Belatacept Pilot Study in Lung Transplantation Immunosuppression in Lung Transplantation

Lung transplantation is the ultimate treatment for patients with advanced lung disease.
However, long-term outcomes remain disappointing and the median survival after
transplantation is approximately 5.5 years. Beyond the first year after transplantation,
chronic lung allograft dysfunction is the leading cause of death. The exact mechanisms that
lead to chronic lung allograft dysfunction are unclear, but the development of donor-specific
HLA antibodies is an independent risk factor. In fact, studies have consistently identified
the development of donor-specific HLA antibodies as a significant and independent risk factor
for chronic lung allograft dysfunction and mortality after transplantation.

Belatacept is a CTLA4-Ig fusion protein that binds CD80 and CD86 thereby blocking CD28
co-stimulatory signals. Belatacept has been extensively studied in kidney transplantation. In
a long-term study, patients treated with Belatacept had better survival than those treated
with Cyclosporine. Importantly, Belatacept-treated patients were significantly less likely to
develop donor-specific HLA antibodies than Cyclosporine-treated patients. Nonetheless,
Belatacept has not been formally evaluated after lung transplantation. The investigators
hypothesize that Belatacept-based immunosuppression would result in a lower incidence of
donor-specific HLA antibodies and that this would result in better chronic lung allograft
dysfunction-free survival after transplantation. Before conducting a large scale randomized
controlled trial to test this hypothesis, the investigators plan to conduct the current pilot
randomized controlled trial to examine the feasibility of conducting the large scale
randomized controlled trial.

The investigators plan to enroll and randomize 40 lung transplant recipients at 2 sites. All
recipients will be treated with anti-thymocyte globulin for induction immunosuppression.
Those randomized to standard of care immunosuppression will be treated with Tacrolimus,
Mycophenolate mofetil, and prednisone. Those randomized to Belatacept-based immunosuppression
will be treated with Belatacept, Tacrolimus, and prednisone for the first 89 days; on day 90,
Mycophenolate mofetil will be substituted for Tacrolimus and patients will be continued on
Belatacept, Mycophenolate mofetil, and prednisone for the remainder of year 1 after
transplantation.

Patients in both groups will be monitored closely for episodes of acute cellular rejection,
lymphocytic bronchiolitis, and antibody-mediated rejection with surveillance bronchoscopy and
transbronchial lung biopsies on days 28, 84, 112, 168, 252, and 365 (± 7 days) as part of the
sites' routine clinical protocols. In addition, patients will be monitored for the
development of donor-specific HLA antibodies with routine blood tests on on days 10 (± 3
days), 28, 56, 84, 112, 168, 252, and 365 (± 7 days).

The primary endpoint of the study is a composite of the development of donor-specific HLA
antibodies, re-transplantation, and death. Secondary endpoints include acute cellular
rejection, lymphocytic bronchiolitis, antibody-mediated rejection, chronic lung allograft
dysfunction, survival, cytomegalovirus infection, bacterial infection, community-acquired
respiratory viral infection, chronic kidney disease stage 3, malignancy, hypertension,
diabetes, and hypercholesterolemia.

Inclusion Criteria:

- Provided written informed consent for study participation

- Underwent single or bilateral lung transplantation

- Negative urine pregnancy test for women of child bearing potential and willingness to
use highly-effective contraception

Exclusion Criteria:

- Requiring invasive mechanical ventilation immediately before transplantation

- Requiring extracorporeal life support (ECLS) (i.e., ECMO) immediately before
transplantation

- Received treatment to deplete HLA antibodies before transplantation to improve the
possibility of transplantation

- Having DSA immediately before transplantation (i.e., positive virtual crossmatch)

- Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung)

- Pregnant or breast-feeding

- Active infection with Hepatitis B or C virus

- Active infection with human immunodeficiency virus (HIV)

- Chronic infection with Burkholderia cepacia complex before transplantation

- Epstein Barr Virus (EBV) seronegative status

- Participation in another interventional clinical trial

- Allograft dysfunction requiring ECMO support after transplantation

- Delayed chest closure after transplantation

- Severe coagulopathy and significant bleeding in the opinion of the PI

- Any condition that in the opinion of the site PI introduces undue risk by
participating in this study