Aurora: a new direction for a new dawn

The success of adoptive immunotherapy in leukemia is hampered partly by lack of sufficient high-avidity antitumor T-cell precursors in most leukemia patients³  and technical difficulties in timely preparation of sufficient numbers of leukemia antigen-specific T cells for each patient. TCR gene transfer using retroviral vectors is an attractive strategy for redirecting the antigen specificity of polyclonal primary T cells to create tumor antigen-specific lymphocytes. This approach can potentially overcome the limitations of current adoptive T-cell therapies, which rely largely on the isolation and expansion of tumor-specific lymphocytes ex vivo from individual patients, and result in the generation of sufficient numbers of potent antitumor immune effectors for adoptive immunotherapy.

Pioneering work from Rosenberg and colleagues at the National Cancer Institute proved the feasibility of this approach in clinical trials of adoptive therapy with autologous TCR gene-transduced T cells directed against cancer-associated antigens for the treatment of metastatic melanoma and synovial cell sarcoma.^4,5  In the setting of hematologic malignancies, TCR gene therapy targeting a number of leukemia-associated antigens such as Wilms tumor gene product 1 (WT1),⁶  and minor histocompatibility antigens such as HA-1 and HA-2⁷  are currently being investigated in preclinical studies or in early-phase clinical trials.

Aurora kinase A is a candidate tumor-associated antigen that is widely expressed in various types of cancer, including hematologic malignancies; its expression in normal tissues is largely limited to the testis, making it an ideal target for immunotherapy.⁸  Previously, Yasukawa and colleagues identified an immunogenic HLA-A2–restricted antigenic epitope of Aurora kinase A, AURKA_207-215, capable of inducing CD8⁺ T cells with in vitro cytotoxicity against AURKA expressing leukemic cells.⁹ 

Here, Nagai and colleagues sought to examine the feasibility of generating engineered T cells bearing Aurora kinase-A specific TCR genes as a strategy for the treatment of leukemia. In elegant experiments, they clearly demonstrate that polycloncal CD8⁺ T cells retrovirally transduced to express the HLA-A2–restricted AURKA_207-215 TCR α/β chains generated from the AURKA CD8⁺ T-cell clone have specific recognition of AURKA-overexpressing human leukemic cells, both in vitro and in a xenogeneic mouse model of human leukemia. Importantly, AURKA_207-215–specific TCR-transduced CD8⁺ T cells were selective in their recognition of leukemic cells and did not lyze HLA-A2 positive normal peripheral blood mononuclear cells or cord blood CD34⁺ cells, suggesting that CD8⁺ T cells targeting AURKA will not result in immune-mediated destruction of normal stem cells.

Intriguingly, Nagai et al show that CD4⁺ T cells could be redirected, using the same TCR that recognized the HLA-A2–restricted AURKA_207-215 epitope, to recognize and secrete T helper 1 cytokines including IL-2, in response to AURKA_207-215–expressing targets. The cytotoxic antitumor effect of CD8⁺ T cells is partly dependent on CD4⁺ T cells, which provide CD8⁺ T cells with growth factors such as IL-2 and can mediate the destruction of tumor cells either directly or indirectly.¹⁰  It is therefore likely that the adoptive transfer of redirected CD4⁺ T cells concurrently with CD8⁺ T cells expressing the same tumor-specific TCR gene could enhance the in vivo expansion, persistence, and antitumor reactivity of adoptively transferred antigen-specific CD8⁺ T cells in vivo. It remains to be determined whether such redirected helper CD4⁺ T cells will also exert direct cytotoxicity against leukemic cells in vivo.

Taken together, these results suggest that adoptive therapy using redirected CD4⁺ and CD8⁺ T cells that recognize AURKA-derived epitopes, may be a promising strategy for the treatment of AURKA-expressing cancers. These encouraging preclinical data support the development of clinical trials to investigate the safety and utility of such an approach in patients with relapsed or refractory leukemia.