Minor Antigen Distribution Predicts Site-Specific Graft-versus-Tumor Activity of Adoptively Transferred, Minor Antigen-Specific CD8 T Cells

Abstract

The clinical success of allogeneic T-cell therapy for cancer relies on the selection of antigens that can effectively elicit antitumor responses with minimal toxicity toward nonmalignant tissues. While minor histocompatibility antigens (MiHA) represent promising targets, broad expression of these antigens has been associated with poor responses and T-cell dysfunction that may not be prevented by targeting MiHA with limited expression. In this study, we hypothesized that antitumor activity of MiHA-specific CD8 T cells after allogeneic bone marrow transplant (BMT) is determined by the distribution of antigen relative to the site of tumor growth. To test this hypothesis, we utilized the clinically relevant male-specific antigen HY and studied the fate of adoptively transferred, HY-CD8+ T cells (HY-CD8) against a HY-expressing epithelial tumor (MB49) and pre-B cell leukemia (HY-E2APBX ALL) in BMT recipients. Transplants were designed to produce broad HY expression in nonhematopoietic tissues (female → male BMT, [F>M]), restricted HY expression in hematopoietic tissues (male → female BMT, [M>F]) tissues, and no HY tissue expression (female → female BMT, [F>F]). Broad HY expression induced poor responses to MB49 despite sublethal GVHD and accumulation of HY-CD8 in secondary lymphoid tissues. Antileukemia responses, however, were preserved. In contrast, restriction of HY expression to hematopoietic tissues restored MB49 responses but resulted in a loss of antileukemia responses. We concluded that target alloantigen expression in the same compartment of tumor growth impairs CD8 responses to both solid and hematologic tumors.

Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD

“…We demonstrated that, despite allogeneic environment-induced immune dysfunction observed with TCR-based immune responses, 21,23 allogeneic CAR T cells retain effectiveness at clearing leukemia. We also demonstrated that C3h.sw → B6 allogeneic minor-mismatched CAR T cells did not lead to clinical GVHD at the T-cell dose required to clear leukemia, but in the presence of leukemia, B6 → C3h.sw CAR T cells drive a lethal acute GVHD.…”

“…We incorporated a murine CD19 CAR 25 into a pre-B-ALL model, generated from C57/Bl6 mice expressing an E2a:PBX transgene 23,24 expressing CD45.2, CD19, B220, CD43, CD127, and CD93, consistent with a pre-B ALL subtype. In vitro CD3/CD28 bead-induced Tcell activation and retroviral transduction resulted in preferential expansion of CD8 1 cells and a CD19 CAR transduction efficiency of over 75% (see supplemental Figure 1A, available on the Blood Web site).…”

“…BMT and adoptive T-cell therapy BMT was as previously described, 23 with the exception of 1000 cGy as the lethal irradiation dose. Adoptive T cell transfer was performed 2 days following BMT (unless otherwise specified).…”

“…by guest www.bloodjournal.org From have diminished capacity to respond to vaccines and mediate antitumor responses even with mild subclinical GVHD, [20][21][22] and that adoptively transferred T cells with dual specificity for tumor and alloantigen through a single receptor demonstrate reduced but variable effectiveness dependent on the distribution of the allogeneic antigen. 23 Thus, we evaluated the efficacy of allogeneic CD19-targeted CAR T cells for the prevention of pre-B-cell ALL relapse in an immunocompetent murine model of HLA-matched, minor mismatched allo-BMT. 2/2 mice (B6.129S2-IL6tm1Kopf/J) strains were purchased from The Jackson Laboratory (Bar Harbor, ME).…”

Challenges and opportunities of allogeneic donor-derived CAR T cells

“…In the presence of both TCR and CAR antigens presented to the CAR T cell, it is not known which receptor will be dominant and how signaling through the endogenous TCR affects the efficacy of the genetically engineered CAR receptor function. Further, there is the possibility of a bystander effect in which the alloreactive T cells may impact the function of T cells that do not possess specificity for alloantigens[24,25] but do express the CAR.. Thus, the use of allogeneic CAR T cells, particularly healthy donor derived CAR T cells, requires an understanding of CAR T cell function in the allogeneic setting.…”