Recipient is Epstein-Barr virus positive (EBV+) by serology

- Ability to provide signed and dated IRB approved written consent in accordance with
regulatory and institutional guidelines prior to any protocol-related procedure

Inclusion criteria for the pre-transplant desensitization cohort

- Elevated HLA antibodies (defined as MFI >1000) such that the calculated panel reactive
antibodies are >60%

- At least 2 HLA antibodies with Mean Fluorescent Intensity (MFI) <10,000 and at least 2
HLA antibodies with MFI <5,000 on undiluted serum that do not demonstrate an increase
in MFI with dilution at 1:16 (no evidence of a prozone effect).

- EBV+ by serology

- Clinically stable defined by not on invasive mechanical ventilation, extracorporeal
membrane oxygenation support or other invasive life support requiring ICU level of
care

- Ability to provide signed and dated IRB approved written consent in accordance with
regulatory and institutional guidelines prior to any protocol-related procedure

Exclusion criteria for both AMR post-transplant cohort and pre-transplant cohort

- Active systemic infection

- Allergy to carfilzomib or belatacept

- Known malignancy in the previous 2 years except for non-melanomatous skin cancer

- Pregnancy

- Inability to commit to complete treatment protocol at Duke as all procedures must be
completed at Duke

- Prisoners or those who are compulsory detained