Evaluation of cyclin A1–specific T cells as a potential treatment for acute myeloid leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for relapsed or refractory acute myeloid leukemia (AML). However, more than half ultimately experience disease relapse that is associated with a dismal median survival of just 6 months, highlighting the need for novel therapies. In the current study we explore the therapeutic potential of targeting cyclin A1 (CCNA1), a cancer-testis antigen that is overexpressed in malignant blasts and leukemic stem cells. We demonstrate the immunogenicity of this antigen to native T cells, with >90% of donors screened mounting a specific response. The expanded cells were Th1 polarized, polyfunctional, and cytotoxic toward CCNA1+/HLA-matched tumor cell lines. Furthermore, these cells were exquisitely specific for CCNA1 and exhibited no reactivity against other cyclin family members, including CCNA2, which shares 56% homology with CCNA1 and is ubiquitously expressed in dividing cells. Lastly, the detection of CCNA1-specific T cells in AML patients post-HSCT was associated with prolonged disease remission, suggesting the protective potential of such endogenous cells. Taken together, our findings demonstrate the feasibility of targeting CCNA1 and the potential for therapeutic benefit associated with the adoptive transfer of reactive cells.

Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant

“…In all 3 cases before mLST infusion we addressed potential mechanisms of failure: intrathecal chemotherapy in patient 6 with CNS-only disease, withdrawal of corticosteroids in patient A1, and higher doses of cells in patient 9. In addition, our platform can support the generation of mLSTs targeting a broader spectrum of TAAs, such as the MAGE family of antigens, 35 PR1, 38 and/or cyclin A1, 39,40 especially given that inter-and intrapatient variability in the expression of individual leukemic blasts can be expected. [39][40][41] In summary, administration of mLSTs at doses comparable to those in DLIs proved safe and produced direct anticancer effects in chemoresistant AML/MDS relapses after HCT.…”

“…In addition, our platform can support the generation of mLSTs targeting a broader spectrum of TAAs, such as the MAGE family of antigens, 35 PR1, 38 and/or cyclin A1, 39,40 especially given that inter-and intrapatient variability in the expression of individual leukemic blasts can be expected. [39][40][41] In summary, administration of mLSTs at doses comparable to those in DLIs proved safe and produced direct anticancer effects in chemoresistant AML/MDS relapses after HCT. These results will be subjected to validation in randomized, multicenter trials, which are currently under way.…”

A single-cell survey of cellular hierarchy in acute myeloid leukemia

“…Cell cycle regulators are considered attractive targets in cancer therapy [83]. CCNA1 is a suitable immuno-therapeutic target for future clinical trials, and generating donor-derived CCNA1-specific T cells seems to be a possible approach to prolonged disease remission in post-HSCT patients [84]. An aberrant expression of Rab proteins has been reported in multiple cancer types [85].…”

Prediction of myeloid malignant cells in Fanconi anemia using machine learning

“…On the other hand, the expression profile of the predicted AML cells suggests that in these cells the transformation process towards malignancy is already ongoing, since few changes in immune modulation are detected, but more changes in tumour progression molecules seem to take place, including increased expression of CCNA1, HLA-C and WISP3. Importantly these molecules have already been reported as therapeutic targets 16,21,[50][51][52] .…”