Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse

Abstract

Leukemia relapse remains the major cause of allogeneic hematopoietic stem cell transplantation (HCT) failure, and the prognosis for patients with post-HCT relapse is poor. There is compelling evidence that potent selective antileukemic effects can be delivered by donor T cells specific for particular minor histocompatibility (H) antigens. Thus, T-cell receptors (TCRs) isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HCT leukemic relapse. Recognizing that several elements may be crucial to the efficacy and safety of engineered T-cell immunotherapy, we developed a therapeutic transgene with 4 components: (1) a TCR specific for the hematopoietic-restricted, leukemia-associated minor H antigen, HA-1; (2) a CD8 coreceptor to promote function of the class I-restricted TCR in CD4 T cells; (3) an inducible caspase 9 safety switch to enable elimination of the HA-1 TCR T cells in case of toxicity; and (4) a CD34-CD20 epitope to facilitate selection of the engineered cell product and tracking of transferred HA-1 TCR T cells. The T-cell product includes HA-1 TCR CD4 T cells to augment the persistence and function of the HA-1 TCR CD8 T cells and includes only memory T cells; naive T cells are excluded to limit the potential for alloreactivity mediated by native TCR coexpressed by HA-1 TCR T cells. We describe the development of this unique immunotherapy and demonstrate functional responses to primary leukemia by CD4 and CD8 T cells transduced with a lentiviral vector incorporating the HA-1 TCR transgene construct.

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

“…CD8 + and CD4 + T cells expressing the HA-1 TCR construct were highly functional against leukemia cell lines and primary leukemia in vitro and could be rapidly eliminated using the safety switch. 65 A phase I clinical trial of CD8 + and CD4 + T cells transduced with this HA-1 TCR construct is now open to patients with hematologic malignancies (NCT03326921). HA-1 TCR-T-cell immunotherapy is also being evaluated in the Netherlands, using a different HA-1-specific TCR, a different transgene (without CD8 coreceptor) and viral vector (retroviral rather than lentiviral), and a different cell product (EudraCT number 2010-024625-20).…”

“…Introducing a CD8 coreceptor can facilitate recognition of class I antigens by CD4 + T cells, and enhance "help" for cytotoxic CD8 + T cells. 65,[87][88][89][90][91] Safety switches, including inducible prodeath proteins, can be used to rapidly remove transferred T cells if toxicities such as CRS or GVHD become an issue. [92][93][94][95][96][97] The ability to secrete IL-12 and other cytokines can increase activity of so-called "armored" CAR-T or TCR-T cells and create a proinflammatory environment that enables antigen presentation, 98-100 albeit with an increased potential for toxicity if cytokine secretion is not tightly regulated.…”

Neoantigens in Hematologic Malignancies

“…Although TCR-T targeting epitopes from wild-type WT1 have shown safety (162)(163)(164) and efficacy (165), no clinical trials of neoantigen-specific TCR-T immunotherapy for hematologic malignancies have opened to date. TCR constructs can be modified to include other features to improve TCR-T safety and function: a CD8 co-stimulatory receptor enables CD4 + T cells to function with a class I-restricted TCR and provide targeted help to neoantigen-specific CD8 + T cells (166)(167)(168), a safety switch (167,169) enables rapid removal of transgenic TCR-T cells in the event of toxicity, and other elements have been advanced [reviewed in (170)]. Lastly, vaccines do not require adoptive cell transfer, have shown clinical efficacy in solid tumors (8-10), and are particularly attractive for targeting highly immunogenic but less prevalent neoantigens.…”

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

“…The transfer of a transgenic TCR in T cells can be achieved using brief manufacturing protocols that maintain early T-cell memory differentiation and that generate a high number of T cells with the desired antigenic specificity. The efficacy and safety of T cells expressing a transgenic HA-1 specific TCR has been established in vitro (120). In this study, an elaborate transgene was used for optimal reactivity and safety.…”