Leukemia Antigen–Specific Donor-Derived T Cells Enhance Graft-Versus-Leukemia Effects in Post-Transplant AML/MDS

For patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) whose disease relapses following a hematopoietic cell transplantation (HCT), unselected donor lymphocytes typically are infused to enhance the graft-versus-leukemia (GVL) effect, which can lead to life-threatening graft-versus-host disease (GVHD). In a report published in Blood, researchers evaluated a new strategy to maximize GVL effects and minimize GVHD: donor-derived T cells that target multi-leukemia antigens (mLSTs).

According to the study authors, led by Premal Lulla, MBBS, of Baylor College of Medicine in Houston, Texas, use of mLSTs (at doses comparable to donor lymphocyte infusions [DLIs] was safe and generated direct anticancer effects in patients with chemotherapy-resistant, relapsed AML or MDS following an HCT.

Findings from this study, according to the researchers, suggest mLSTs may be a safer alternative to DLIs. ​Dr. Lulla commented that additional research is needed to determine whether the findings hold relevancy for clinical practice. “Now that we have established safety, an ongoing efficacy-based trial of the same product will prove if we can use these T cells to prevent or treat AML/MDS relapse post-transplant,” he said.

“Given the simplicity and robustness of mLST manufacture … , we believe that mLSTs addresses a major unmet need in the management of AML/MDS post-HCT.”

—Premal Lulla, MBBS

The small, single-center study included 29 patients with AML or MDS following HCT who were intended to receive mLSTs to treat refractory/relapsed disease (active arm) or to maintain remission post-HCT (adjuvant arm). All participants entered the study at least 30 days after HCT. The patients had donors who provided peripheral blood mononuclear cells to generate mLSTs for infusion. A total of 31 products were produced from the 29 donors.

Following enrollment, patients were treated with a single infusion of mLSTs at various dose levels (DLs):

  • DL1:  0.5×107 cells/m2
  • DL2: 1×107 cells/m2
  • DL3: 2×107 cells/m2
  • DL4: 5×107 cells/m2
  • DL5: 10×107 cells/m2

Nine patients were not infused, while 20 patients, including five who were treated twice, received mLSTs, the authors reported. This included 17 patients in the adjuvant arm and eight in the active arm.

Forty-eight infusions were administered to 25 enrollees across both arms, and only three (12%) developed de novo (grade 1) or worsening (grade 2) acute GVHD post-infusion. Four enrollees (16%) developed de novo mild chronic GVHD. One patient with grade 2 upper gastrointestinal GVHD required systemic steroid treatment. “Importantly, there were no cases of cytokine release syndrome, neurotoxicity, or persistent myelotoxicity (>28 days),” the authors noted.

In in vitro models of the mLSTs efficacy, the cells selectively recognized and killed leukemia-antigen-pulsed cells, but there was no effect against recipient-derived normal cells. This was replicated in this study, with the mLSTs demonstrating anti-leukemia effects and leading to a prolonged leukemia-free survival. The median survival was not reached at a follow up of 1.9 years among survivors in the adjuvant arm and the estimated two-year overall survival in these patients was 77%.

The investigators also observed two responses in the active disease cohort (1 complete response and 1 partial response), and, among the eight patients with relapsed disease resistant to salvage therapies, two achieved an objective response following treatment with mLSTs.

Limitations of this phase I study include its single-center design and its relatively small sample size. In spite of these limitations, the researchers wrote that, “given the simplicity and robustness of mLST manufacture … that can be made available to all patients with AML/MDS undergoing HCT as well as the demonstrated anti-leukemia effects, we believe that mLSTs addresses a major unmet need in the management of AML/MDS post-HCT.”

The study authors reported no conflicts of interest.

Reference

Lulla P, Naik S, Vasileiou S, et al. Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS post-allogeneic transplant. Blood. 2020 December 3. [Epub ahead of print]