Cell therapies for hematological malignancies: don't forget non-gene-modified t cells!

Abstract

Cell therapy currently performs an important role in the treatment of patients with various hematological malignancies. The response to the cell therapy is regulated by multiple factors including the patient's immune system status, genetic profile, stage at diagnosis, age, and underlying disease. Cell therapy that does not require genetic manipulation can be mediated by donor lymphocyte infusion strategies, selective depletion in the post-transplant setting and the ex vivo expansion of antigen-specific T cells. For hematologic malignancies, cell therapy is contributing to enhanced clinical responses and overall survival and the immune response to cell therapy is predictive of response in multiple cancer types. In this review we summarize the available T cell therapeutics that do not rely on gene engineering for the treatment of patients with blood cancers.

Keywords: Adoptive T cell therapy; EBV; Leukemia; Lymphoma; Tumor associated antigens.

Figure 1. Non-gene-modified selective depletion-based T cell immunotherapeutics for hematological malignancies

Donor peripheral blood stem cell (PBSC) populations can be enriched for cell subsets of interest or depleted of undesirable subsets such as regulatory T cells (T_REGs), naïve T cells (T_N) and allo-reactive T cells. A) Monoclonal antibodies (mAB) linked to metal spheres bind to cellular targets and, when passed through a magnetic column, cells attached to the spheres are retained within the column. This positive fraction, or the negative fraction, can be collected for downstream application, such as T_N (CD34-CD3+CD45RO-), T_REG (CD3+CD4+FoxP3+CD25+) or allo-reactive T cell (CD69+) selective depletion. B)The interleukin-2 (IL-2) receptor α chain CD25, a T cell activation marker, can also be targeted by pharmaceutical approaches. CD25 immunotoxin is a murine anti-CD25 mAb linked to deglycosylated ricin α chain. Co-culture of recipient lymphoblastoid cell lines (LCL) with donor peripheral blood mononuclear cells (PBMC) results in allo-reactivity of donor T cells. Allo-reactive cells can be removed by overnight treatment with CD25 immunotoxin, or by 72 hour culture with 2 mmol/L adenosine. Following haploidentical stem cell transplant (HSCT) the allo-depleted donor cells are also transfused. C) Allo-depletion can also be achieved by incubating mixed lymphocyte reactions (MLR) in the presence of the photo sensitizer 4,5-dibromorhodamine 123 (TH9402). Activated cells retain TH9402 and are eliminated upon exposure to visible light. Patients received infusions of autologous photo-depleted (PD) effector T cells along with CD34-selected stem cells from HLA-matched siblings.