Allogeneic donor CD19-specific CAR T-cells promote anti-lymphoma activity with minimal incidence of GvHD

Currently, there is much excitement about the potential use of Chimeric Antigen Receptor (CAR) T-cell therapy in lymphoma. However, there is a concern that this type of therapy can potentially increase the incidence of Graft Versus Host Disease (GvHD).

Arnab Ghosh from the Memorial Sloan Kettering Cancer Center, New York, US, and colleagues analyzed donor-derived CD19 specific CAR T-cells in allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT) and lymphoma murine models with the aim of understanding the mechanism by which allogeneic CD19 CAR T-cells potentially mediate anti-lymphoma activity without causing significant increase in the risk of GvHD occurrence. Their findings were published in Nature Medicine in January 2017.

The group constructed a panel of retroviral vectors encoding CARs targeting mouse CD19 and tested them in a number of murine models.

• The authors summarized their findings by stating that their data indicate that allogeneic donor CD19-specific CAR T-cells promote anti-lymphoma activity with minimal incidence of GvHD
• They also found that the transfer of large numbers of non-transduced T-cells was sufficient to promote comparable levels of GvHD in recipients of both m1928z (CD19 specific CAR) and m19delta (non-signaling control) T-cells argues against the existence of a mechanism where changes in the host environment (e.g. B-cell depletion by CAR T-cells) dominantly inhibits GvHD incidence
• The group’s results also support a model in which alloreactive CD19 specific T-cells undergo cumulative activation via TCR and CAR signaling, followed by exhaustion and then possible deletion of CAR T-cells; supported by reduced proliferation and cytokine production of m1928z versus m19delta T-cells
• Their data therefore also disagree with a model that states enhanced cytokine secretion by CD19 specific CAR T-cells in response to lymphoma cells promotes GvHD or cytokine-release-mediated lethality
• Lastly, the group also showed that the presence of CD19 antigen, on either mature B-cells or tumor cells, is critical to inducing protection from GvHD. Hence, when CAR T-cell therapy is intended for the management of MRD, adoptive transfer of CAR T-cells should take place after a period of B-cell recovery

Abstract:

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.