Study of Gene Modified Donor T Cell Infusion in Patients With Recurrent Disease After Allogeneic Transplant

Study ID
STU 072015-091

Study Sites

  • Clements University Hospital

Contact
Courtney Saltarski
214/648-7030
courtney.saltarski@utsouthwestern.edu

Principal Investigator
Madhuri Vusirikala, M.D.

Official Title

A Phase I/II Study of Donor BPX-501 T Cell Infusion for Adults With Recurrent or Minimal Residual Disease Hematologic Malignancies Post-Allogeneic Transplant

Brief Overview

A Phase I study of BPX-501 T cell infusion in adults with recurrent or minimal residual disease (MRD) hematologic malignancies post-allogeneic transplant. The treatment consists of increasing doses of BPX-501 T cell infusions to achieve a clinical response. AP1903 will be investigated for the treatment of aGvHD after BPX-501 T cell infusion to determine a dose that can mitigate GvHD and preserve the graft-versus tumor effect.

Description

Un-manipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. The addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral antigens, as well as against cancer antigens, might provide a clinical benefit. However, an expected side effect of the presence of mature T cells is the potential occurrence of acute graft-versus-host disease (aGvHD). The use of a suicide gene switch which would trigger the initiation of the apoptosis of the alloreactive T cells by the infusion of a drug would represent the potential optimal strategy for restoring early immunity with a built in "safety switch" against GvHD side effects. Evidence has emerged that low-dose DLI followed by dose escalation can achieve higher clinical response rate with lower GvHD occurrence. Optimization of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the consistent ability to separate GvHD from GvT (graft-versus-tumor) activity and improve the safety of DLI treatment. Our strategy is to infuse escalating doses of manipulated T cells (from the same donor who provided the original hematopoietic stem cell graft) in adults with recurrent or minimal residual disease (MRD) hematologic malignancies post-allogeneic transplant to accelerate immune reconstitution thus improving graft versus leukemic effect while reducing the severity of GvHD.

Eligibility

Inclusion Criteria:
1. Clinical diagnosis of one of the following:
1. leukemia
2. myelodysplasia
3. lymphoma
4. multiple myeloma
5. Other high-risk hematologic malignancies eligible for stem cell transplantation per institutional standard
2. Recurrent disease that presents >100 days after, or minimal residual disease (MRD) that presents > 30 days after either:
1. Matched related HSCT
2. Mismatched related HSCT
3. Life expectancy >10 weeks;
4. Signed donor and patient/guardian informed consent;
5. A minimum genotypic identical match of 4/8 is required, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, and HLA- DRB1.
6. Performance status: Karnofsky/Lansky score > 50%.
7. Subjects with adequate organ function as measured by:
1. Bone marrow: > 25% donor T-cell chimerism in peripheral blood, obtained after 3 weeks post-transplant; ANC >1 x 10E9/L
2. Cardiac: left ventricular ejection fraction at rest must be ≥ 45%
3. Pulmonary: FEV 1, FVC, DLCO (diffusion capacity) ≥ 50% predicted (corrected for hemoglobin)
4. Hepatic: direct bilirubin ≤ 3 x upper limit of normal, or AST/ALT ≤ 5 x upper limit of normal
5. Renal: creatinine ≤ 2x of ULN for age
Exclusion Criteria:
1. ≥ Grade II acute GvHD or chronic extensive GvHD due to a previous allograft at the time of screening
2. Active CNS involvement by malignant cells (≤ 2 months from the conditioning)
3. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings); the principal investigator is the final arbiter of this criterion
4. Positive HIV serology or viral RNA
5. Pregnancy (positive serum or urine βHCG test) or breast-feeding
6. Fertile men or women unwilling to use effective forms of birth control or abstinence for one year after transplantation
7. Bovine product allergy