Non-Engineered T Cells to Prevent or Treat Relapse in Post-Transplant AML/MDS

Infusion with “non-engineered” adoptive T-cell products induced responses in select patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) who had undergone allogeneic hematopoietic cell transplantation (alloHCT) and subsequently relapsed. One complete response (CR) lasted for 13 months, according to research presented by Premal Lulla, MBBS, from the Baylor College of Medicine in Houston, at the 2019 Transplantation & Cellular Therapy (TCT) Meetings of ASBMT and CIBMTR.

“With this study, we proposed using donor lymphocytes that have been enriched ex vivo for leukemia reactivity and then infused back to recipients,” Dr. Lulla explained. “The intention is to infuse recipients first to prevent relapse and second to treat ongoing relapsed disease.”

Attendees gather at the 2019 TCT Meetings.

After investigators identified four antigens frequently expressed in disease cells from patients with MDS/AML (PRAME, WT1, NYESO1, and Survivin), they developed donor products that have demonstrated activity against them. The donor-derived T-cell products were polyclonal, containing both CD4- and CD8-positive, antigen-specific populations, and the cells were expanded and enriched in the laboratory without genetic engineering approaches, Dr. Lulla added.

To determine the safety and efficacy of this T-cell therapy, the investigators conducted a phase I study that enrolled patients with MDS/AML into two groups: Group A included patients whose disease was in remission at the time of infusion; group B included patients whose disease was in ongoing relapse.

T cells were infused at three escalating dose levels, ranging from 5×106 to 2×107 cells/m². Dr. Lulla noted that the products were successfully manufactured and maintained specificity against target antigens.

At the time of data presentation, 27 patients (24 with AML, 3 with MDS) were enrolled; 20 patients had been infused with the T-cell product (13 in group A and 7 in group B).

Infusion of the T-cell products was safe, the authors reported, with only four documented infusion-related adverse events (AEs): three grade I liver function test (LFT) elevations and one grade III LFT elevation. “Notably, no patient had infusion-related cytokine release syndrome, neurotoxicity, or graft-versus-host disease,” Dr. Lulla added.

Among the 13 patients in group A who were infused, four patients experienced a relapse, and each relapse occurred between four and 10 months after T-cell infusion. Of these four patients, one was moved to group B for additional T-cell treatment and subsequently experienced a CR that lasted for 13 months. Another two patients had isolated central nervous system relapse and were successfully treated with intrathecal chemotherapy without T-cell infusion. The remaining patient of the four had bone marrow relapse and was treated with systemic chemotherapy and another alloHCT and remained alive in relapse at 1.5 years post initial T-cell infusion.

Seven patients were enrolled in group B. Three patients had progressive disease, two had stable disease, and two responded to T-cell treatment. Responders included the patient initially treated in group A and another who experienced a partial response and was able to undergo a second alloHCT. For patients in group B, overall survival after T-cell infusion ranged from four to 21 months, the authors observed.

To determine any correlation between response and in vivo expansion of the infused leukemia-specific T-cell clones, the investigators monitored circulating T-cell clones with T-cell receptor deep sequencing. Compared with nonresponders, patients who responded to treatment had demonstrated greater expansion of product-derived clones.

“T cells targeted against multiple leukemia-associated antigens directed to PRAME, WT1, NYESO1, and Survivin can be safely administered to patients with AML/MDS, in whom long-term and produce sustained responses can subsequently be detected,” Dr. Lulla concluded.

The results of the trial are limited by the small patient population, and Dr. Lulla noted that the investigators are now analyzing these data to determine the effects of antigen spreading, “as well as to elucidate mechanisms of antigen escape.”

The authors report relationships with Marker Therapeutics, which sponsored this trial.

Reference

Lulla P, Naik S, Tzannou I, et al. Administering leukemia-directed donor lymphocytes to patients with AML or MDS to prevent or treat post-allogeneic HSCT relapse. Abstract #11. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 20, 2019; Houston, TX.

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