Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity

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. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells.1–5 CD19 is an attractive CAR target, expressed in most B cell malignancies as well as normal B cells.6,7 Clinical trails using autologous CD19-targeted T cells have shown remarkable outcomes in various B cell malignancies8–15. The use of allogeneic CAR T cells poses a concern of increased GVHD, which however has not been reported in selected patients infused with donor-derived CD19-CAR T cells after allo-HSCT.16,17 To understand the mechanism whereby allogeneic CD19-CAR T cells may mediate anti-lymphoma activity without significant 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 experienced enhanced T cell stimulation, resulting in progressive loss of effector function and proliferative potential, clonal deletion, and significantly decreased GVHD. Concurrently, other CAR T cells present in bulk donor T cell populations retained their anti-lymphoma activity consistent with the requirement for engaging both the TCR and the CAR to accelerate T cell exhaustion. In contrast, first generation and 4-1BB-costimulated CARs increased GVHD. These findings could explain reduced risk of GVHD with cumulative TCR and CAR signaling.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…The propensity of adoptive transfer to cause autoimmunity seems to be low, although there is not as much experience with adoptive transfer as with checkpoint therapy. Consistent with a reduced propensity for autoimmunity, infusions of allogeneic CAR T cells might cause diminished GVHD [97][98][99] .…”

Donor-derived CAR-T Cells Serve as a Reduced-intensity Conditioning Regimen for Haploidentical Stem Cell Transplantation in Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: Case Report and Review of the Literature

“…No GVHD and a strong GVL effect were observed. 13 ATG can continually exist for ∼1 month after infusion in vivo and may also kill CAR-T cells. 15 In our study, considering the control of GVHD after haploidentical HSCT and the possible killing and inhibition of the proliferation of CAR-T cells by ATG, the ATG was administered on day +14 and day +15 after the infusion of the HSCs and after the 18th day after the last day of CAR-T cell infusion, which exceeded the optimal time of proliferation of the CAR-T cells.…”

“…[9][10][11] Allogeneic CAR-T cells have been found to exert a GVL effect and diminish GVHD in a xenograft model and in a murine acute GVHD model. 12,13 CAR-T cells as a part of RIC regimens may be an approach for treating r/r ALL in haploidentical HSCT. Thus, we hypothezied that the donorderived CAR-T cells can be used as a part of RIC regimens in the treatment of r/r ALL in haploidentical HSCT.…”

Use of Chimeric Antigen Receptor T Cells in Allogeneic Hematopoietic Stem Cell Transplantation

“…The study showed that CAR-T cells have GVL effect [36]. In another murine haploidentical HSCT model, donor-derived CD19-CAR-T cells constructed with retroviral vector can induce GVL effect and diminish GVHD effect at day 1 [37].…”