PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells

Abstract

Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR)genes IntroductionHematopoietic stem cell transplantation (HCT) from human leukocyte antigen-mismatched family donors is a potentially curative option for patients with high-risk hematologic malignancies lacking a human leukocyte antigen-matched donor. 1,2 For haploidentical HCT, this procedure typically requires rigorous T-cell depletion of the graft eliminating the cellular component, which can contribute to the curative potential of an allogeneic HCT. 3 To overcome this limitation, donor-derived lymphocytes have been infused later after transplantation to provide a graft-versus-malignancy effect. Although preclinical and clinical studies were initiated to minimize the side effects of such a procedure, 4,5 the risk of inducing severe graft-versus-host disease (GVHD) remains substantial, and relapse rates continue to be significant in part because of tumor escape mechanisms that evolve over time. 6 Enforced expression of T-cell receptor (TCR) genes directed against a tumor-associated antigen (TAA) has been explored as a means by which the potency of T-cell adoptive transfer (AT) may be augmented. When using allogeneic T cells, such an approach may serve to direct the donor T-cell response preferentially to the host leukemia cells instead of the normal host cells, thereby increasing the therapeutic index of T cell AT. Lessons from studies of murine autologous T-cell AT models have shown that: (1) TCR gene therapy can be expected to break tolerance against selfantigens, such as tumor-associated antigens; (2) with few exceptions, TCR gene transfer was associated with an acceptable toxicity profile; and (3) the transfer of TCR-engineered T cells has been shown to impact large tumor burdens. 7 However, clinical translation of TCR gene-modified T-cell AT has been hampered by the growing evidence that in vivo proliferation and persistence of engineered T cells are more limited than needed for an optimal antitumor response. 8,9 Increasingly, T-cell AT is performed in the context of a lymphodepleted recipient to provide a more favorable environment for their homeostatic expansion. 10 However, whereas cytokines that accumulate in lymphodepleted recipients can drive T-cell expansion until the cytokines are consumed, 11 long-term T-cell activation and expansion require continued TCR engagement. In this study, we sought to take advantage of dual-specific TCR-transduced T cells obtained from major histocompatibility complex (MHC)-mismatched donors that would receive allogeneic MHC antigenic signals via the endogenous TCR that may be useful in sustaining the persistence of adoptively transferred T cells. In support of this hypothesis, virus-specific T cells reprogrammed to express a TCR-directed against host hematopoietically restricted minor histocompatibility antigens remained responsive against their allo-targets without losing their viral reactivity. 12 Here, we evaluated the converse concept that the in vivo infusion of T cells forced...

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

“…In this setting, blocking a negative regulatory pathway (programmed cell death protein 1 [PD1]/programmed death-ligand 1 [PD-L1] pathway) can provide a potent means of achieving GVL effects without GVHD effects, an approach that uses negative regulatory molecules such as anti-PD-1 or anti-CTLA4 to achieve GVL without GVHD late post-BMT. 18 Lethally irradiated BALB/c mice were given 10 7 BALB/c BM. Cohorts were infused with B6-WT or B7-H3 2/2 splenocytes at a dose of 30 3 10 6 (day 50) in saline without supplemental cells as a control.…”

Expression of a dominant T-cell receptor can reduce toxicity and enhance tumor protection of allogeneic T-cell therapy

“…The results described here are similar to the results obtained by Koestner et al, when they showed that allogeneic T cells engineered to express the OT1-TCR displayed increased GvL and reduced GvHD activity. 11 In these studies, the engineered T cells contained some untransduced cells and the OT1-TCR achieved only 20%-70% reduction in the level of endogenous TCR expression. In our case, we purified T cells for high expression of the introduced F5-TCR, and this 'dominant' TCR was capable of suppressing endogenous TCR expression to undetectable levels.…”

“…In this study, Koestner et al transferred the OT1-TCR, specific for a peptide epitope of ovalbumin, into donor T cells and achieved 20%-70% reduction of the endogenous TCR repertoire. 11 Here, we explored whether 'dominant' TCR can mediate complete inhibition of endogenous TCR expression in donor T cells in vivo. Together with other groups, we had previously shown that 'dominant' TCR can suppress the expression of 'non-dominant' TCR on the surface of genemodified T cells in vitro.…”

Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease

“…K14-OVA and Act-mOVA mice) may be a straightforward strategy to compare the two disease modalities, or even mechanisms of skin-and gut-directed homing of CD8+ T cells in aGvHD, within a highly controlled experimental environment. leukemia effect, as well, as it has been shown elsewhere [38]. Nevertheless, the downside of this approach that due to its very nature, it is highly simplistic, relies mostly on CD8+ T cell activation, is limited to a single mismatched antigen, and hence even if it accurately depicts CD8+ T cell activation, it certainly does not recapitulate the full complexity of human aGvHD [39].…”