Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation

Rousseau, Raphaël F.; Biagi, Ettore; Dutour, Aurélie; Yvon, Éric; Brown, Michael P.; Lin, Tiffany; Mei, Zhuyong; Grilley, Bambi; Popek, Edwina J.; Heslop, Helen E.; Gee, Adrian P.; Krance, Robert A.; Popat, Uday; Carrum, George; Margolin, Judith F.; Brenner, Malcolm K.

doi:10.1182/blood-2005-03-1259

Cited by 65 publications

(50 citation statements)

References 58 publications

(63 reference statements)

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“…Our study adds to a growing body of clinical studies that established safety, feasibility, and biological activity of whole tumor cell-based vaccination for patients with hematologic malignancies (17,29,30). A number of features unique to our vaccination approach may have contributed to the observed expansion of leukemia-reactive CD8 + T cell responses.…”

Section: Discussionmentioning

confidence: 86%

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

Burkhardt

Hainz²,

Stevenson³

et al. 2013

J. Clin. Invest.

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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.

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Section: Discussionmentioning

confidence: 86%

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

Burkhardt

Hainz²,

Stevenson³

et al. 2013

J. Clin. Invest.

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“…A previous study showed that CD40L and IL-2 exert a congenerous antitumor effect (23), and Rousseau et al applied these results from the in vitro and animal experiments into a clinical setting in which a mixture of primary cultured skin fibroblasts infected with Ad IL-2 and Ad CD40L, and autologous leukemia cells were administered by intradermal injection. The pertinent leukemia cell responses of the patients were then monitored (24). CD40L and IL-2 are co-expressed in the same carrier, and in future applications it may be possible to reduce the number of steps (by only producing a carrier) and reduce the cost.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

et al. 2016

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Abstract. The aim of the present study was to construct a chimeric adenovirus (Ad)5/F35 co-expressing human CD4O ligand (CD4OL) and interleukin (IL)-2 (Ad5/F35 CD40L-IL-2). The infection efficiency to human monocyte-derived dendritic cells (Mo-DCs), expression of genes, phenotype changes and IL-12 production of Mo-DC by Ad5/F35 CD40L-IL-2 were investigated. CD40L and IL-2 from total RNA extracted from human peripheral blood mononuclear cells (PBMCs) were cloned by reverse transcription-polymerase chain reaction and used to construct Ad5/F35 CD40L-IL-2. The infection efficiency, expression of CD40L, and phenotype changes of Mo-DC infected with Ad5/F35 CD40L-IL-2 were analyzed using flow cytometry. The quantities of IL-2 and IL-12 in the supernatants of Mo-DC following infection of Ad5/F35 CD40L-IL-2 were measured by enzyme-linked immunosorbent assay. The CD40L and IL-2 genes were successfully cloned and the Ad5/F35 CD40L-IL-2 was constructed. Ad5/F35 CD40L-IL-2 efficiently infected Mo-DCs with an infection efficiency of >75%, and the infected Mo-DCs expressed CD40L and secreted IL-2. The expression levels of cluster of differentiation (CD)80, CD86, CD40, and human leukocyte antigen-antigen D related on Mo-DC were moderate; however, CD83 was low prior to infection of Ad5/ F35 CD40L-IL-2. Those molecules, particularly CD83, were markedly upregulated 24 h after the infection. Increasing quantities of IL-12 in the supernatants were detected subsequent to infection at different time points in a time-dependent manner. Thus, Ad5/F35 CD40L-IL-2 efficiently infected human Mo-DCs and its products, CD40L and IL-2, were subsequently expressed. In addition, infection with Ad5/F35 CD40L-IL-2 stimulated the maturation of Mo-DC and high levels of IL-12 production.

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“…The promising vaccine responses achieved recently using leukemia cells combined with CD40 ligand and IL-2 indicate that antigen-presenting cell maturation in the presence of leukemia antigens can lead to the generation of detectable anti-ALL T-cell responses in patients. 31 Our study suggests that the use of CpG ODN may provide a simpler strategy to achieve both the killing of the residual leukemia and coincident maturation of antigen-presenting cells necessary to efficiently prime protective T-cell responses in vivo.…”

Section: Durable Protection From All Induced Bymentioning

confidence: 99%

Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses

Seif

Barrett

Milone³

et al. 2009

Blood

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a major cause of mortality in children with recurrent disease and in adults. Despite observed graft-versusleukemia effects after stem cell transplantation, successful immune therapies for ALL have proven elusive. We previously reported immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG ODN) enhance allogeneic T h 1 responses and reduce leukemic burden of primary human ALL xenografts. To further the development of CpG ODN as a novel ALL therapy, we investigated the antileukemia activity induced by CpG ODN in a transplantable syngeneic pre-B ALL model. CpG ODN induced early killing of leukemia by innate immune effectors both in vitro and in vivo. Mice were treated with CpG ODN starting 7 days after injection with leukemia to mimic a minimal residual disease state and achieved T cell-dependent remissions of more than 6 months. In addition, mice in remission after CpG ODN treatment were protected from leukemia rechallenge, and adoptive transfer of T cells from mice in remission conferred protection against leukemia growth. To our knowledge, this is the first demonstration that CpG ODN induce a durable remission and ongoing immune-mediated protection in ALL, suggesting this treatment may have clinical utility in patients with minimal residual disease. (Blood. 2009;114:2459-2466) IntroductionAcute lymphoblastic leukemia (ALL) is the most common form of cancer in children, accounting for one-third of all childhood malignancies and nearly 80% of all pediatric leukemias. 1 Although current therapies have resulted in event-free survival approaching 75%, 2 relapsed ALL comprises nearly 6% of all childhood cancers 1,3 and has a much lower event-free survival of 47%. 4 Furthermore, nearly half of all ALL cases occur in adults, who have a much poorer prognosis, with the majority dying of the disease. 5 New treatment strategies are urgently needed for this condition.The strategy of pursuing immune therapy as a novel therapeutic approach for ALL is supported by the observed graft-versusleukemia effect after hematopoietic stem cell transplantation. Although transplantations and donor lymphocyte infusions have lower efficacy in ALL than in other leukemias, the consistently higher relapse rates associated with autologous and especially syngeneic transplantations compared with allogeneic transplantations are supportive of significant therapeutic immune activity. [6][7][8][9] In pediatric transplantations, the development of chronic graft-versushost disease correlates strongly with decreased relapse. 8 Furthermore, posttransplantation immune suppression is associated with an increased risk of relapse. 10 Despite evidence of a graft-versus-leukemia effect against ALL, enhancing the anti-ALL immune response has proven difficult to achieve. Several features of ALL may undermine the immune system's ability to mount a targeted response, including a lack of costimulatory molecule expression, 11,12 the impairment of dendritic cell (DC) antige...

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Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation

Cited by 65 publications

References 58 publications

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

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

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses

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