Study of Matched Unrelated Donor T Cell Infusion for Hematologic Malignancies After Allo-HSCT

This is a Phase I, multicenter, open-label, non-randomized study of matched unrelated donor BPX-501 T cell infusion in adult subjects with hematological malignancies presenting with recurrent disease minimal residual disease (MRD) post-allogeneic transplant.

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 graft-versus-tumor (GvT) 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 and children 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 Criteria:
Inclusion Criteria:

* Subjects aged ≥ 18 yrs and ≤ 65 yrs;
* Clinical diagnosis of one of the following hematological malignancies:

  * Leukemia
  * Myelodysplastic Syndromes
  * Lymphomas
  * Multiple Myeloma
  * Other high-risk hematological malignancy eligible for stem cell transplantation per institutional standard;
* Recurrent disease that presents ≥100 days after, or minimal residual disease (MRD) that presents ≥ 30 days following a hematopoietic stem cell transplant (HSCT) using a matched unrelated donor located through the National Marrow Donor Program (NMDP);
* Life expectancy \>10 weeks;
* Signed donor and patient/guardian informed consent;
* A 8/8 genotypic identical match as determined by high resolution typing for the following genetic loci: human leukocyte antigen (HLA)-A, HLA-B, HLA-C and HLA-DRB1;
* Performance status: Karnofsky score \> 50%;
* Subjects with adequate organ function as measured by:

  * Bone marrow:

    * \> 25% donor T-cell chimerism post-transplant
    * Absolute neutrophil count (ANC) \>1 x 109/L
  * Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 45%
  * Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC), diffusion capacity of lunch for carbon monoxide (DLCO) ≥ 50% predicted (corrected for hemoglobin)
  * Hepatic: direct bilirubin ≤ 3x upper limit of normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5x ULN
  * Renal: creatinine ≤ 2x of ULN for age.

Exclusion Criteria:

* ≥ Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of screening;
* Active central nervous system (CNS) involvement with malignant cells (≤ 2 months prior to consenting);
* 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;
* Positive HIV serology or viral RNA;
* Pregnancy (positive serum β human chorionic gonadotropin \[HCG\] test) or breast-feeding;
* Fertile men or women unwilling to use effective forms of birth control or abstinence for one year after transplantation;
* Bovine product allergy.