Donor-derived multiple leukemia antigen-specific T-cell therapy to prevent relapse after transplant in patients with ALL.
Swati NaikSpyridoula VasileiouIfigeneia TzannouManik KuvalekarAyumi WatanabeCatherine RobertsonNatalia LaptevaNicholas WangMengfen WuBambi GrilleyGeorge CarrumRammurti T KambleLaQuisa C HillRobert A KranceCaridad MartinezPriti TewariBilal OmerStephen GottschalkHelen E HeslopMalcom K BrennerCliona M RooneyJuan F VeraAnn M LeenPremal D LullaPublished in: Blood (2022)
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, which are leukemia-associated antigens frequently expressed in B- and T-ALL. Our goal was to maximize the graft-versus-leukemia effect while minimizing the risk of graft-versus-host disease (GVHD). We administered mLSTs (dose range, 0.5 × 107 to 2 × 107 cells per square meter) to 11 patients with ALL (8 pediatric, 3 adult), and observed no dose-limiting toxicity, acute GVHD or cytokine release syndrome. Six of 8 evaluable patients remained in long-term complete remission (median: 46.5 months; range, 9-51). In these individuals we detected an increased frequency of tumor-reactive T cells shortly after infusion, with activity against both targeted and nontargeted, known tumor-associated antigens, indicative of in vivo antigen spreading. By contrast, this in vivo amplification was absent in the 2 patients who experienced relapse. In summary, infusion of donor-derived mLSTs after allogeneic HSCT is feasible and safe and may contribute to disease control, as evidenced by in vivo tumor-directed T-cell expansion. Thus, this approach represents a promising strategy for preventing relapse in patients with ALL.
Keyphrases
- hematopoietic stem cell
- bone marrow
- acute myeloid leukemia
- free survival
- acute lymphoblastic leukemia
- allogeneic hematopoietic stem cell transplantation
- end stage renal disease
- low dose
- prognostic factors
- ejection fraction
- cancer therapy
- dendritic cells
- newly diagnosed
- stem cell transplantation
- chronic kidney disease
- magnetic resonance
- liver failure
- oxidative stress
- stem cells
- systemic lupus erythematosus
- magnetic resonance imaging
- hepatitis b virus
- drug delivery
- intensive care unit
- mass spectrometry
- high dose
- rectal cancer
- cell death
- cell proliferation
- combination therapy
- drug induced
- aortic dissection
- replacement therapy
- extracorporeal membrane oxygenation
- childhood cancer