Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Abstract

Background. Patients with advanced hematologic malignancies remain at risk for relapse following reducedintensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. Methods. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.Results. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8 + T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8 + T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Conclusion.Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance longterm leukemia control following allo-HSCT.Trial registration. Clinicaltrials.gov NCT00442130.

Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT

“…The unusual immune reconstitution in this patient characterized by alterations in innate and adaptive responses may also have contributed to the persistence of the GM-K562 cells. Although no other cases of persistent GM-K562 cells or prolonged eosinophilia were observed in this or our previously published study of GM-K562 admixed CLL vaccine, 25 this event raises concern over the safety of irradiated K562 cells as vaccines in severely immune compromised patients after allogeneic HSCT. In this context, other approaches using highly immunogenic scaffolds as vaccine implants have been developed.…”

“…Median age was 57 years (range, 20-70). Diseases included AML (25) and MDS (8). Twenty (61%) had high or very high Disease Risk Index.…”

“…[22][23][24] Investigators at our center have previously reported a trial using GM-K562 bystander vaccination after allogeneic HSCT for patient with chronic lymphoid leukemia (CLL). 25 In this study, 18 patients received vaccinations with GM-K562 admixed with autologous CLL cells early after a reduced intensity conditioning (RIC) HSCT, with a 2-year progression-free survival (PFS) and overall survival (OS) of 82% and 88%, respectively. They further showed that the vaccination expanded CD8…”

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

“…We sought to generate exosomes expressing high levels of functional TRAIL, to combine the advantage of a transmembrane conformation with nanovesicular structures for systemic delivery (11). K562 cells transduced with a human lentiviral vector were chosen as exosome producers, for their resistance to TRAIL-mediated apoptosis, the ability to grow at large scale level in vitro and the approved use for human application (36)(37)(38). Nevertheless, other donor cells, such as CD34 from healthy volunteers and different transfection tools (i.e., AdenoTRAIL vectors; refs.…”

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

“…66 A novel approach to augment antigen presenting activity in patients with cancer has been to vaccinate them with irradiated autologous tumor cells engineered to secrete GM-CSF. It is thought that paracrine production of GM-CSF can stimulate the recruitment, maturation, and function of dendritic cells in vivo, 67,68 overcoming the described qualitative and quantitative deficiencies of antigen presenting cells in cancer patients. Ho et al conducted a Phase I clinical trial whereby high-risk acute myeloid leukemia or patients with MDS were immunized with autologous, irradiated, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT.…”