Donor-derived multiple leukemia antigen–specific T-cell therapy to prevent relapse after transplant in patients with ALL

Abstract

Hematopoietic stem cell transplant (HSCT) is a curative option for patients with high-risk acute lymphoblastic leukemia (ALL) but relapse remains a major cause of treatment failure. To prevent disease relapse, we prepared and infused donor-derived multiple leukemia-antigen specific T-cells (mLSTs) targeting PRAME, WT1, and Survivin, leukemia-associated antigens that are frequently expressed in B- and T-ALL. Our goal was to maximize graft-versus-leukemia (GvL) effect while minimizing the risk of graft-versus-host disease (GVHD). We administered mLSTs (doses range: 0.5-2x107/m2) to 11 ALL patients (8 pediatric, 3 adult), and observed no dose-limiting toxicity, acute GVHD, cytokine release syndrome or other adverse events. Six of 8 evaluable patients remain in long-term complete remission (median: 46.5 [range: 9-51] months). In these individuals we detected an increased frequency of tumor-reactive T cells shortly after infusion, with activity against both targeted and non-targeted known tumor-associated antigens indicative of in vivo antigen spreading. By contrast, this in vivo amplification was absent in the two patients who relapsed. In summary, infusion of donor-derived mLSTs post allogeneic HSCT is feasible, safe and may contribute to disease control as evidenced by in vivo tumor-directed T cell expansion. Thus, this approach represents a promising strategy to prevent relapse in ALL patients. Clinical trial is registered under NCT02475707 at clinicaltrials.gov

PRAME Expression in Mimickers of Melanoma in Situ: Paget's Disease, Extramammary Paget's Disease, and Pagetoid Squamous Cell Carcinoma In Situ

“…This is consistent with the previously reported pattern of PRAME expression in squamous cell carcinoma [19]. PRAME is not specific to a cell lineage and has been described in tumors of non-melanocytic origin including colon adenocarcinoma, cellular neurothekeoma, and some lymphomas [20][21][22]. Not surprisingly, expression of PRAME was identified in several of our non-melanocytic lesions.…”

Children's Oncology Group's 2023 blueprint for research: Cellular therapy and stem cell transplantation

“…A trial of CMV-directed prophylaxis will open within the year. In addition, COG has existing infrastructure and CT expertise to explore multicenter trials evaluating antigen-specific T cells targeting viruses, 51 tumor-associated antigens, 54,55 and to control viral infections and malignancy in HCT patients. Finally, the broadening applicability of CAR-T cells targeting CD19 ± CD22 and other com-bination targets in the pediatric setting 56 represents a unique opportunity for the COG CT committee to support advanced-phase clinical trials for CAR-T approaches.…”

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer

“… 9 – 11 To address this issue and with the goal of developing an effective immunotherapy for BC, we developed a non-engineered T-cell product containing both CD4+ (helper) and CD8+ (cytotoxic) T cells with native TCR specificity for multiple TAAs. Our target antigens were chosen based on the frequency of expression in BC of all subtypes (PRAME: 27–97%; SSX family: 4–65%; MAGE-A4: 4–86%; NY-ESO-1: 8–64%; and Survivin: 26–96%) 16 – 28 , 30 , 37 and immunogenicity to T cells. 24 , 28 , 30 , 31 We hypothesized that the infusion of such multiTAA T cells would be safe and promote anti-BC activity, minimizing the risk for antigen-negative relapses.…”

“…Having demonstrated the tolerability and clinical benefit of multi-antigen-targeted T cells (multiTAA-T) in the setting of hematological diseases (lymphoma, 12 multiple myeloma, 13 and leukemia 14 , 15 ), we sought to examine whether a similar strategy might be effective in patients with refractory/metastatic BC when other therapeutic options had been exhausted. Thus, we developed a multi-specific T-cell product reactive against the tumor-associated antigens (TAAs), PRAME, SSX2, MAGEA4, NY-ESO1, and Survivin, which in BC are collectively expressed in more than 90% of tumors.…”

“…[9][10][11] To address the issue of immune escape, our group prepared autologous, polyclonal T-cell lines targeting a spectrum of lymphoma-expressed antigens and when administered to lymphoma patients at high risk of relapse or to treat chemorefractory disease the cell infusions proved safe and induced durable complete remissions (>3 years), without prior lymphodepletion. 12 Having demonstrated the tolerability and clinical benefit of multi-antigen-targeted T cells (multi-TAA-T) in the setting of hematological diseases (lymphoma, 12 multiple myeloma, 13 and leukemia 14,15 ), we sought to examine whether a similar strategy might be effective in patients with refractory/metastatic BC when other therapeutic options had been exhausted. Thus, we developed a multispecific T-cell product reactive against the tumorassociated antigens (TAAs), PRAME, SSX2, MAGEA4, NY-ESO1, and Survivin, which in BC are collectively expressed in more than 90% of tum ors.…”