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

Abstract

Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes. Thus, to minimize GVHD and maximize GVL we selectively activated and expanded stem-cell donor-derived T cells that were reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, NY-ESO-1). Products were successfully generated from 29 HCT donors, and they demonstrated multi-leukemia antigen specificity (mLSTs). In contrast to DLIs, mLSTs selectively recognized and killed leukemia-antigen-pulsed cells with no activity against recipient-derived normal cells in vitro. We have now administered escalating doses of these mLSTs (0.5-10x107 cells/m2) to 25 trial enrollees with AML/MDS after HCT, 17 of whom were at high risk for relapse and 8 of whom had relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD up to a dose of 10x107 cells/m2. We observed anti-leukemia effects in vivo that translated into not yet reached median LFS and OS at 1.9 years of follow-up among survivors, evidence of sustained immune pressure and objective responses in the active disease cohort (1 CR and 1 PR). In conclusion, mLSTs are safe and promising for the prevention or treatment of AML/MDS following HCT.

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

“…Although either adoptive or vaccine-based immunotherapies to elicit endogenous immune responses are unlikely to be highly effective in patients with full-blown either newly diagnosed or relapsed leukemia, these strategies, potentially in combination with ICPIs, could be promising in maintaining CR or preemptively eradicating persistent MRD, following conventional chemotherapy in older NPM1-mutated AML patients not eligible for allogeneic HSCT [19,21,42,93]. Alternatively, neoantigen-specific DLI derived from healthy donors and targeting NPM1-mutated protein to selectively elicit GvL may be an attractive therapeutic option in subjects experiencing morphological or, preferentially, molecular relapse after allogeneic HSCT, as previously demonstrated in Philadelphia chromosome-positive B-acute lymphoblastic leukemia patients (Figure 1) [19,37,58,59,61,62,94,95]. In conclusion, even though it has thoroughly been documented that NPM1-mutated protein is immunogenic and may elicit neoantigen-specific immune responses in vivo, further prospective studies are warranted to investigate whether individualized anti-leukemic immunotherapeutic approaches could have a potential clinical utility in NPM1-mutated AML patients throughout their disease course [1,3,4,19,20,70].…”

“…Collectively, the authors suggested that increased specific T-cell responses against several different LAA, enhancing GvL effect and potentially able to target LSC population, as well as decreased numbers of Tregs after prophylactic/therapeutic DLI, could contribute to favorable clinical outcomes [59][60][61]. To maximize the GvL effect minimizing the risk of GvHD, Lulla et al, selectively activated and expanded stem cell donor-derived T cells reactive to multiple antigens expressed by AML/MDS cells, namely PRAME, WT1, survivin and NY-SEO-1 [62]. In contrast to DLI, leukemia-specific T cells selectively recognized and killed leukemia antigen-pulsed cells, with no activity against recipient's normal cells in vitro.…”

“…Additionally, anti-leukemic effects in vivo were demonstrated, with long-term post-HSCT remissions in the adjuvant patient group at a high risk of relapse (median leukemia-free survival not reached at a median follow-up of 1.9 years and estimated 2-year OS 77%), and objective responses observed in two out of eight patients with HSCT-refractory active disease. Therefore, allogeneic leukemia-specific T cells could represent a safe and promising preventative/therapeutic tool in the management of AML post-HSCT [62].…”

Murine Leukemia-Derived Extracellular Vesicles Elicit Antitumor Immune Response

“…A study by Lulla et al showed that activating and expanding leukemia antigen-specific T cells from stem cell donor lymphocytes enhanced anti-leukemic responses and minimized graft-versus-host disease when infused into recipients following a hematopoietic stem cell transplant. 23 Because CD3+ cells from a non-tumor bearing haploidentical donor are infused into the patient with refractory hematological malignancy, one possibility is that the circulating EVs isolated from the patient could be used to activate leukemia-specific donor CD3+ cells prior to infusion. The EVs could induce effector cells restricted to peptides presented by syngeneic MHC molecules or alloreactive effector cells able to recognize and lyse the patient’s leukemic cells.…”

Allogeneic Hematopoietic Cell Transplantation and Cellular Therapy

“…Adoptive immunotherapies using stratified WT1specific vaccine, WT1-specific CTLs, CART/NK cells, bispecific killer cell engager T cells, gene transferred mesenchymal stromal cells (MSCs), and the combination of various immunomodulating novel agents or well-designed sequential approaches have been introduced. These adoptive immunotherapies should be applied to many high-risk patients with acute leukemias in need of treatment and to prevent relapse [10][11][12][13][14] .…”