T cell optimization for graft-versus-leukemia responses

Abstract

Protection from relapse after allogeneic hematopoietic cell transplantation (HCT) is partly due to donor T cell-mediated graft-versus-leukemia (GVL) immune responses. Relapse remains common in HCT recipients, but strategies to augment GVL could significantly improve outcomes after HCT. Donor T cells with αβ T cell receptors (TCRs) mediate GVL through recognition of minor histocompatibility antigens and alloantigens in HLA-matched and -mismatched HCT, respectively. αβ T cells specific for other leukemia-associated antigens, including nonpolymorphic antigens and neoantigens, may also deliver an antileukemic effect. γδ T cells may contribute to GVL, although their biology and specificity are less well understood. Vaccination or adoptive transfer of donor-derived T cells with natural or transgenic receptors are strategies with potential to selectively enhance αβ and γδ T cell GVL effects.

Figure 1. Overview of allogeneic hematopoietic cell transplantation, including cellular components of an unmanipulated T cell–replete peripheral blood stem cell (PBSC) graft.

Key cellular components of the hematopoietic graft are indicated by pictograms, including αβ T cells (CD4⁺CD3⁺, green; CD8⁺CD3⁺, blue; Tn are indicated in lighter colors and Tm darker) and γδ T cells (gray with TCR). The green bar indicates the approximate time frame in which patients receive immunosuppressive medications for prevention and/or treatment of GVHD. Blue bars indicate usual periods of risk for post-HCT complications: light blue indicates early post-HCT risks primarily related to conditioning, darker blue indicates later post-HCT risks related primarily to immunosuppression and GVHD. Gray shading indicates the primary origin of relapse protection at different times after HCT: in the first 12 months due to conditioning therapy (dark gray), and after 12 months due to donor-derived GVL responses (lighter gray). Illustrated by Rachel Davidowitz.

Figure 2. Illustration of 3 PBSC graft engineering strategies to reduce GVHD.

(A) In pan-T cell–depleted (pan-TCD) grafts, only CD34⁺ HSCs (purple) that have been positively selected from donor PBSCs are infused into the recipient. (B) In naive T cell–depleted grafts, CD34⁺ HSCs are first isolated from PBSCs by positive selection as in A. The CD34^– fraction is then depleted of CD45RA⁺ cells, which removes CD45RA⁺ naive T cells. The CD34⁺ HSC and CD45RA^– fractions (CD4⁺CD3⁺ Tm, dark green; CD8⁺CD3⁺ Tm, dark blue; iNKT, yellow) are then infused into the recipient. (C) In αβ T cell–depleted (αβ-TCD) grafts, donor PBSCs are depleted of αβ TCR⁺ cells and often CD19⁺ cells, which removes αβ T cells and iNKT cells, and B cells, respectively. The αβ TCR^–CD19^– fraction, including NK (red with granules) and γδ (orange with TCR) T cells, is infused into the recipient. Illustrated by Rachel Davidowitz.

Figure 3. Strategies to augment donor LAA– and/or minor H antigen–specific T cell immunity.

(A) Generation of transgenic antigen-specific T cells. Donor leukocytes are collected, enriched for Tm by CD45RA depletion or selection of virus-specific cells, transduced to express a transgenic TCR specific for a defined minor H antigen or LAA, purified, expanded, and infused into the recipient at the time of HCT or subsequently. The box depicts a schematic of transgenic TCR development (left to right): a T cell clone with a well-characterized high-affinity hematopoietically restricted minor H antigen– or LAA-specific TCR is identified and the α and β chains of the TCR are sequenced, and then cloned into a viral vector for transfer. (B) Primary in vitro stimulation of antigen-specific T cells. Donor leukocytes are stimulated with antigen-presenting cells (APCs) pulsed with peptides for one or multiple LAAs and/or minor H antigens to produce a T cell product with an expanded population of LAA- and/or minor H antigen–specific effector T cells for infusion into the recipient with or without additional enrichment. (C) In vivo expansion of antigen-specific T cells using vaccination. Donors are vaccinated against one or multiple LAAs and/or minor H antigens several months before HCT, using peptide- or cell-based vaccines, to allow formation of Tcm responses against the antigens. Antigen-specific Tcm are then transferred either with the PBSC graft at the time of HCT, or as DLI after HCT, with or without additional manipulation (e.g., further enrichment of Tcm or depletion of CD45RA⁺ cells) to reduce the risk of GVHD. Illustrated by Rachel Davidowitz.